The acute effects of heavy and light resistances on the flight time of a basketball push-pass during upper body complex training.
The aim of this study was to investigate the acute effect of high-load and low-load complex training on upper-body performance-determined by the flight time of a basketball push-pass. Twelve competitive male athletes (21.8 +/- 4.5 years, 82.0 +/- 11.7 kg, 181.6 +/- 5.6 cm), with at least 6 months weight training experience and no musculoskeletal disorders, undertook 3 testing conditions. Condition 1 involved 5 repetitions at 85% of a 1 repetition maximum (1RM) bench press; Condition 2 involved 5 repetitions of a 2.3-kg medicine ball push-pass; and Condition 3 was the control, where participants rested for the equivalent time of the other conditions ( approximately 20 seconds). Each condition was preceded and followed by an electronically timed basketball push-pass. Results indicate a significant (3.99%, P = 0.001) reduction in flight time following the completion of Condition 1 (85% 1RM) but no significant changes (1.96%, P = 0.154) were seen following Condition 2 (medicine ball push-pass). Furthermore, there was a significant difference (P = 0.016) between Condition 1 (85% 1RM) and Condition 2 (medicine ball throw). This study appears to confirm previous research suggesting that high loads are required to elicit a potentiation effect. For those athletes wishing to produce a short-term enhancement of power, they should consider loads in the region of 85% 1RM. Results with the lower load showed greater variation, with some individuals responding and others not. Because there appears to be an individual potentiation response to lighter loads, we recommend that, when equipment is limited, athletes and coaches experiment with a range of loads when performing contrast training.


A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q/J mice to infection and autoimmunity.
The B10.Q/J strain of mice was serendipitously discovered to be highly susceptible to infection by the intracellular protozoan parasite, Toxoplasma gondii but markedly resistant to induction of autoimmune arthritis. We have previously shown that the B10.Q/J phenotype is controlled by a single recessive locus and is associated with lymphocyte hyporesponsiveness to IL-12. Using genetic approaches, we have now localized the B10.Q/J locus to chromosome 9 and established its identity as Tyk2, a Janus kinase essential for IL-12 and IFN-alpha/beta cytokine signaling. The B10.Q/J Tyk2 gene contained a single missense mutation resulting in a nonconservative amino acid substitution (E775K) in an invariant motif of the pseudokinase (Janus kinase homology 2) domain. This mutation appeared to result in the absence of the B10.Q/J-encoded Tyk2 protein, despite presence of Tyk2-specific transcripts. Phenotypically, B10.Q/J cells were indistinguishable from Tyk2-deficient cells, showing impaired signaling and biologic responses to IL-12, IL-23, and type I IFNs. The analogous E782K mutant of human Tyk2 failed to restore IFN-alpha responsiveness in Tyk2 null 11,1 cells. Our results indicate a crucial role for Tyk2 in T helper 1-mediated protective and pathogenic immune responses. An additional implication of our findings is that naturally occurring mutations in the Tyk2 gene may underlie altered susceptibilities to infectious or autoimmune diseases in human and animal populations.


Conducting research on the web: 2007 update for the bioinformatics links directory.
The Bioinformatics Links Directory, http://bioinformatics.ca/links_directory, is an actively maintained compilation of servers published in this and previous issues of Nucleic Acids Research issues together with many other useful tools, databases and resources for life sciences research. The 2007 update includes the 130 websites highlighted in the July 2007 Web Server issue of Nucleic Acids Research and brings the total number of servers listed in the Bioinformatics Links Directory to just under 1200 links. In addition to the updated content, the 2007 update of the Bioinformatics Links Directory includes new features for improved navigation, accessibility and open data exchange. A complete listing of all links listed in this Nucleic Acids Research 2007 Web Server issue can be accessed online at, http://bioinformatics.ca/links_directory/narweb2007. The 2007 update of the Bioinformatics Links Directory, which includes the Web Server list and summaries is also available online, at the Nucleic Acids Research web site, http://nar.oupjournals.org.


Antimicrobial gum bio-based nanocomposites and their industrial and biomedical applications.
Gum polysaccharides are derived from renewable sources. They are readily available, inexpensive, non-hazardous and eco-friendly. Depending upon the source, gums may be categorized as microbial gums, plant exudate gums or seed gums. Naturally occurring gum carbohydrates find multiple applications in the biomedical arena, compared with synthetic compounds, because of their unique structures and functionalities. Gums and their biocomposites are preferred for sustained drug delivery because they are safe and edible as well as more susceptible to biodegradation. The present review provides a state-of-the-art conspectus on the industrial and biomedical applications of antimicrobial gum-based biocomposites. Different kinds of gums polysaccharides will first be addressed based on their sources. Metal-, carbon- and organic-based nanostructures that are used in gum nanocomposites will then be reviewed with respect to their industrial and biomedical applications, to provide a backdrop for future research.


