Does the FIFA 11+ Injury Prevention Program Reduce the Incidence of ACL Injury in Male Soccer Players?
The FIFA 11+ injury prevention program has been shown to decrease the risk of soccer injuries in men and women. The program has also been shown to decrease time loss resulting from injury. However, previous studies have not specifically investigated how the program might impact the rate of anterior cruciate ligament (ACL) injury in male soccer players. The purpose of this study was to examine if the FIFA 11+ injury prevention program can (1) reduce the overall number of ACL injuries in men who play competitive college soccer and whether any potential reduction in rate of ACL injuries differed based on (2) game versus practice setting; (3) player position; (4) level of play (Division I or II); or (5) field type. This study was a prospective cluster randomized controlled trial, which was conducted in 61 Division I and Division II National Collegiate Athletic Association men's soccer teams over the course of one competitive soccer season. The FIFA 11+ is a 15- to 20-minute on-the-field dynamic warm-up program used before training and games and was utilized as the intervention throughout the entire competitive season. Sixty-five teams were randomized: 34 to the control group (850 players) and 31 to the intervention group (675 players). Four intervention teams did not complete the study and did not submit their data, noting insufficient time to complete the program, reducing the number for per-protocol analysis to 61. Compliance to the FIFA 11+ program, athletic exposures, specific injuries, ACL injuries, and time loss resulting from injury were collected and recorded using a secure Internet-based system. At the end of the season, the data in the injury surveillance system were crosshatched with each individual institution's internal database. At that time, the certified athletic trainer signed off on the injury collection data to confirm their accuracy and completeness. A lower proportion of athletes in the intervention group experienced knee injuries (25% [34 of 136]) compared with the control group (75% [102 of 136]; relative risk [RR], 0.42; 95% confidence interval [CI], 0.29-0.61; p < 0.001). When the data were stratified for ACL injury, fewer ACL injuries were reported in the intervention group (16% [three of 19]) compared with the control group (84% [16 of 19]), accounting for a 4.25-fold reduction in the likelihood of incurring ACL injury (RR, 0.236; 95% CI, 0.193-0.93; number needed to treat = 70; p < 0.001). With the numbers available, there was no difference between the ACL injury rate within the FIFA 11+ group and the control group with respect to game and practice sessions (games-intervention: 1.055% [three of 15] versus control: 1.80% [12 of 15]; RR, 0.31; 95% CI, 0.09-1.11; p = 0.073 and practices-intervention: 0% [zero of four] versus control: 0.60% [four of four]; RR, 0.14; 95% CI, 0.01-2.59; p = 0.186). With the data that were available, there were no differences in incidence rate (IR) or injury by player position for forwards (IR control = 0.339 versus IR intervention = 0), midfielders (IR control = 0.54 versus IR intervention = 0.227), defenders (IR control = 0.339 versus IR intervention = 0.085), and goalkeepers (IR control = 0.0 versus IR intervention = 0.0) (p = 0.327). There were no differences in the number of ACL injuries for the Division I intervention group (0.70% [two of nine]) compared with the control group (1.05% [seven of nine]; RR, 0.30; CI, 0.06-1.45; p = 0.136). However, there were fewer ACL injuries incurred in the Division II intervention group (0.35% [one of 10]) compared with the control group (1.35% [nine of 10]; RR, 0.12; CI, 0.02-0.93; p = 0.042). There was no difference between the number of ACL injuries in the control group versus in the intervention group that occurred on grass versus turf (Wald chi square [1] = 0.473, b = 0.147, SE = 0.21, p = 0.492). However, there were more ACL injuries that occurred on artificial turf identified in the control group (1.35% [nine of 10]) versus the intervention group (0.35% [one of 10]; RR, 0.14; 95% CI, 0.02-1.10; p = 0.049). This program, if implemented correctly, has the potential to decrease the rate of ACL injury in competitive soccer players. In addition, this may also enhance the development and dissemination of injury prevention protocols and may mitigate risk to athletes who utilize the program consistently. Further studies are necessary to analyze the cost-effectiveness of the program implementation and to analyze the efficacy of the FIFA 11+ in the female collegiate soccer cohort. Level I, therapeutic study.


Involvement of norepinephrine in startle arousal after acute and chronic d-amphetamine administration.
Treatment with d-amphetamine produced a dose-dependent increase in startle amplitude in response to a buzzer. This increase appeared to be a reflection of a sensitization effect, i.e., enhanced responsivity as a function of repeated stimulus presentations. Treatment with alpha-methyl-p-tyrosine, which reduced whole brain concentrations of dopamine (DA) and norepinephrine (NE), or treatment with FLA-63, which reduced only NE, antagonized the effects of d-amphetamine on the startle reflex, suggesting a role of NE in this behavior. Startle amplitude was also reduced following chronic d-amphetamine treatment. The effect of d-amphetamine on startle was found to be independent of changes in drug-induced locomotor excitation. The data of the present investigation, together with earlier reports, suggests that tolerance occurs to those behaviors that involve a noradrenergic component.


Generalized ISAR--part I: an optimal method for imaging large naval vessels.
We describe a generalized inverse synthetic aperture radar (ISAR) process that performs well under a wide variety of conditions common to the naval ISAR tests of large vessels. In particular, the generalized ISAR process performs well in the presence of moderate intensity ship roll. The process maps localized scatterers onto peaks on the ISAR plot. However, in a generalized ISAR plot, each of the two coordinates of a peak is a fixed linear combination of the three ship coordinates of the scatterer causing the peak. Combining this process with interferometry will then provide high-accuracy three-dimensional location of the important scatterers on a ship. We show that ISAR can be performed in the presence of simultaneous roll and aspect change, provided the two Doppler rates are not too close in magnitude. We derive the equations needed for generalized ISAR, both roll driven and aspect driven, and test them against simulations performed in a variety of conditions, including large roll amplitudes.


Drug resistance in sea lice: a threat to salmonid aquaculture.
Sea lice are copepod ectoparasites with vast reproductive potential and affect a wide variety of fish species. The number of parasites causing morbidity is proportional to fish size. Natural low host density restricts massive parasite dispersal. However, expanded salmon farming has shifted the conditions in favor of the parasite. Salmon farms are often situated near wild salmonid migrating routes, with smolts being particularly vulnerable to sea lice infestation. In order to protect both farmed and wild salmonids passing or residing in the proximity of the farms, several measures are taken. Medicinal treatment of farmed fish has been the most predictable and efficacious, leading to extensive use of the available compounds. This has resulted in drug-resistant parasites occurring on farmed and possibly wild salmonids.


A meta-analysis and systematic review of the risks associated with childhood attention-deficit hyperactivity disorder on long-term outcome of arrests, convictions, and incarcerations.
The primary aim of this study was to systematically review and estimate the risk of arrests, convictions, and incarcerations associated with childhood Attention Deficit/Hyperactivity Disorder (ADHD) in long-term outcome studies. In addition, all included studies were qualitatively and systematically reviewed for predictors of long-term crimes. The databases Pubmed, PsycINFO and Embase were searched for all controlled studies that included children and adolescents (age 4-15) with ADHD who had been followed longitudinally and reported the frequency of arrests, convictions or incarcerations based on data from official sources. Using random-effects models, the relative risk (RR) with 95% confidence intervals (95% CI) was estimated. A total of 15,442 individuals with childhood ADHD from nine unique samples were included. Childhood ADHD was significantly associated with adolescent and adulthood arrests (RR: 2.2, 95% CI: 1.3-3.5), convictions (RR: 3.3, 95% CI: 2.1-5.2) and incarcerations (RR: 2.9, 95% CI: 1.9-4.3). Individuals with ADHD had a younger age at onset of antisocial involvement and an increased risk of criminal recidivism. The most frequently committed criminal offenses were theft, assault, drug- and weapon-related crimes. Early antisocial behavior problems, childhood maltreatment, sex, and IQ were identified as potentially relevant predictors for antisocial outcomes. The findings support a substantial long-term risk associated with ADHD for later antisocial involvement. Early intensive and specifically targeted multimodal intervention including psychosocial, and pharmacological treatment is warranted to alter these negative long-term developmental trajectories.


Proteomic analysis of the thermophilic methylotroph Bacillus methanolicus MGA3.
Bacillus methanolicus MGA3 is a facultative methylotroph of industrial relevance that is able to grow on methanol as its sole source of carbon and energy. The Gram-positive bacterium possesses a soluble NAD(+) -dependent methanol dehydrogenase and assimilates formaldehyde via the ribulose monophosphate (RuMP) cycle. We used label-free quantitative proteomics to generate reference proteome data for this bacterium and compared the proteome of B. methanolicus MGA3 on two different carbon sources (methanol and mannitol) as well as two different growth temperatures (50°C and 37°C). From a total of approximately 1200 different detected proteins, approximately 1000 of these were used for quantification. While the levels of 213 proteins were significantly different at the two growth temperatures tested, the levels of 109 proteins changed significantly when cells were grown on different carbon sources. The carbon source strongly affected the synthesis of enzymes related to carbon metabolism, and in particular, both dissimilatory and assimilatory RuMP cycle enzyme levels were elevated during growth on methanol compared to mannitol. Our data also indicate that B. methanolicus has a functional tricarboxylic acid cycle, the proteins of which are differentially regulated on mannitol and methanol. Other proteins presumed to be involved in growth on methanol were constitutively expressed under the different growth conditions. All MS data have been deposited in the ProteomeXchange with the identifiers PXD000637 and PXD000638 (http://proteomecentral.proteomexchange.org/dataset/PXD000637, http://proteomecentral.proteomexchange.org/dataset/PXD000638).