Adapting machine-learning algorithms to design gene circuits.
Gene circuits are important in many aspects of biology, and perform a wide variety of different functions. For example, some circuits oscillate (e.g. the cell cycle), some are bistable (e.g. as cells differentiate), some respond sharply to environmental signals (e.g. ultrasensitivity), and some pattern multicellular tissues (e.g. Turing's model). Often, one starts from a given circuit, and using simulations, asks what functions it can perform. Here we want to do the opposite: starting from a prescribed function, can we find a circuit that executes this function? Whilst simple in principle, this task is challenging from a computational perspective, since gene circuit models are complex systems with many parameters. In this work, we adapted machine-learning algorithms to significantly accelerate gene circuit discovery. We use gradient-descent optimization algorithms from machine learning to rapidly screen and design gene circuits. With this approach, we found that we could rapidly design circuits capable of executing a range of different functions, including those that: (1) recapitulate important in vivo phenomena, such as oscillators, and (2) perform complex tasks for synthetic biology, such as counting noisy biological events. Our computational pipeline will facilitate the systematic study of natural circuits in a range of contexts, and allow the automatic design of circuits for synthetic biology. Our method can be readily applied to biological networks of any type and size, and is provided as an open-source and easy-to-use python module, GeneNet.


Ten milestone issues in AOTA history.
This paper identifies 10 professional questions that the author has labeled milestone issues in the history of the American Occupational Therapy Association. Subjects encompassed by these issues are medical control, certified occupational therapy assistants, licensure, proficiency testing, entry-level degrees, treatment media, maintenance of competency, whether occupational therapists serve patients or clients, professional autonomy, and the status of occupational therapy as a profession. Although this paper is primarily a factual record of events and discussions referenced in official publications, the reader will recognize the insertion of author commentary and opinion in several of the issues discussed.


Postcoital Dysphoria: Prevalence and Correlates Among Males.
Consensual sexual activity is believed to be associated with a positive emotional experience, however, postcoital dysphoria (PCD) is a counterintuitive phenomenon characterized by inexplicable feelings of tearfulness, sadness, or irritability following otherwise satisfactory consensual sexual activity. Prevalence of PCD has been reported among females, but not among males. The present study utilized an anonymous online questionnaire to examine the prevalence and correlates of PCD among an international sample including 1,208 male participants. Forty-one percent reported experiencing PCD in their lifetime and 20.2% reported experiencing PCD in the previous four weeks. Between 3% and 4% of the sample reported experiencing PCD on a regular basis. PCD was found to be associated with current psychological distress, childhood sexual abuse, and several sexual dysfunctions. Results indicate that the male experience of the resolution phase may be far more varied, complex, and nuanced than previously thought and lays a foundation for future research investigating PCD among males. Findings have implications for therapeutic settings as well as the general discourse regarding the male sexual experience.


SSR_pipeline: a bioinformatic infrastructure for identifying microsatellites from paired-end Illumina high-throughput DNA sequencing data.
SSR_pipeline is a flexible set of programs designed to efficiently identify simple sequence repeats (e.g., microsatellites) from paired-end high-throughput Illumina DNA sequencing data. The program suite contains 3 analysis modules along with a fourth control module that can automate analyses of large volumes of data. The modules are used to 1) identify the subset of paired-end sequences that pass Illumina quality standards, 2) align paired-end reads into a single composite DNA sequence, and 3) identify sequences that possess microsatellites (both simple and compound) conforming to user-specified parameters. The microsatellite search algorithm is extremely efficient, and we have used it to identify repeats with motifs from 2 to 25 bp in length. Each of the 3 analysis modules can also be used independently to provide greater flexibility or to work with FASTQ or FASTA files generated from other sequencing platforms (Roche 454, Ion Torrent, etc.). We demonstrate use of the program with data from the brine fly Ephydra packardi (Diptera: Ephydridae) and provide empirical timing benchmarks to illustrate program performance on a common desktop computer environment. We further show that the Illumina platform is capable of identifying large numbers of microsatellites, even when using unenriched sample libraries and a very small percentage of the sequencing capacity from a single DNA sequencing run. All modules from SSR_pipeline are implemented in the Python programming language and can therefore be used from nearly any computer operating system (Linux, Macintosh, and Windows).


Shared influence of pathogen and host genetics on a trade-off between latent period and spore production capacity in the wheat pathogen, Puccinia triticina.
Crop pathogens are notorious for their rapid adaptation to their host. We still know little about the evolution of their life cycles and whether there might be trade-offs between fitness components, limiting the evolutionary potential of these pathogens. In this study, we explored a trade-off between spore production capacity and latent period in Puccinia triticina, a fungal pathogen causing leaf rust on wheat. Using a simple multivariate (manova) technique, we showed that the covariance between the two traits is under shared control of host and pathogen, with contributions from host genotype (57%), pathogen genotype (18.4%) and genotype × genotype interactions (12.5%). We also found variation in sign and strength of genetic correlations for the pathogen, when measured on different host varieties. Our results suggest that these important pathogen life-history traits do not freely respond to directional selection and that precise evolutionary trajectories are contingent on the genetic identity of the interacting host and pathogen.


The transition from linear to highly branched poly(β-amino ester)s: Branching matters for gene delivery.
Nonviral gene therapy holds great promise but has not delivered treatments for clinical application to date. Lack of safe and efficient gene delivery vectors is the major hurdle. Among nonviral gene delivery vectors, poly(β-amino ester)s are one of the most versatile candidates because of their wide monomer availability, high polymer flexibility, and superior gene transfection performance both in vitro and in vivo. However, to date, all research has been focused on vectors with a linear structure. A well-accepted view is that dendritic or branched polymers have greater potential as gene delivery vectors because of their three-dimensional structure and multiple terminal groups. Nevertheless, to date, the synthesis of dendritic or branched polymers has been proven to be a well-known challenge. We report the design and synthesis of highly branched poly(β-amino ester)s (HPAEs) via a one-pot "A2 + B3 + C2"-type Michael addition approach and evaluate their potential as gene delivery vectors. We find that the branched structure can significantly enhance the transfection efficiency of poly(β-amino ester)s: Up to an 8521-fold enhancement in transfection efficiency was observed across 12 cell types ranging from cell lines, primary cells, to stem cells, over their corresponding linear poly(β-amino ester)s (LPAEs) and the commercial transfection reagents polyethyleneimine, SuperFect, and Lipofectamine 2000. Moreover, we further demonstrate that HPAEs can correct genetic defects in vivo using a recessive dystrophic epidermolysis bullosa graft mouse model. Our findings prove that the A2 + B3 + C2 approach is highly generalizable and flexible for the design and synthesis of HPAEs, which cannot be achieved by the conventional polymerization approach; HPAEs are more efficient vectors in gene transfection than the corresponding LPAEs. This provides valuable insight into the development and applications of nonviral gene delivery and demonstrates great prospect for their translation to a clinical environment.


Zinc for the prevention or treatment of acute viral respiratory tract infections in adults: a rapid systematic review and meta-analysis of randomised controlled trials.
To evaluate the benefits and risks of zinc formulations compared with controls for prevention or treatment of acute viral respiratory tract infections (RTIs) in adults. Seventeen English and Chinese databases were searched in April/May 2020 for randomised controlled trials (RCTs), and from April/May 2020 to August 2020 for SARS-CoV-2 RCTs. Cochrane rapid review methods were applied. Quality appraisals used the Risk of Bias 2.0 and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Twenty-eight RCTs with 5446 participants were identified. None were specific to SARS-CoV-2. Compared with placebo, oral or intranasal zinc prevented 5 RTIs per 100 person-months (95% CI 1 to 8, numbers needed to treat (NNT)=20, moderate-certainty/quality). Sublingual zinc did not prevent clinical colds following human rhinovirus inoculations (relative risk, RR 0.96, 95% CI 0.77 to 1.21, moderate-certainty/quality). On average, symptoms resolved 2 days earlier with sublingual or intranasal zinc compared with placebo (95% CI 0.61 to 3.50, very low-certainty/quality) and 19 more adults per 100 were likely to remain symptomatic on day 7 without zinc (95% CI 2 to 38, NNT=5, low-certainty/quality). There were clinically significant reductions in day 3 symptom severity scores (mean difference, MD -1.20 points, 95% CI -0.66 to -1.74, low-certainty/quality), but not average daily symptom severity scores (standardised MD -0.15, 95% CI -0.43 to 0.13, low-certainty/quality). Non-serious adverse events (AEs) (eg, nausea, mouth/nasal irritation) were higher (RR 1.41, 95% CI 1.17 to 1.69, NNHarm=7, moderate-certainty/quality). Compared with active controls, there were no differences in illness duration or AEs (low-certainty/quality). No serious AEs were reported in the 25 RCTs that monitored them (low-certainty/quality). In adult populations unlikely to be zinc deficient, there was some evidence suggesting zinc might prevent RTIs symptoms and shorten duration. Non-serious AEs may limit tolerability for some. The comparative efficacy/effectiveness of different zinc formulations and doses were unclear. The GRADE-certainty/quality of the evidence was limited by a high risk of bias, small sample sizes and/or heterogeneity. Further research, including SARS-CoV-2 clinical trials is warranted. CRD42020182044.