Role of Probiotics in Non-alcoholic Fatty Liver Disease: Does Gut Microbiota Matter?
Non-alcoholic fatty liver disease (NAFLD) is the hepatic consequence of metabolic syndrome, which often also includes obesity, diabetes, and dyslipidemia. The connection between gut microbiota (GM) and NAFLD has attracted significant attention in recent years. Data has shown that GM affects hepatic lipid metabolism and influences the balance between pro/anti-inflammatory effectors in the liver. Although studies reveal the association between GM dysbiosis and NAFLD, decoding the mechanisms of gut dysbiosis resulting in NAFLD remains challenging. The potential pathophysiology that links GM dysbiosis to NAFLD can be summarized as: (1) disrupting the balance between energy harvest and expenditure, (2) promoting hepatic inflammation (impairing intestinal integrity, facilitating endotoxemia, and initiating inflammatory cascades with cytokines releasing), and (3) altered biochemistry metabolism and GM-related metabolites (i.e., bile acid, short-chain fatty acids, aromatic amino acid derivatives, branched-chain amino acids, choline, ethanol). Due to the hypothesis that probiotics/synbiotics could normalize GM and reverse dysbiosis, there have been efforts to investigate the therapeutic effect of probiotics/synbiotics in patients with NAFLD. Recent randomized clinical trials suggest that probiotics/synbiotics could improve transaminases, hepatic steatosis, and reduce hepatic inflammation. Despite these promising results, future studies are necessary to understand the full role GM plays in NAFLD development and progression. Additionally, further data is needed to unravel probiotics/synbiotics efficacy, safety, and sustainability as a novel pharmacologic approaches to NAFLD.


Release of small hydrophilic molecules from polyelectrolyte capsules: effect of the wall thickness.
Polymer nanocapsules assembled on cationic liposomes have been built through the layer-by-layer (LbL) technique. Chitosan and alginate, two biocompatible polyelectrolytes, were used to cover the template, where the Rhodamine B was previously loaded. The multishell formed with the alternate deposition of the polyelectrolytes, according to the principles of the LbL assembly, was supposed to change the permeability of the capsule wall. The thickness of the multishell was seen increasing with the number of layers deposited through the observations with the Transmission Electron Microscope. The permeability of the capsules was studied through Rhodamine B release assays. Nanocapsules with seven layers of polyelectrolytes released the dye slowly compared to the capsules with three or five layers. The Ritger-Peppas model was applied to investigate the release mechanisms and a non-Fickian transport behavior was detected regardless of the number of layers. Values of diffusion coefficients of Rhodamine B through the capsule wall were also calculated.


MICU1-dependent mitochondrial calcium uptake regulates lung alveolar type 2 cell plasticity and lung regeneration.
Lung alveolar type 2 (AT2) cells are progenitors for alveolar type 1 (AT1) cells. Although many factors regulate AT2 cell plasticity, the role of mitochondrial calcium (mCa2+) uptake in controlling AT2 cells remains unclear. We previously identified that the miR-302 family supports lung epithelial progenitor cell proliferation and less differentiated phenotypes during development. Here, we report that a sustained elevation of miR-302 in adult AT2 cells decreases AT2-to-AT1 cell differentiation during the Streptococcus pneumoniae-induced lung injury repair. We identified that miR-302 targets and represses the expression of mitochondrial Ca2+ uptake 1 (MICU1), which regulates mCa2+ uptake through the mCa2+ uniporter channel by acting as a gatekeeper at low cytosolic Ca2+ levels. Our results reveal a marked increase in MICU1 protein expression and decreased mCa2+ uptake during AT2-to-AT1 cell differentiation in the adult lung. Deletion of Micu1 in AT2 cells reduces AT2-to-AT1 cell differentiation during steady-state tissue maintenance and alveolar epithelial regeneration after bacterial pneumonia. These studies indicate that mCa2+ uptake is extensively modulated during AT2-to-AT1 cell differentiation and that MICU1-dependent mCa2+ uniporter channel gating is a prominent mechanism modulating AT2-to-AT1 cell differentiation.


Novel engineered cationic antimicrobial peptides display broad-spectrum activity against Francisella tularensis, Yersinia pestis and Burkholderia pseudomallei.
Broad-spectrum antimicrobials are needed to effectively treat patients infected in the event of a pandemic or intentional release of a pathogen prior to confirmation of the pathogen's identity. Engineered cationic antimicrobial peptides (eCAPs) display activity against a number of bacterial pathogens including multi-drug-resistant strains. Two lead eCAPs, WLBU2 and WR12, were compared with human cathelicidin (LL-37) against three highly pathogenic bacteria: Francisella tularensis, Yersinia pestis and Burkholderia pseudomallei. Both WLBU2 and WR12 demonstrated bactericidal activity greater than that of LL-37, particularly against F. tularensis and Y. pestis. Only WLBU2 had bactericidal activity against B. pseudomallei. WLBU2, WR12 and LL-37 were all able to inhibit the growth of the three bacteria in vitro. Because these bacteria can be facultative intracellular pathogens, preferentially infecting macrophages and dendritic cells, we evaluated the activity of WLBU2 against F. tularensis in an ex vivo infection model with J774 cells, a mouse macrophage cell line. In that model WLBU2 was able to achieve greater than 50% killing of F. tularensis at a concentration of 12.5 μM. These data show the therapeutic potential of eCAPs, particularly WLBU2, as a broad-spectrum antimicrobial for treating highly pathogenic bacterial infections.


Compound K, a metabolite of ginseng saponin, induces apoptosis via caspase-8-dependent pathway in HL-60 human leukemia cells.
Compound K [20-O-beta-(D-glucopyranosyl)-20(S)-protopanaxadiol], a metabolite of the protopanaxadiol-type saponins of Panax ginseng C.A. Meyer, has been reported to possess anti-tumor properties to inhibit angiogenesis and to induce tumor apoptosis. In the present study, we investigated the effect of Compound K on apoptosis and explored the underlying mechanisms involved in HL-60 human leukemia cells. We examined the effect of Compound K on the viabilities of various cancer cell lines using MTT assays. DAPI assay, Annexin V and PI double staining, Western blot assay and immunoprecipitation were used to determine the effect of Compound K on the induction of apoptosis. Compound K was found to inhibit the viability of HL-60 cells in a dose- and time-dependent manner with an IC50 of 14 muM. Moreover, this cell death had typical features of apoptosis, that is, DNA fragmentation, DNA ladder formation, and the externalization of Annexin V targeted phosphatidylserine residues in HL-60 cells. In addition, compound-K induced a series of intracellular events associated with both the mitochondrial- and death receptor-dependent apoptotic pathways, namely, (1) the activation of caspases-3, -8, and -9; (2) the loss of mitochondrial membrane potential; (3) the release of cytochrome c and Smac/DIABLO to the cytosol; (4) the translocation of Bid and Bax to mitochondria; and (5) the downregulations of Bcl-2 and Bcl-xL. Furthermore, a caspase-8 inhibitor completely abolished caspase-3 activation, Bid cleavage, and subsequent DNA fragmentation by Compound K. Interestingly, the activation of caspase-3 and -8 and DNA fragmentation were significantly prevented in the presence of cycloheximide, suggesting that Compound K-induced apoptosis is dependent on de novo protein synthesis. The results indicate that caspase-8 plays a key role in Compound K-stimulated apoptosis via the activation of caspase-3 directly or indirectly through Bid cleavage, cytochrome c release, and caspase-9 activation.


Bragg-effect grating couplers integrated in multicomponent polymeric waveguides.
A new reactive multicomponent polymeric system is presented for the real-time optical recording of volume phase holograms integrated in waveguiding thin films. Efficient Bragg-effect grating couplers are produced holographically. In a multimodeplanar waveguide, the input coupling efficiency reaches 62% for an incident 633-nm He-Ne laser beam. Almost 96% of the mode power is emitted by a second coupler into one single-output beam.


Cyclic metal(oid) clusters control platinum-catalysed hydrosilylation reactions: from soluble to zeolite and MOF catalysts.
The Pt-catalysed addition of silanes to functional groups such as alkenes, alkynes, carbonyls and alcohols, i.e. the hydrosilylation reaction, is a fundamental transformation in industrial and academic chemistry, often claimed as the most important application of Pt catalysts in solution. However, the exact nature of the Pt active species and its mechanism of action is not well understood yet, particularly regarding regioselectivity. Here, experimental and computational studies together with an ad hoc graphical method show that the hydroaddition of alkynes proceeds through Pt-Si-H clusters of 3-5 atoms (metal(oid) association) in parts per million amounts (ppm), which decrease the energy of the transition state and direct the regioselectivity of the reaction. Based on these findings, new extremely-active (ppm) microporous solid catalysts for the hydrosilylation of alkynes, alkenes and alcohols have been developed, paving the way for more environmentally-benign industrial applications.


Dose-dependent linkage, assembly inhibition and disassembly of vimentin and cytokeratin 5/14 filaments through plectin's intermediate filament-binding domain.
Plectin, the largest and most versatile member of the cytolinker/plakin family of proteins characterized to date, has a tripartite structure comprising a central 200 nm-long (&agr;)-helical rod domain flanked by large globular domains. The C-terminal domain comprises a short tail region preceded by six highly conserved repeats (each 28-39 kDa), one of which (repeat 5) contains plectin's intermediate filament (IF)-binding site. We used recombinant and native proteins to assess the effects of plectin repeat 5-binding to IF proteins of different types. Quantitative Eu(3+)-based overlay assays showed that plectin's repeat 5 domain bound to type III IF proteins (vimentin) with preference over type I and II cytokeratins 5 and 14. The ability of both types of IF proteins to self-assemble into filaments in vitro was impaired by plectin's repeat 5 domain in a concentration-dependent manner, as revealed by negative staining and rotary shadowing electron microscopy. This effect was much more pronounced in the case of vimentin compared to cytokeratins 5/14. Preassembled filaments of both types became more and more crosslinked upon incubation with increasing concentrations of plectin repeat 5. However, at high proportions of plectin to IF proteins, disassembly of filaments occurred. Again, vimentin filaments proved considerably more sensitive towards disassembly than those composed of cytokeratins 5 and 14. In general, IFs formed from recombinant proteins were found to be slightly more responsive towards plectin influences than their native counterparts. A dose-dependent plectin-inflicted collapse and putative disruption of IFs was also observed in vivo after ectopic expression of vimentin and plectin's repeat 5 domain in cotransfected vimentin-deficient SW13 (vim(-)) cells. Our results suggest an involvement of plectin not only in crosslinking and stabilization of cytoskeletal IF networks, but also in regulation of their dynamics.


Evaluation of the influence of electric nets on the behaviour of oviposition site seeking Anopheles gambiae s.s.
Electric nets (e-nets) are used to analyse the flight behaviour of insects and have been used extensively to study the host-oriented flight of tsetse flies. Recently we adapted this tool to analyse the oviposition behaviour of gravid malaria vectors, Anopheles gambiae s.s., orienting towards aquatic habitats and traps by surrounding an artificial pond with e-nets and collecting electrocuted mosquitoes on sticky boards on the ground next to the nets. Here we study whether e-nets themselves affect the responses of gravid An. gambiae s.s.. Dual-choice experiments were carried out in 80 m2 screened semi-field systems where 200 gravid An. gambiae s.s. were released each night for 12 nights per experiment. The numbers of mosquito landing on or approaching an oviposition site were studied by adding detergent to the water in an artificial pond or surrounding the pond with a square of e-nets. We also assessed whether the supporting framework of the nets or the sticky boards used to retain electrocuted mosquitoes influenced the catch. Two similar detergent treated ponds presented in choice tests caught an equal proportion of the mosquitoes released, whereas a pond surrounded by e-nets caught a higher proportion than an open pond (odds ratio (OR) 1.7, 95% confidence interval (CI) 1.1 - 2.7; p<0.017). The separate evaluation of the impact of the square of electric nets and the yellow boards on the approach of gravid females towards a pond suggests that the tower-like construction of the square of electric nets did not restrict the approach of females but the yellow sticky boards on the ground attract gravid females to a source of water (OR 2.7 95% CI 1.7 - 4.3; p<0.001). The trapping efficiency of the electric nets is increased when large yellow sticky boards are placed on the ground next to the e-nets to collect electrocuted mosquitoes, possibly because of increased visual contrast to the aquatic habitat. It is therefore important when comparing two treatments that the same trapping device is used in both. The importance of contrast around artificial habitats might be exploited to improve collections of An. gambiae s.s. in gravid traps.


Cutting Edge: The Aging Immune System Reveals the Biological Impact of Direct Antigen Presentation on CD8 T Cell Responses.
The vertebrate immune system uses multiple, sometimes redundant, mechanisms to contain pathogenic microorganisms that are always evolving to evade host defenses. Thus, the cowpox virus (CPXV) uses genes encoding CPXV12 and CPXV203 to prevent direct MHC class I presentation of viral peptides by infected cells. However, CD8 T cells are effectively primed against CPXV by cross-presentation of viral Ags in young mice. Old mice accumulate defects in both CD8 T cell activation and cross-presentation. Using a double-deletion mutant (∆12∆203) of CPXV, we show that direct priming of CD8 T cells in old mice yields superior recall responses, establishing a key contribution of this mechanism to host antipoxvirus responses and enhancing our fundamental understanding of how viral manipulation of direct presentation impacts pathogenesis. This also provides a proof of principle that suboptimal CD8 T cell in old organisms can be optimized by manipulating Ag presentation, with implications for vaccine design.


ADP-ribosylation is involved in the integration of foreign DNA into the mammalian cell genome.
The most commonly used DNA transfection method, which employs the calcium phosphate co-precipitation of the donor DNA, involves several discrete steps (1,2). These include the uptake of the donor DNA by the recipient cells, the transport of the DNA to the nucleus, transient expression prior to integration into the host cell genome, concatenation and integration of the transfected DNA into the host cell genome and finally the stable expression of the integrated genes (2,3). Both the concatenation and the integration of the donor DNA into the host genome involve the formation and ligation of DNA strand-breaks. In the present study we demonstrate that the nuclear enzyme, adenosine diphosphoribosyl transferase (ADPRT, E.C. 220.127.116.11), which is dependent on the presence of DNA strand breaks for its activity (4,5) and necessary for the efficient ligation of DNA strand-breaks in eukaryotic cells (4,6), is required for the integration of donor DNA into the host genome. However, ADPRT activity does not influence the uptake of DNA into the cell, its episomal maintenance or replication, nor its expression either before or after integration into the host genome. These observations strongly suggest the involvement of ADPRT activity in eukaryotic DNA recombination events.


Administration of Kampo medicine through a tube at an advanced critical care center.
n emergency and critical care medical centers, tube administration is employed for patients who have difficulty swallowing oral drugs owing to decreased consciousness or mechanical ventilation. However, tube clogging due to drug injection is a concern. We compared the crushing method with the simple suspension method for the passage of amlodipine, an antihypertensive drug, in combination with rikkunshito, which has been used to treat upper gastrointestinal disorders such as functional dyspepsia and gastroesophageal reflux in emergency and critical care medical centers, to ascertain the effect of Kampo products on the passage of other drugs during tube administration. When the crushing method was employed, poorly water-soluble solid products were formed, while a uniformly dispersed suspension was obtained using the simple suspension method. In addition, the passage rate of amlodipine through the tube was 64% and 93% in the crushing and simple suspension methods, respectively, thereby indicating that the simple suspension method provided more favorable than the crushing method. The results of this study suggested that the passage rate of amlodipine for patients who received Kampo products concurrently was higher when the simple suspension method was used, and an appropriate drug amount might well be able to administered to patients using this method. J. Med. Invest. 65:32-36, February, 2018.


Development and implementation of a psychotherapy tracking database in primary care.
Although there is a rapid increase in the integration of behavioral health services in primary care, few studies have evaluated the effectiveness of these services in real-world clinical settings, in part due to the difficulty of translating traditional mental health research designs to this setting. Accordingly, innovative approaches are needed to fit the unique challenges of conducting research in primary care. The development and implementation of one such approach is described in this article. A continuously populating database for psychotherapy services was implemented across 5 primary care clinics in a large health system to assess several levels of patient care, including service utilization, symptomatic outcomes, and session-by-session use of psychotherapy principles by providers. Each phase of implementation revealed challenges, including clinician time, dissemination to clinics with different resources, and fidelity of data collection strategy across providers, as well as benefits, including the generation of useful data to inform clinical care, program development, and empirical research. The feasible and sustainable implementation of data collection for routine clinical practice in primary care has the potential to fuel the evidence base around integrated care. The current project describes the development of an innovative approach that, with further empirical study and refinement, could enable health care professionals and systems to understand their population and clinical process in a way that addresses essential gaps in the integrated care literature. (PsycINFO Database Record


Angiotensinogen gene null-mutant mice lack homeostatic regulation of glomerular filtration and tubular reabsorption.
Chronic volume depletion by dietary salt restriction causes marked decrease in glomerular filtration rate (GFR) with little increase in urine osmolality in angiotensinogen gene null mutant (Agt-/-) mice. Moreover, urine osmolality is insensitive to both water and vasopressin challenge. In contrast, in normal wild-type (Agt+/+) mice, GFR remains remarkably constant and urine osmolality is adjusted promptly. Changes in volume status also cause striking divergence in renal structure between Agt-/- and Agt+/+ mice. Thus, in contrast to the remarkably stable glomerular size of Agt+/+ mice, glomeruli of Agt-/- mice are atrophied during a low salt and hypertrophied during a high salt diet. Moreover, the renal papilla, a structure unique to mammals and essential for urine diluting and concentrating mechanisms, is hypoplastic in Agt-/- mice. Thus, angiotensin is essential for the two fundamental homeostatic functions of the mammalian kidney, namely stable GFR and high urine diluting and concentrating capacity during alteration in extracellular fluid (ECF) volume. This is not only accompanied by angiotensin's tonic effects on renal vasomotor tone and tubule transporters, but also accomplished through its capacity to affect the structure of both the glomerulus and the papilla directly or indirectly.


The warfarin-cranberry juice interaction revisited: A systematic in vitro-in vivo evaluation.
BACKGROUND: Cranberry products have been implicated in several case reports to enhance the anticoagulant effect of warfarin. The mechanism could involve inhibition of the hepatic CYP2C9-mediated metabolic clearance of warfarin by components in cranberry. Because dietary/natural substances vary substantially in bioactive ingredient composition, multiple cranberry products were evaluated in vitro before testing this hypothesis in vivo. METHODS: The inhibitory effects of five types of cranberry juices were compared with those of water on CYP2C9 activity (S-warfarin 7-hydroxylation) in human liver microsomes (HLM). The most potent juice was compared with water on S/R-warfarin pharmacokinetics in 16 healthy participants given a single dose of warfarin 10 mg. RESULTS: Only one juice inhibited S-warfarin 7-hydroxylation in HLM in a concentration-dependent manner (P < 0.05), from 20% to >95% at 0.05% to 0.5% juice (v/v), respectively. However, this juice had no effect on the geometric mean AUC(0-∞) and terminal half-life of S/R-warfarin in human subjects. CONCLUSIONS: A cranberry juice that inhibited warfarin metabolism in HLM had no effect on warfarin clearance in healthy participants. The lack of an in vitro-in vivo concordance likely reflects the fact that the site of warfarin metabolism (liver) is remote from the site of exposure to the inhibitory components in the cranberry juice (intestine).


Biologics in the treatment of systemic lupus erythematosus.
The pathogenesis of systemic lupus erythematosus (SLE) involves aberrancy in multiple components of the immune system including B cells, T cells, cytokines and growth factors. Therapeutic agents targeting these mediators selectively have been tested for the treatment of SLE. This review summarizes the recent advances in the fast expanding field of these biological therapies. The two large phase 2/3 randomized placebo-controlled trials of B-cell depletion, using anti-CD20 antibody, rituximab, in SLE, reported unexpected negative results. On the contrary, two large phase 3 trials of belimumab, the monoclonal antibody against B-lymphocyte stimulator (BLyS), showed significant clinical benefit. Response rates were 57.6 and 43.2% for 10 mg/kg belimumab, compared with 43.6 and 33.8% for placebo in BLISS-52 and BLISS-76, respectively. Studies of a co-stimulation blocker (abatacept), tumor necrosis factor inhibitor (infliximab), and interleukin-6 inhibitor (tocilizumab) were either negative (abatacept) or were associated with high rates of adverse events. Studies of T cell and interferon inhibition remain in the early development phase. Despite the enthusiasm in the field of biologic therapies, the majority of these new modalities have fallen short of expectations for various reasons. Only belimumab has recently met its primary outcome in two phase 3 trials.


Experimental demonstration of phase-only circular harmonic filtering using computer generated filters.
Experimental results of phase-only circular harmonic filtering implemented in a standard Fourier transform correlator are presented. The filter is a computer generated hologram which contains only the phase information of a single circular harmonic component of the target. The result with simple binary objects bears out the simulation result published earlier [H. F. Yau and C. C. Chang, Appl. Opt. 28, 2070-2074 (1989)] in that the filter is indeed shift- and rotational-invariant and that the correlation peak is more prominent than that produced by ordinary circular harmonic filtering.