Ultrastructure of the proteoliaisin-ovoperoxidase complex and its spatial organization within the Strongylocentrotus purpuratus fertilization envelope.
Ovoperoxidase is a cortical granule-derived enzyme that hardens the sea urchin fertilization envelope by catalyzing the formation of dityrosine residues. Ovoperoxidase works in concert with a second protein, proteoliaisin, which anchors ovoperoxidase to the nascent fertilization envelope in a divalent cation-dependent manner. In this study, we examined the Ca(2+)-dependent interaction of proteoliaisin with ovoperoxidase in rotary-shadowed Pt replicas. Ovoperoxidase, a uniformly sized globular molecule, binds to a distal portion of rod-shaped proteoliaisin when low concentrations of Ca2+ are present. Higher Ca2+ concentrations lead to the formation of extended proteoliaisin strands that are decorated along their lengths with ovoperoxidase. Using immunogold labeling, we also examined the assimilation of these two proteins into the fertilization envelope in quick-frozen, deeply etched samples. Both proteins are abundant in the fertilization envelope as early as one minute after fertilization. Coincident with paracrystalline coating of the envelope, the labeling density is markedly reduced, suggesting that antigenic sites may be masked by the paracrystalline coat. This suggests that the ovoperoxidase-proteoliaisin complex resides within the central portion of the fertilization envelope, rather than in the paracrystalline coat.


How does stress increase risk of drug abuse and relapse?
The notion that stress leads to drug abuse in vulnerable individuals and relapse in addicts is not new. Most major theories of addiction postulate that stress plays an important role in increasing drug use and relapse. Several animal studies and some human laboratory studies have shown that stress exposure enhances drug self-administration. Although clinical observations suggest that exposure to stress increases drug use, and are associated with craving and relapse in addicts, human research in this area is largely correlational and at times contradictory. Given the growing preclinical evidence that supports the key role of stress in substance abuse, careful examination of this research area in humans is warranted. This paper examines empirical evidence on how stress may increase the vulnerability to drug abuse, and explores whether chronic drug abuse alters the stress response and coping in addicts, thereby increasing the likelihood of drug seeking and relapse. Unanswered questions on the association between stress and substance abuse in humans are identified. Preclinical research has shown that stress, in addition to drug itself, plays a key role in perpetuating drug abuse and relapse. However, the mechanisms underlying this association in humans remain unclear. A greater understanding of how stress may perpetuate drug abuse will likely have a significant impact on both prevention and treatment development in the field of addiction.


Terpinen-4-ol, the main component of the essential oil of Melaleuca alternifolia (tea tree oil), suppresses inflammatory mediator production by activated human monocytes.
To evaluate potential antiinflammatory properties of tea tree oil, the essential oil steam distilled from the Australian native plant, Melaleuca alternifolia. The ability of tea tree oil to reduce the production in vitro of tumour necrosis factor-alpha (TNFalpha), interleukin (IL)-1beta, IL-8, IL-10 and prostaglandin E2 (PGE2) by lipopolysaccharide (LPS)-activated human peripheral blood monocytes was examined. Tea tree oil emulsified by sonication in a glass tube into culture medium containing 10% fetal calf serum (FCS) was toxic for monocytes at a concentration of 0.016% v/v. However, the water soluble components of tea tree oil at concentrations equivalent to 0.125% significantly suppressed LPS-induced production of TNFalpha, IL-1beta and IL-10 (by approximately 50%) and PGE2 (by approximately 30%) after 40 h. Gas chromatography/mass spectrometry identified terpinen-4-ol (42 %), a-terpineol (3 %) and 1,8-cineole (2%, respectively, of tea tree oil) as the water soluble components of tea tree oil. When these components were examined individually, only terpinen-4-ol suppressed the production after 40 h of TNFalpha, IL-1beta, IL-8, IL-10 and PGE2 by LPS-activated monocytes. The water-soluble components of tea tree oil can suppress pro-inflammatory mediator production by activated human monocytes.