High-specificity antibodies and detection methods for quantifying phosphorylated tau from clinical samples.
The ability to measure total and phosphorylated tau levels in clinical samples is transforming the detection of Alzheimer's disease (AD) and other neurodegenerative diseases. In particular, recent reports indicate that accurate detection of low levels of phosphorylated tau (p-tau) in plasma provides a reliable biomarker of AD long before sensing memory loss. Therefore, the diagnosis and monitoring of neurodegenerative diseases progression using blood samples is becoming a reality. These major advances were achieved by using antibodies specific to p-tau as well as sophisticated high-sensitivity immunoassay platforms. This review focuses on these enabling advances in high-specificity antibody development, engineering, and novel signal detection methods. We will draw insights from structural studies on p-tau antibodies, engineering efforts to improve their binding properties, and efforts to validate their specificity. A comprehensive survey of high-sensitivity p-tau immunoassay platforms along with sensitivity limits will be provided. We conclude that although robust approaches for detecting certain p-tau species have been established, systematic efforts to validate antibodies for assay development is still needed for the recognition of biomarkers for AD and other neurodegenerative diseases.


Changes in corneal endothelial apical junctional protein organization after corneal cold storage.
Understanding the mechanisms regulating corneal endothelial permeability during storage and recovery is of critical importance both to improving Eye Banking practices and preventing corneal transplant failure. The goal of this study was to determine the effects of cold storage on the organization of apical junctional complex (AJC) proteins and their relationship to F-actin in corneal endothelium. Immunostaining using antibodies to the AJC proteins, ZO-1, cadherin, and alpha- and beta-catenin was performed on 16 eye bank corneas and four cat corneas after 2-8 days of storage at 4 degrees C in Optisol-GS, and compared with fresh corneas. The 3-D in situ localization of the AJC proteins was then determined by using laser confocal microscopy. AJC organization also was assessed after stored human corneas were further incubated at 37 degrees C in Optisol-GS or in serum-free media. In normal human and cat corneas, F-actin was organized into dense peripheral bands (DPBs) along the apical cell border. The tight-junction protein, ZO-1, and the adherens junction proteins, cadherin and alpha- and beta-catenin, each formed a uniquely discontinuous hexagonal apical band with the largest gaps occurring at the Y-junctions between adjacent endothelial cells. In stored eye bank and cat corneas, cells lost their normal hexagonal F-actin staining pattern and appeared rounded and distorted, with increased cytoplasmic staining and incomplete and condensed DPBs. Similar distortions were observed in the apical bands of cadherin, catenin, and ZO-1 staining between endothelial cells. Gaps in staining at the endothelial Y-junctions were significantly enlarged; corresponding gaps also were observed with phalloidin staining. These changes were reversed after overnight incubation at 37 degrees C in either serum-free media or Optisol-GS. Quantitative analysis demonstrated a significant increase in the size of the Y-junctional gaps (p < 0.0001) after cold storage of cat corneas as compared with fresh corneas. These results suggest that disruption of the F-actin cytoskeleton and AJC may explain, in part, the loss of function (corneal swelling) after prolonged cold storage.


Effects of vigabatrin on evoked potentials in dogs.
1. The purpose of this study was to evaluate possible changes in brain morphology and evoked potentials associated with daily administration of 300 mg kg-1 vigabatrin in dogs. 2. Somatosensory evoked potentials (SEP) and auditory evoked potentials (AEP) were recorded at baseline and weekly for 12 weeks of treatment and every 2 weeks for 17 weeks of recovery. Morphology was assessed immediately after treatment for two treated dogs and after recovery for the remaining five treated and two control dogs. 3. Vigabatrin produced a significant slowing of the central transmission measure of the SEP with no alteration in the AEP. Vigabatrin was associated with microvacuolation in select regions of the brain including the fornix, septum, optic tract, hypothalamus, thalamus and cortex. In addition, some microglial proliferation was noted. 4. Changes in SEP and the microvacuolation fully recovered after 17 weeks of treatment. 5. The study confirms vigabatrin-induced microvacuolation in the dog and suggests these changes are associated with functional slowing of conduction in the somatosensory pathways.


Self-emulsifying drug delivery systems (SEDDS): formulation development, characterization, and applications.
Self-emulsifying drug delivery systems (SEDDS) possess unparalleled potential in improving oral bioavailability of poorly water-soluble drugs. Following their oral administration, these systems rapidly disperse in gastrointestinal fluids, yielding micro- or nanoemulsions containing the solubilized drug. Owing to its miniscule globule size, the micro/nanoemulsifed drug can easily be absorbed through lymphatic pathways, bypassing the hepatic first-pass effect. We present an exhaustive and updated account of numerous literature reports and patents on diverse types of self-emulsifying drug formulations, with emphasis on their formulation, characterization, and systematic optimization strategies. Recent advancements in various methodologies employed to characterize their globule size and shape, ability to encapsulate the drug, gastrointestinal and thermodynamic stability, rheological characteristics, and so forth, are discussed comprehensively to guide the formula-tor in preparing an effective and robust SEDDS formulation. Also, this exhaustive review offers an explicit discussion on vital applications of the SEDDS in bioavailability enhancement of various drugs, outlining an overview on myriad in vitro, in situ, and ex vivo techniques to assess the absorption and/ or permeation potential of drugs incorporated in the SEDDS in animal and cell line models, and the subsequent absorption pathways followed by them. In short, the current article furnishes an updated compilation of wide-ranging information on all the requisite vistas of the self-emulsifying formulations, thus paving the way for accelerated progress into the SEDDS application in pharmaceutical research.


The fate of plastic in the ocean environment - a minireview.
The presence of plastics in the marine environment poses a threat to ocean life and has received much scientific and public attention in recent years. Plastics were introduced to the market in the 1950s and since then, global production figures and ocean plastic littering have increased exponentially. Of the 359 million tonnes (Mt) produced in 2018, an estimated 14.5 Mt has entered the ocean. In particular smaller plastic particles can be ingested by marine biota causing hazardous effects. Plastic marine debris (PMD) is exposed to physical, chemical and biological stressors. These cause macro and microplastic to break down into smaller fragments, including sub micrometre sized nanoplastic particles, which may account for an important but so far unevaluated fraction of the ocean plastic budget. Physicochemical and biological deterioration of PMD also leads to the release of more volatile compounds and the terminal oxidation of PMD, which most likely accounts for an important but also unevaluated fraction in the ocean plastic budget. This minireview provides an overview on (1) the quantity of plastic production and waste, pathways for plastics to enter the marine realm, the inventory of PMD and the negative effects of PMD to ocean life. (2) We discuss plastic degradation mechanisms in the ocean, expanding on the processes of photodegradation and biodegradation. (3) This review also highlights the emerging topic of nanoplastics in the sea and provides an overview on their specific physical and chemical properties, potential harm to ocean life, and nanoplastic detection techniques.


Serological assessment for celiac disease in IgA deficient adults.
Selective immunoglobulin A deficiency is the most common primary immunodeficiency disorder that is strongly overrepresented among patients with celiac disease (CD). IgG antibodies against tissue transglutaminase (tTG) and deamidated gliadin peptides (DGP) serve as serological markers for CD in IgA deficient individuals, although the diagnostic value remains uncertain. The aim of this study was to investigate the prevalence of these markers in a large cohort of IgA deficient adults with confirmed or suspected CD and relate the findings to gluten free diet. Sera from 488,156 individuals were screened for CD in seven Swedish clinical immunology laboratories between 1998 and 2012. In total, 356 out of 1,414 identified IgA deficient adults agreed to participate in this study and were resampled. Forty-seven IgA deficient blood donors served as controls. Analyses of IgG antibodies against tTG and DGP as well as HLA typing were performed and a questionnaire was used to investigate adherence to gluten free diet. Available biopsy results were collected. Out of the 356 IgA deficient resampled adults, 67 (18.8%) were positive for IgG anti-tTG and 79 (22.2%) for IgG anti-DGP, 54 had biopsy confirmed CD. Among the 47 IgA deficient blood donors, 4 (9%) were positive for IgG anti-tTG and 8 (17%) for anti-DGP. Four were diagnosed with biopsy verified CD, however, 2 of the patients were negative for all markers. Sixty-eight of 69 individuals with positive IgG anti-tTG were HLA-DQ2/DQ8 positive whereas 7 (18.9%) of the 37 individuals positive for IgG anti-DGP alone were not. IgG anti-tTG seems to be a more reliable marker for CD in IgA deficient adults whereas the diagnostic specificity of anti-DGP appears to be lower. High levels of IgG antibodies against tTG and DGP were frequently found in IgA deficient adults despite adhering to gluten free diet.


Metformin use and its effect on gastric cancer in patients with type 2 diabetes: A systematic review of observational studies.
Increasing evidence suggests that metformin use is associated with a decreased risk of cancer. The traditional therapies for gastric cancer (GC) are gastrectomy and chemoradiotherapy; however, these therapies may cause certain adverse effects, which affect a patient's quality of life, and the overall survival rate is low. At present, little is known about whether the use of metformin decreases the risk of GC in patients with type 2 diabetes. Therefore, in the present study, a systematic review was performed to analyze the effect of metformin on GC. A literature search was conducted in PubMed, EMBASE, and the Cochrane Library databases for articles published up to June 30th, 2016. The studies that evaluated GC patients treated with metformin and compared them with GC patients treated with other antidiabetic drugs were reviewed. Eligible studies were evaluated using the Newcastle-Ottawa Scale. Adjusted hazard ratio and 95% confidence intervals were determined to evaluate the effect of metformin on GC. From the 422 articles evaluated, 5 studies involving a total of 1,804,479 patients met the inclusion criteria and were qualitatively analyzed. The quality of all selected articles was classified as moderate. These studies reported that the long-term use of metformin was associated with a lower risk of GC compared with the lack of use of metformin or the use of other hypoglycemic drugs. In GC patients with diabetes who were subjected to gastrectomy, the cumulative use of metformin reduced the rates of disease recurrence and of all-cause and cancer-specific mortality. Despite the limited number of studies on this subject, currently available evidence indicates that metformin is associated with a decreased risk of GC and improves survival in patients with type 2 diabetes. However, more well-designed trials are required to elucidate this association.


Evaluating the effects of the Lunchtime Enjoyment Activity and Play (LEAP) school playground intervention on children's quality of life, enjoyment and participation in physical activity.
An emerging public health strategy is to enhance children's opportunities to be physically active during school break periods. The aim of this study was to evaluate the effects of the Lunchtime Enjoyment Activity and Play (LEAP) school playground intervention on primary school children's quality of life (QOL), enjoyment and participation in physical activity (PA). This study consisted of a movable/recycled materials intervention that included baseline, a 7-week post-test and an 8-month follow-up data collection phase. Children within an intervention school (n = 123) and a matched control school (n = 152) aged 5-to-12-years-old were recruited for the study. Children's PA was measured using a combination of pedometers and direct observation (SOPLAY). Quality of life, enjoyment of PA and enjoyment of lunchtime activities were assessed in the 8-12 year children. A multi-level mixed effect linear regression model was applied in STATA (version 12.0) using the xtmixed command to fit linear mixed models to each of the variables to examine whether there was a significant difference (p < 0.05) between the intervention and control school at the three time points (pre, post and follow-up). Significant overall interaction effects (group × time) were identified for children's mean steps and distance (pedometers) in the intervention school compared to the control school. Intervention school children also spent significantly higher proportions within specified target areas engaged in higher PA intensities in comparison to the control school at both the 7-week post-test and 8-month follow-up. A short-term treatment effect was revealed after 7-weeks for children's physical health scale QOL, enjoyment of PA and enjoyment of intra-personal play activities. Examining the effects of this school playground intervention over a school year suggested that the introduction of movable/recycled materials can have a significant, positive long-term intervention effect on children's PA. The implications from this simple, low-cost intervention provide impetus for schools to consider introducing the concept of a movable/recycled materials intervention on a wider scale within primary school settings. Australian and New Zealand Clinical Trials Registration Number: ACTRN12613001155785.


Using photovoice to understand and amplify youth voices to prevent sexual and relationship violence.
Efforts to improve prevention of sexual and relationship violence (SRV) among adolescents call for more centering of youth voices, experiences, and skills to design prevention programs that incorporate youth engagement rather than those that are designed by adults for youth. Amplifying the voices of historically marginalized youth are especially needed. Photovoice (PV) is a participatory action method that can empower youth and generate prevention knowledge. The current project used PV to engage youth in late middle and early high school to discuss how they could work to prevent SRV in their community. A convenience sample of nine youth (predominately Native American) participated over seven sessions. A key theme they generated is that SRV prevention needs to be viewed as relational. Participants described the complexity of prevention, including how youth need social support to thrive and prevent SRV and that asking for help can be challenging. Results also highlighted that youth can provide help and support, but it is not always welcome in addition to underscoring that youth are resilient and can be prevention leaders. Innovations in SRV prevention, especially for older adolescents, should work to engage youth as prevention partners. Participatory research methods like photovoice can be an important part of that process.


Synergistic effect of chlorine dioxide and drying treatments for inactivating Escherichia coli O157:H7 on radish seeds.
Studies were done to determine whether calcium hypochlorite (Ca(OCl)(2)) and chlorine dioxide (ClO(2)) treatment followed by drying had a synergistic killing effect on microorganisms on radish seeds intended for sprout production. Uninoculated radish seeds and seeds inoculated with Escherichia coli O157:H7 were treated with water, Ca(OCl)(2) (free chlorine concentrations of 50 or 200 microg/ml), or ClO(2) (50 or 200 microg/ml) for 5 min and subsequently dried at 25 degrees C for up to 24 h. Populations of total aerobic bacteria (TAB), molds and yeasts (MY), and E. coli O157:H7 on the seeds treated with Ca(OCl)(2) were not significantly different (P = 0.05) than populations on seeds treated with ClO(2) at the same concentrations. However, populations of microorganisms on seeds treated with ClO(2) decreased more rapidly during drying. Treatment with ClO(2) (200 microg/ml) followed by drying caused reductions in TAB, MY, and E. coli O157:H7 of 3.1, 2.0, and 3.8 log CFU/g, respectively. When seeds were treated with water, Ca(OCl)(2) (50 or 200 microg/ml), and ClO(2) (50 microg/ml) and subsequently dried, reductions in TAB, MY, and E. coli O157:H7 were 0.2 to 2.0, 0.4 to 2.0, and 1.4 to 2.2 log CFU/g, respectively. Results indicate that inactivation of E. coli O157:H7 on radish seeds is greater after treatment with ClO(2) followed by drying than after treatment with Ca(OCl)(2) followed by drying, thus providing a synergistic treatment combination for reducing the safety risk associated with sprouts produced from these seeds.


Role of family factors in adolescent delinquency in an Elazig/Turkey reformatory.
Family is one of the most important factors in the social and psychological progress of an adolescent. Social behavior disorders in childhood have been reported to be caused by many factors that may lead children to commit a crime. Our study included a total of 106 convicted adolescents from Eastern Turkey in a reformatory and 126 unconvicted adolescents with a similar socio-economic status. A survey form was completed during a face-to-face interview and a review of official records was undertaken. The role of family disruption, education levels of parents, the rate of imprisonment among first- and second-degree relatives, migration as a family from their place of birth, and the number of delinquent children in the family were evaluated. There was a significant difference between the conditions in the families of convicted and unconvicted adolescents. Family factors play an important role in the development of adolescent delinquency. To prevent or decrease this rate of childhood or adolescent delinquency, there needs to be an improvement in the socio-cultural conditions of families.


Cefprozil treatment of persistent and recurrent acute otitis media.
We identified the pathogens causing persistent and recurrent acute otitis media (AOM) and the clinical efficacy of cefprozil as treatment. This was a noncomparative, open label multicenter trial. Children ages 6 months to 12 years with signs and symptoms of AOM and evidence of middle ear effusion, as confirmed by pneumatic otoscopy or tympanometry, underwent tympanocentesis and subsequent treatment with cefprozil (15 mg/kg given twice daily) for 10 days. Patients with recurrent otitis media or failure of previous antibiotic therapy or prophylaxis were particularly sought for the study. Two hundred sixty-two (99%) of 265 enrolled children were considered evaluable. The median age of the study group was 1 year. Ninety-eight (37%) of the children had a history (within 30 days) of prior antibiotic use. Ninety-seven (37%) met our definition of recurrent AOM, 48 (18%) met our definition of persistent AOM and 132 (50%) children had 3 or more previous episodes of acute otitis media within 12 months before study. Eighty-two (31%) of the enrollment tympanocentesis had no growth, 150 (57%) had a single bacterial pathogen and 29 (11%) had multiple bacterial pathogens. Of the 93 Streptococcus pneumoniae pretreatment isolates, 50 (54%) were penicillin-susceptible, 12 (13%) were penicillin-intermediate resistant and 31 (33%) were penicillin-resistant. Of the 75 Haemophilus influenzae pretreatment isolates, 42 (56%) produced beta-lactamase as did 4 (27%) of the 15 Moraxella catarrhalis strains. A satisfactory clinical response by pathogen was found in 75% (70 of 93) with S. pneumoniae, 75% (56 of 75) with H. influenzae and 93% (13 of 14) with M. catarrhalis; the response with single pathogen infections was higher than those with multiple pathogens (118 of 150 (78%) and 17 of 29 (59%), respectively; P = 0.03). The response for patients with isolates of S. pneumoniae that were penicillin-susceptible, -intermediate or -resistant were 39 of 50 (78%), 11 of 12 (92%) and 21 of 31 (68%), respectively. Older children had a satisfactory clinical outcome more frequently than younger children (P < 0.001), and the response to therapy varied for persistent, recurrent and recently untreated AOM (P < 0.01). Persistent and recurrent AOM involves the same pathogens as recently untreated AOM but bacteria with reduced antibiotic susceptibility may be more frequently present. This noncomparative study suggests that cefprozil 30 mg/kg/day given in two divided doses for 10 days may be effective in the treatment of children with persistent and recurrent AOM.


Differences between the CD34+ and CD34- blast compartments in apoptosis resistance in acute myeloid leukemia.
Altered expression of members of the Bcl-2 family might account for the observed apoptosis resistance to chemotherapy in acute myeloid leukemia (AML). Given the poor prognosis associated with CD34+ expression in AML, we studied the role of spontaneous apoptosis and apoptosis regulatory proteins in sorted CD34+ and CD34- primary AML fractions. The expression levels of apoptosis regulatory proteins and spontaneous apoptosis were measured in primary AML samples by Western blot analysis and flow cytometry. To determine the role of CD34+ cells in apoptosis resistance, spontaneous apoptosis in serum-free conditions and apoptosis regulatory protein levels were measured in CD34+ and CD34- sorted cells from CD34+ primary AML samples. We show that CD34+ AML fractions are more resistant to apoptosis than are corresponding CD34- AML fractions, and that this is paralleled by higher Bcl-2, Bcl-xL, Mcl-1, Pgp and lower Bax expression levels. Interestingly, as the percentage of CD34 cells increased in the primary AML sample, so too did the apoptosis resistance in the corresponding CD34- fraction, which was reflected by an increasing anti-apoptosis protein profile. The data show that the CD34+ fraction is more resistant to apoptosis than is the corresponding CD34- fraction and secondly that the AML as a whole is more apoptosis resistant with increasing CD34 percentage.


Stationary-phase quorum-sensing signals affect autoinducer-2 and gene expression in Escherichia coli.
Quorum sensing via autoinducer-2 (AI-2) has been identified in different strains, including those from Escherichia, Vibrio, Streptococcus, and Bacillus species, and previous studies have suggested the existence of additional quorum-sensing signals working in the stationary phase of Escherichia coli cultures. To investigate the presence and global effect of these possible quorum-sensing signals other than AI-2, DNA microarrays were used to study the effect of stationary-phase signals on the gene expression of early exponential-phase cells of the AI-2-deficient strain E. coli DH5alpha. For statistically significant differential gene expression (P < 0.05), 14 genes were induced by supernatants from a stationary culture and 6 genes were repressed, suggesting the involvement of indole (induction of tnaA and tnaL) and phosphate (repression of phoA, phoB, and phoU). To study the stability of the signals, the stationary-phase supernatant was autoclaved and was used to study its effect on E. coli gene expression. Three genes were induced by autoclaved stationary-phase supernatant, and 34 genes were repressed. In total, three genes (ompC, ptsA, and btuB) were induced and five genes (nupC, phoB, phoU, argT, and ompF) were repressed by both fresh and autoclaved stationary-phase supernatants. Furthermore, supernatant from E. coli DH5alpha stationary culture was found to repress E. coli K-12 AI-2 concentrations by 4.8-fold +/- 0.4-fold, suggesting that an additional quorum-sensing system in E. coli exists and that gene expression is controlled as a network with different signals working at different growth stages.


PLANT U-BOX PROTEIN10 Regulates MYC2 Stability in Arabidopsis.
MYC2 is an important regulator for jasmonic acid (JA) signaling, but little is known about its posttranslational regulation. Here, we show that the MYC2 C-terminal region interacted with the PLANT U-BOX PROTEIN10 (PUB10) armadillo repeats in vitro. MYC2 was efficiently polyubiquitinated by PUB10 with UBC8 as an E2 enzyme and the conserved C249 in PUB10 was required for activity. The inactive PUB10(C249A) mutant protein retained its ability to heterodimerize with PUB10, thus blocking PUB10 E3 activity as a dominant-negative mutant. Both MYC2 and PUB10 were nucleus localized and coimmunoprecipitation experiments confirmed their interaction in vivo. Although unstable in the wild type, MYC2 stability was enhanced in pub10, suggesting destabilization by PUB10. Moreover, MYC2 half-life was shortened or prolonged by induced expression of PUB10 or the dominant-negative PUB10(C249A) mutant, respectively. Root growth of pub10 seedlings phenocopied 35S:MYC2 seedlings and was hypersensitive to methyl jasmonate, whereas 35S:PUB10 and jin1-9 (myc2) seedlings were hyposensitive. In addition, the root phenotype conferred by MYC2 overexpression in double transgenic plants was reversed or enhanced by induced expression of PUB10 or PUB10(C249A), respectively. Similar results were obtained with three other JA-regulated genes, TAT, JR2, and PDF1.2. Collectively, our results show that MYC2 is targeted by PUB10 for degradation during JA responses.


The impact of mindfulness-based interventions on doctors' well-being and performance: A systematic review.
The well-being of doctors is at risk, as evidenced by high burnout rates amongst doctors around the world. Alarmingly, burned-out doctors are more likely to exhibit low levels of professionalism and provide suboptimal patient care. Research suggests that burnout and the well-being of doctors can be improved by mindfulness-based interventions (MBIs). Furthermore, MBIs may improve doctors' performance (eg in empathy). However, there are no published systematic reviews that clarify the effects of MBIs on doctor well-being or performance to inform future research and professional development programmes. We therefore systematically reviewed and narratively synthesised findings on the impacts of MBIs on doctors' well-being and performance. We searched PubMed and PsycINFO from inception to 9 May 2018 and independently reviewed studies investigating the effects of MBIs on doctor well-being or performance. We systematically extracted data and assessed study quality according to the Medical Education Research Study Quality Instrument (MERSQI), and narratively reported study findings. We retrieved a total of 934 articles, of which 24 studies met our criteria; these included randomised, (un)controlled or qualitative studies of average quality. Effects varied across MBIs with different training contents or formats: MBIs including essential mindfulness training elements, or employing group-based training, mostly showed positive effects on the well-being or performance of doctors across different educational and hospital settings. Doctors perceived both benefits (enhanced self- and other-understanding) and challenges (time limitations and feasibility) associated with MBIs. Findings were subject to the methodological limitations of studies (eg the use of self-selected participants, lack of placebo interventions, use of self-reported outcomes). This review indicates that doctors can perceive positive impacts of MBIs on their well-being and performance. However, the evidence was subject to methodological limitations and does not yet support the standardisation of MBIs in professional development programmes. Rather, health care organisations could consider including group-based MBIs as voluntary modules for doctors with specific well-being needs or ambitions regarding professional development.


Can simple rules control development of a pioneer vertebrate neuronal network generating behavior?
How do the pioneer networks in the axial core of the vertebrate nervous system first develop? Fundamental to understanding any full-scale neuronal network is knowledge of the constituent neurons, their properties, synaptic interconnections, and normal activity. Our novel strategy uses basic developmental rules to generate model networks that retain individual neuron and synapse resolution and are capable of reproducing correct, whole animal responses. We apply our developmental strategy to young Xenopus tadpoles, whose brainstem and spinal cord share a core vertebrate plan, but at a tractable complexity. Following detailed anatomical and physiological measurements to complete a descriptive library of each type of spinal neuron, we build models of their axon growth controlled by simple chemical gradients and physical barriers. By adding dendrites and allowing probabilistic formation of synaptic connections, we reconstruct network connectivity among up to 2000 neurons. When the resulting "network" is populated by model neurons and synapses, with properties based on physiology, it can respond to sensory stimulation by mimicking tadpole swimming behavior. This functioning model represents the most complete reconstruction of a vertebrate neuronal network that can reproduce the complex, rhythmic behavior of a whole animal. The findings validate our novel developmental strategy for generating realistic networks with individual neuron- and synapse-level resolution. We use it to demonstrate how early functional neuronal connectivity and behavior may in life result from simple developmental "rules," which lay out a scaffold for the vertebrate CNS without specific neuron-to-neuron recognition.


The vulnerable atherosclerotic plaque: scope of the literature.
The scope of recent literature on the concept of "vulnerable plaque" was reviewed by examining 463 abstracts of primary and review articles identified through MEDLINE (2003 to April 2010). Proposed definition criteria of vulnerable plaque included active inflammation, a thin cap with a large lipid core, endothelial denudation, fissured cap, severe stenosis, or combinations of these findings. In 242 primary studies, histopathology, biomarkers, and imaging of carotid and coronary artery plaques were evaluated for features suggestive of vulnerability. Notably, 89% of these studies were cross-sectional in design and were exclusively conducted in patients with known cardiovascular disease. None of the imaging studies documented whether the identified lesions were responsible for cardiovascular events. Cross-sectional design precludes evaluation of the predictive utility of biomarkers. Because vulnerable plaque is not an established medical diagnosis, no studies have been done that explicitly evaluate the treatment of vulnerable plaques. Few studies examined potential systemic treatments (for example, statins) to modify vulnerability features. Large prospective studies in patients with and without previous cardiovascular events during long follow-up are required to validate this concept.


Dietary supplementation of gamma-linolenic acid improves skin parameters in subjects with dry skin and mild atopic dermatitis.
Disruption of the skin barrier function caused by epidermal hyper-proliferation, results in the skin becoming dry and showing high transepidermal water loss (TEWL). Gamma linolenic acid (GLA) is reportedly efficacious for treating TEWL and epidermal hyper-proliferation. In this study, to elucidate the effect of GLA-rich oil on skin function, GLA-containing food was given to adults with dry skin or mild atopic dermatitis and skin parameters were evaluated. In the results, we recognized beneficial effects on the TEWL index. The efficacy of GLA was also demonstrated to be statistically significant especially in subjects with pro-inflammatory features. The results suggest that the mechanism of improvement of skin barrier has been associated with possible generation of anti-inflammatory metabolites from GLA. The clinical physician also confirmed that none of the subjects showed any noteworthy side effects. GLA-enriched food appears to be safe and to improve skin barrier function in subjects with dry skin conditions and mild atopic dermatitis.


Distinct Trajectories of Individual Physical Performance Measures Across 9 Years in 60- to 70-Year-Old Adults.
Physical performance is an important factor for successful aging. This study aimed to identify distinct trajectories of multiple physical performance measures over 9 years in individuals aged 60-70 years and to evaluate their characteristics and the overlap between measures. Four physical performance measures were assessed in 440 participants of the Longitudinal Aging Study Amsterdam: tandem stand, gait speed, chair stand, and handgrip strength. Gender-specific latent class models were conducted to obtain distinct trajectories and their degree of overlap. Mean age at baseline was 67.9 (SD 1.7) years for males and 68.0 (SD 1.7) years for females. The optimal number of trajectories differed across measures. For tandem stand, no distinct trajectories were found (all 179 males, 198 females). For gait speed, three trajectories were identified, dependent on baseline speed: high-stable (47 males, 27 females), intermediate-stable (132 males, 130 females), and low-declining performance (6 males, 48 females). Two trajectories were identified for the chair stand: a stable (168 males, 150 females) and declining trajectory (10 males, 38 females). For handgrip strength, three declining trajectories were identified differing in baseline performance: high (55 males, 75 females), intermediate (111 males, 118 females), and low (17 males, 10 females). Overall, 11.9% of males and 5.7% of females were classified in similar trajectories across measures. Trajectories of physical performance were heterogeneous, but showed similar patterns for males and females. Little overlap between measures was shown, suggesting different mechanisms for decline. This study emphasizes the use of multiple domains to assess physical performance.


The current status and clinical value of circulating tumor cells and circulating cell-free tumor DNA in bladder cancer.
Urothelial carcinoma of the bladder (UCB) is a complex disease, which is associated with highly aggressive tumor biologic behavior, especially in patients with muscle-invasive and advanced tumors. Despite multimodal therapy options including surgery, radiotherapy and chemotherapy, UCB patients frequently suffer from poor clinical outcome. Indeed, the potential of diverse opportunities for modern targeted therapies is not sufficiently elucidated in UCB yet. To improve the suboptimal treatment situation in UCB, biomarkers are urgently needed that help detecting minimal residual disease (MRD), predicting therapy response and subsequently prognosis as well as enabling patient stratification for further therapies and therapy monitoring, respectively. To date, decision making regarding treatment planning is mainly based on histopathologic evaluation of biopsies predominantly derived from the primary tumors and on clinical staging. However, both methods are imperfect for sufficient outcome prediction. During disease progression, individual disseminated tumor cells and consecutively metastases can acquire characteristics that do not match those of the corresponding primary tumors, and often are only hardly assessable for further evaluation. Therefore, during recent years, strong efforts were directed to establish non-invasive biomarkers from liquid biopsies. Urine cytology and serum tumor markers have been established for diagnostic purposes, but are still insufficient as universal biomarkers for decision-making and treatment of UCB patients. To date, the clinical relevance of various newly established blood-based biomarkers comprising circulating tumor cells (CTCs), circulating cell-free nucleic acids or tumor-educated platelets is being tested in cancer patients. In this review we summarize the current state and clinical application of CTCs and circulating cell-free tumor DNA originating from blood as biomarkers in patients with different UCB stages.


Evaluation of air pollution phytotoxicity downwind of a phosphate fertilizer factory in India.
The effects of air pollution on plants downwind of a fertilizer factory at Udaipur, India, were studied using three woody perennials. Seedlings of these species including a shrub (Carissa carandas L.), a leguminous avenue tree (Cassia fistula L.) and a fruit tree (Psidium guajava L.) were grown in earthen pots at different study sites receiving varying levels of air pollution input. Changes in plant growth, morphological characteristics, photosynthetic pigment, ascorbic acid, N and S contents and in dry matter allocation were considered in relation to the status of ambient air quality. Observations with these parameters have indicated that the ambient air around the factory contained pollutants at phytotoxic levels. Plant height, basal diameter, conopy area, leaf area and chlorophyll, ascorbic acid and foliar-N concentrations decreased with increasing pollution load. However, foliar-S increased slightly at polluted sites. Air pollution load around the factory have also altered the biomass allocation. Root:shoot ratios increased in C. fistula and P. guajava at polluted sites. In contrast, for C. carandas the above ground parts, where foliage assumed predominance showed precedence over the root growth. This species responded characteristically to air pollution stress by allocating more of its photosynthate towards leaf production and shoot growth.


Method of phase-Doppler anemometry free from the measurement-volume effect.
A novel method is developed to improve the accuracy of particle sizing in laser phase-Doppler anemometry (PDA). In this method the vector sum of refractive and reflective rays is taken into consideration in describing a dual-mechanism-scattering model caused by a nonuniformly illuminated PDA measurement volume. The constraint of the single-mechanism-scattering model in the conventional PDA is removed. As a result the error caused by the measurement-volume effect, which consists of a Gaussian-beam defect and a slit effect, can be eliminated. This new method can be easily implemented with minimal modification of the conventional PDA system. The results of simulation based on the generalized Lorenz-Mie theory show that the new method can provide a PDA system free from the measurement-volume effect.


Visualization and cellular hierarchy inference of single-cell data using SPADE.
High-throughput single-cell technologies provide an unprecedented view into cellular heterogeneity, yet they pose new challenges in data analysis and interpretation. In this protocol, we describe the use of Spanning-tree Progression Analysis of Density-normalized Events (SPADE), a density-based algorithm for visualizing single-cell data and enabling cellular hierarchy inference among subpopulations of similar cells. It was initially developed for flow and mass cytometry single-cell data. We describe SPADE's implementation and application using an open-source R package that runs on Mac OS X, Linux and Windows systems. A typical SPADE analysis on a 2.27-GHz processor laptop takes ∼5 min. We demonstrate the applicability of SPADE to single-cell RNA-seq data. We compare SPADE with recently developed single-cell visualization approaches based on the t-distribution stochastic neighborhood embedding (t-SNE) algorithm. We contrast the implementation and outputs of these methods for normal and malignant hematopoietic cells analyzed by mass cytometry and provide recommendations for appropriate use. Finally, we provide an integrative strategy that combines the strengths of t-SNE and SPADE to infer cellular hierarchy from high-dimensional single-cell data.


Integrating community health workers within Patient Protection and Affordable Care Act implementation.
The Patient Protection and Affordable Care Act's (PPACA) emphasis on community-based initiatives affords a unique opportunity to disseminate and scale up evidence-based community health worker (CHW) models that integrate CHWs within health care delivery teams and programs. Community health workers have unique access and local knowledge that can inform program development and evaluation, improve service delivery and care coordination, and expand health care access. As a member of the PPACA-defined health care workforce, CHWs have the potential to positively impact numerous programs and reduce costs. This article discusses different strategies for integrating CHW models within PPACA implementation through facilitated enrollment strategies, patient-centered medical homes, coordination and expansion of health information technology (HIT) efforts, and also discusses payment options for such integration. Title V of the PPACA outlines a plan to improve access to and delivery of health care services for all individuals, particularly low-income, underserved, uninsured, minority, health disparity, and rural populations. Community health workers' role as trusted community leaders can facilitate accurate data collection, program enrollment, and provision of culturally and linguistically appropriate, patient- and family-centered care. Because CHWs already support disease management and care coordination services, they will be critical to delivering and expanding patient-centered medical homes and Health Home services, especially for communities that suffer disproportionately from multiple chronic diseases. Community health workers' unique expertise in conducting outreach make them well positioned to help enroll people in Medicaid or insurance offered by Health Benefit Exchanges. New payment models provide opportunities to fund and sustain CHWs. Community health workers can support the effective implementation of PPACA if the capacity and potential of CHWs to serve as cultural brokers and bridges among medically underserved communities and health care delivery systems is fully tapped. Patient Protection and Affordable Care Act and current payment structures provide an unprecedented and important vehicle for integrating and sustaining CHWs as part of these new delivery and enrollment models.


Using costing to facilitate policy making towards Universal Health Coverage: findings and recommendations from country-level experiences.
As countries progress towards universal health coverage (UHC), they frequently develop explicit packages of health services compatible with UHC goals. As part of the Disease Control Initiative 3 Country Translation project, a systematic survey instrument was developed and used to review the experience of five low-income and lower-middle-income countries-Afghanistan, Ethiopia, Pakistan, Somalia and Sudan-in estimating the cost of their proposed packages. The paper highlights the main results of the survey, providing information about how costing exercises were conducted and used and what country teams perceived to be the main challenges. Key messages are identified to facilitate similar exercises and improve their usefulness. Critical challenges to be addressed include inconsistent application of costing methods, measurement errors and data reliability issues, the lack of adequate capacity building, and the lack of integration between costing and budgeting. The paper formulates four recommendations to address these challenges: (1) developing more systematic guidance and standard ways to implement costing methodologies, particularly regarding the treatment of health systems-related common costs, (2) acknowledging ranges of uncertainty of costing results and integrating sensitivity analysis, (3) building long-term capacity at the local level and institutionalising the costing process in order to improve both reliability and policy relevance, and (4) closely linking costing exercises to public budgeting.


Oxidant and non-enzymatic antioxidant status in measles.
Measles is a highly contagious viral disease of childhood associated with serious complications and significant morbidity and mortality. In the present study, antioxidant and oxidant status was investigated in children with measles. Our aim was to evaluate the possible changes in non-enzymatic antioxidant levels and their relationship to the oxidative stress in measles. According to our knowledge, there are no data about the blood levels of malondialdehyde (MDA), reduced glutathione (GSH) and vitamin C in measles. We measured the whole blood MDA (as a marker of lipid peroxidation) and GSH, and serum beta-carotene, retinol, alpha-tocopherol and ascorbic acid levels in all subjects. There was a statistically significant difference between the groups for all parameters (p < 0.05). Non-enzymatic antioxidant status was found to be decreased but, lipid peroxidation was increased in the study group. As a conclusion, these findings suggested that oxidant and antioxidant defence system were altered in children with measles.


Utilization of the Eμ-Myc mouse to model heterogeneity of therapeutic response.
Human aggressive B-cell non-Hodgkin lymphomas (NHL) encompass the continuum between Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL), and display considerable clinical and biologic heterogeneity, most notably related to therapy response. We previously showed that lymphomas arising in the Eμ-Myc transgenic mouse are heterogeneous, mirroring genomic differences between Burkitt lymphoma and DLBCL. Given clinical heterogeneity in NHL and the need to develop strategies to match therapeutics with discrete forms of disease, we investigated the extent to which genomic variation in the Eμ-Myc model predicts response to therapy. We used genomic analyses to classify Eμ-Myc lymphomas, link Eμ-Myc lymphomas with NHL subtypes, and identify lymphomas with predicted resistance to conventional and NF-κB-targeted therapies. Experimental evaluation of these predictions links genomic profiles with distinct outcomes to conventional and targeted therapies in the Eμ-Myc model, and establishes a framework to test novel targeted therapies or combination therapies in specific genomically defined lymphoma subgroups. In turn, this will rationally inform the design of new treatment options for aggressive human NHL.


Beverage intake and obesity in early childhood: evidence form primary health care clients in Northwest Argentina.
Sugar sweetened beverages (SSB) are thought to play an important role in weight gain. We examined the relationship between the intake of caloric and noncaloric beverages (SSB and water) and the nutritional status of children. In 2014, we randomly selected 16 public health clinics in four cities of Northwest Argentina and conducted a survey among mothers of children 0-6 years of age. Children's beverage intake was ascertained by 24-h dietary recall provided by the mothers. Children's weight and height measures were obtained from clinic's registries. We calculated the body mass index using the International Obesity Task Force standards. The analysis included 562 children 25 months to 6 years of age with normal or above normal nutritional status. Children's beverage consumption was as follows, water 81.8%, carbonated soft drinks (CSD) 49.7%, coffee/tea/cocoa 44.0%, artificial fruit drinks 35.6%, flavored water 17.9%, natural fruit juice 14.5%. In multivariate logistic regression models the likelihood of being obese v. being overweight or having normal weight doubled with an intake of one to five glasses of CSD (OR=2.2) and increased by more than three-fold with an intake of more than five glasses (OR=3.5). Drinking more than five glasses of water decreased the likelihood of being obese by less than half (OR=0.3). The percentage of children drinking more than five glasses of other beverages was low (3.3-0.9%) and regression models did not yield significant results. The study contributed evidence for reducing children's CSD intake and for promoting water consumption, together with the implementation of comprehensive regulatory public health policies.


Supervisor support training effects on veteran health and work outcomes in the civilian workplace.
This randomized controlled trial involved the development and evaluation of a supervisor support training intervention in the civilian workforce called VSST: Veteran-Supportive Supervisor Training. A theoretically based intervention in the workplace is critical to ensuring a smooth transition for service members and their families to civilian life, leading to improved psychological and physical health and improved work outcomes among service members. Thirty-five organizations were recruited and randomized to the VSST training program or a waitlist control group. Within those organizations, 497 current or former (post 9/11) service member employees were asked to complete baseline and 3- and 9-month follow-up surveys covering work, family, and health domains. The computerized 1-hr training, and the behavior tracking that followed were completed by 928 supervisors from the participating organizations. Intervention training effects were evaluated using an intent-to-treat approach, comparing outcomes for service members who were in organizations assigned to the training group versus those who were in organizations assigned to the control group. Moderation effects revealed the intervention was effective for employees who reported higher levels of supervisor and coworker support at baseline, demonstrating the importance of the organizational context and trainee readiness. The results did not show evidence of direct effects of the intervention on health and work outcomes. Qualitative data from supervisors who took the training also demonstrated the benefits of the training. This study affirms and adds to the literature on the positive effects of organizational programs that train supervisors to provide social support, thereby improving health and work outcomes of employees who receive more support. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Genome Sequence and Metabolic Analysis of a Fluoranthene-Degrading Strain Pseudomonas aeruginosa DN1.
Pseudomonas aeruginosa DN1, isolated from petroleum-contaminated soil, showed excellent degradation ability toward diverse polycyclic aromatic hydrocarbons (PAHs). Many studies have been done to improve its degradation ability. However, the molecular mechanisms of PAHs degradation in DN1 strain are unclear. In this study, the whole genome of DN1 strain was sequenced and analyzed. Its genome contains 6,641,902 bp and encodes 6,684 putative open reading frames (ORFs), which has the largest genome in almost all the comparative Pseudomonas strains. Results of gene annotation showed that this strain harbored over 100 candidate genes involved in PAHs degradation, including those encoding 25 dioxygenases, four ring-hydroxylating dioxygenases, five ring-cleaving dioxygenases, and various catabolic enzymes, transcriptional regulators, and transporters in the degradation pathways. In addition, gene knockout experiments revealed that the disruption of some key PAHs degradation genes in DN1 strain, such as catA, pcaG, pcaH, and rhdA, did not completely inhibit fluoranthene degradation, even though their degradative rate reduced to some extent. Three intermediate metabolites, including 9-hydroxyfluorene, 1-acenaphthenone, and 1, 8-naphthalic anhydride, were identified as the dominating intermediates in presence of 50 μg/mL fluoranthene as the sole carbon source according to gas chromatography mass spectrometry analysis. Taken together, the genomic and metabolic analysis indicated that the fluoranthene degradation by DN1 strain was initiated by dioxygenation at the C-1, 2-, C-2, 3-, and C-7, 8- positions. These results provide new insights into the genomic plasticity and environmental adaptation of DN1 strain.


Dihydromyricetin Alleviates Diabetic Neuropathic Pain and Depression Comorbidity Symptoms by Inhibiting P2X7 Receptor.
Diabetic neuropathic pain (DNP) and major depressive disorder (MDD) are common complications of diabetes mellitus and mutually affect each other. As a member of the ATP-gated ion channel family, P2X7 receptor is associated with the transduction of pain signal and the onset of depression. The aim of this study was to investigate the effects of dihydromyricetin (DHM) on rats with comorbid DNP and MDD. After the comorbid model was established, rat behavior changes were monitored by measuring the mechanical withdrawal threshold, thermal withdrawal latency, sugar water preference, immobility time in the forced-swim test, and open-field test parameters. The expressions of P2X7 receptor in the dorsal root ganglia (DRGs), spinal cord, and hippocampus were assessed by quantitative real-time PCR, Western blotting, and double immunofluorescence. We found that hyperalgesia, allodynia, and depressive behaviors of rats with comorbid DNP and MDD were relieved by treatment with DHM or application of a short-hairpin RNA for P2X7 receptor. The expression levels of P2X7, phosphorylated extracellular signal-regulated kinase 1/2, tumor necrosis factor α, and interleukin 1ß were increased in the DRGs, spinal cord, and hippocampus of rats in the model group but restored after DHM or P2X7 short-hairpin RNA treatment. In conclusion, P2X7 receptor in the DRGs, spinal cord, and hippocampus participates in the transduction of DNP and MDD signals. DHM seems to relieve comorbid DNP and MDD by reducing the expression of P2X7 receptor in the DRGs, spinal cord, and hippocampus and may be an effective new drug for the treatment of patients with both DNP and MDD.


Efficient computation of 2D point-spread functions for diffractive lenses.
Diffractive lenses, such as Fresnel zone plates, photon sieves, and their modified versions, have been of significant recent interest in high-resolution imaging applications. As the advent of diffractive lens systems with different configurations expands, the fast and accurate simulation of these systems becomes crucial for both the design and image reconstruction tasks. Here we present a fast and accurate method for computing the 2D point-spread function (PSF) of an arbitrary diffractive lens. The method is based on the recently derived closed-form mathematical formula for the PSF and the transfer function of a diffractive lens. In the method, first, the samples of the transfer function are computed using the transmittance function of the diffractive lens, and then the inverse Fourier transform of this transfer function is computed to obtain the PSF. For accurate computation, the selection of the sampling parameters is handled with care, and simple selection rules are provided for this purpose. The developed method requires a single fast Fourier transform, and, therefore, has little computational complexity. Moreover, it is also applicable to any diffractive lens configuration with arbitrary-shaped structures and modulation. As a result, this fast and accurate PSF computation method enables efficient simulation, analysis, and development of diffractive lens systems under both focused and defocused settings.


Specific binding of the human T-cell leukemia virus type I Rex protein to a short RNA sequence located within the Rex-response element.
Expression of the structural proteins of human T-cell leukemia virus type I is dependent upon the interaction of the viral Rex trans activator with its highly structured cis-acting RNA target sequence, the 254-nucleotide Rex-response element. Nucleotides critical for Rex binding in vitro have been mapped by modification interference analysis to a discrete 12-nucleotide RNA sequence that is predicted to form a stem-bulge-stem structure. This minimal RNA binding site was sufficient to mediate specific Rex binding in vitro when analyzed in the context of a short RNA probe. The critical importance of this short RNA sequence in mediating Rex function in vivo is supported by its complete conservation among all primate T-cell leukemia virus isolates.


Investigation of normal flatus production in healthy volunteers.
Flatulence can cause discomfort and distress but there are few published data of normal patterns and volumes. Twenty four hour collections were made using a rectal catheter in 10 normal volunteers taking their normal diet plus 200 g baked beans. Total daily volume ranged from 476 to 1491 ml (median 705 ml). Women and men (both n = 5) expelled equivalent amounts. The median daily flatus hydrogen volume was 361 ml/24 h (range 42-1060) and the carbon dioxide volume 68 ml/24 h (range 25-116), three volunteers produced methane (3, 26, and 120 ml/24 h), and the remaining unidentified gas (presumably nitrogen) or gases contributed a median 213 ml/24 h (range 61-476). Larger volumes of flatus were produced after meals than at other times. Flatus produced at a faster rate tended to contain more fermentation gases. Flatus was produced during the sleeping period, but the rate was significantly lower than the daytime rate (median 16 and 34 ml/h respectively). Ingestion of a 'fibre free' diet (Fortisip) for 48 hours significantly reduced the total volume collected in 24 hours (median 214 ml/24 h), reduced the carbon dioxide volume (median 6 ml/24 h), and practically eradicated hydrogen production. The volume of unidentified gas was not significantly affected (median 207 ml/24 h). Thus fermentation gases make the highest contribution to normal flatus volume. A 'fibre free' diet eliminates these without changing residual gas release of around 200 ml/24 h.


Retrospective observational study of patients with chemotherapy-related anemia receiving erythropoietic agents.
Epoetin alfa (EPO) and darbepoetin alfa (DARB) are approved for the treatment of chemotherapy-related anemia (CRA) in patients with nonmyeloid malignancies. This study examined dosing and hematologic outcomes with these agents in community oncology clinics. Medical charts were abstracted retrospectively for 1005 patients (527 EPO, 478 DARB) with CRA (hemoglobin [Hb] < or = 11 g/dL) who received EPO or DARB at 10 U.S. oncology clinics between January 2002 and March 2003. Outcome measures included dose and frequency of erythropoietic therapy, change in Hb at 4, 8, and 12 weeks after initiation of therapy, and transfusion of packed red blood cells. Baseline characteristics were generally similar between groups. Most EPO-treated patients received EPO once weekly, but 25% received EPO every 2-3 weeks, with 40,000 U the predominant dose. DARB was usually given every 1-2 weeks in doses ranging from 200-400 mcg/injection. Mean treatment duration was relatively short (< 8 weeks) in both groups, with a similar number of Hb determinations and similar incidence of red blood transfusion between groups. Hb increased from baseline in the EPO and DARB groups at 4 weeks (0.99 vs. 0.69 g/dL, p = 0.003), 8 weeks (1.39 vs. 1.06 g/dL, p = 0.011), and 12 weeks (1.43 vs. 1.11 g/dL, p = 0.055). Early Hb response (> or = 1 g/dL increase by 4 weeks) was more common with EPO than DARB (48% vs. 38%, p = 0.008). EPO was superior to DARB for early hematologic outcomes in patients with CRA in community oncology clinics. Retrospective data collection and relative inexperience with DARB at the time of the study may limit the generalization of these results. Randomized, controlled trials comparing EPO and DARB are warranted.


A detailed clinical study of pain in 1957 participants with early/moderate Parkinson's disease.
The causes of pain in early/moderate Parkinson's disease (PD) are not well understood. Although peripheral factors such as rigidity, reduced joint movements and poor posture may contribute towards the development of pain, central mechanisms including altered nociceptive processing may also be involved. We performed a large clinical study to investigate potential factors contributing towards pain in early/moderate PD. We recruited 1957 PD participants who had detailed assessments of pain, motor and non-motor symptoms. The King's Parkinson's Pain scale was used to quantify different subtypes of pain. 85% of participants reported pain (42% with moderate to severe pain). Pain influenced quality of life more than motor symptoms in a multiple regression model. Factors predicting overall pain severity included affective symptoms, autonomic symptoms, motor complications, female gender and younger age, but not motor impairment or disease duration. There was negligible correlation between the severity of motor impairment and the severity of musculoskeletal or dystonic pain as well as between the severity of OFF period motor problems and the severity of OFF period pain or OFF period dystonic pain. Features of central sensitization, including allodynia and altered pain sensation were common in this population. The use of drugs targeting central pain was very low. Pain in early/moderate PD cannot be explained by peripheral factors. Central causes may play a much more important role than previously considered. These results should lead to a major shift in the investigation and management of this common and disabling symptom.