MET inhibitors in combination with other therapies in non-small cell lung cancer.
MET and its ligand hepatocyte growth factor/scatter factor (HGF) influence cell motility and lead to tumor growth, invasion, and angiogenesis. Alterations in MET have been observed in non-small cell lung cancer (NSCLC) tumors, with increased expression associated with more aggressive cancer, as well as acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). MET inhibitors act via two basic mechanisms. Small molecule inhibitors antagonize ATP in the intracellular tyrosine kinase domain of MET, with studies on the following agents reviewed here: tivantinib (ARQ-197), cabozantinib (XL-184), crizotinib (PF-02341066), amuvatinib (MP470), MGCD265, foretinib (EXEL-2880), MK2461, SGX523, PHA665752, JNJ-38877605, SU11274, and K252A. The monoclonal monovalent antibody fragment onartuzumab (MetMAb) is also discussed here, which binds to and prevents the extracellular activation of the receptor by ligand. MET inhibition may both overcome the negative prognostic effect of MET tumor expression as well as antagonize MET-dependent acquired resistance to EGFR inhibitors. Here we discuss MET inhibitors in combination with other therapies in lung cancer.


State-based Marketplaces using 'clearinghouse' plan management models are associated with lower premiums.
The state-based and federally facilitated health insurance Marketplaces, or exchanges, enrolled more than eight million people during the first open enrollment period, which ended March 31, 2014. There is significant variation in how states have designed and implemented their Marketplaces. We examined how premiums varied with states' involvement in the Marketplaces through governance, plan management authority, and strategy during the first year that the exchanges have been open. State-based Marketplaces using "clearinghouse" plan management models had significantly lower adjusted average premiums for all plans within each metal level compared to state-based Marketplaces using "active purchaser" models and the federally facilitated and partnership Marketplaces. Clearinghouse management models are those in which all health plans that meet published criteria are accepted. Active purchaser models are those in which states negotiate premiums, provider networks, number of plans, and benefits. Our baseline estimates provide valuable benchmarks for evaluating future performance of states' involvement in governance, plan management, and regulatory authority of the insurance Marketplaces.


Bacterial nucleoid structure probed by active drag and resistive pulse sensing.
Recent biophysical approaches have provided key insights into the enthalpic and entropic forces that compact the nucleoid in the cell. Our biophysical approach combines two complementary, non-invasive and label-free techniques: a precisely timed steerable optical trap and a high throughput microcapillary Coulter counter. We demonstrate the ability of the latter technique to probe the physical properties and size of many purified nucleoids, at the individual nucleoid level. The DNA-binding protein H-NS is central to the organization of the bacterial genome. Our results show that nucleoids purified from the Δhns strain in the stationary phase expand approximately five fold more than the form observed in WT bacteria. This compaction is consistent with the role played by H-NS in regulating the nucleoid structure and the significant organizational changes that occur as the cell adapts to the stationary phase. We also study the permeability to the flow of ions and find that in the experiment nucleoids behave as solid colloids.


Impact of Docetaxel on blood-brain barrier function and formation of breast cancer brain metastases.
Breast cancer (BC) is the most frequent malignant tumor in females and the 2nd most common cause of brain metastasis (BM), that are associated with a fatal prognosis. The increasing incidence from 10% up to 40% is due to more effective treatments of extracerebral sites with improved prognosis and increasing use of MRI in diagnostics. A frequently administered, potent chemotherapeutic group of drugs for BC treatment are taxanes usually used in the adjuvant and metastatic setting, which, however, have been suspected to be associated with a higher incidence of BM. The aim of our study was to experimentally analyze the impact of the taxane docetaxel (DTX) on brain metastasis formation, and to elucidate the underlying molecular mechanism. A monocentric patient cohort was analyzed to determine the association of taxane treatment and BM formation. To identify the specific impact of DTX, a murine brain metastatic model upon intracardial injection of breast cancer cells was conducted. To approach the functional mechanism, dynamic contrast-enhanced MRI and electron microscopy of mice as well as in-vitro transendothelial electrical resistance (TEER) and tracer permeability assays using brain endothelial cells (EC) were carried out. PCR-based, immunohistochemical and immunoblotting analyses with additional RNA sequencing of murine and human ECs were performed to explore the molecular mechanisms by DTX treatment. Taxane treatment was associated with an increased rate of BM formation in the patient cohort and the murine metastatic model. Functional studies did not show unequivocal alterations of blood-brain barrier properties upon DTX treatment in-vivo, but in-vitro assays revealed a temporary DTX-related barrier disruption. We found disturbance of tubulin structure and upregulation of tight junction marker claudin-5 in ECs. Furthermore, upregulation of several members of the tubulin family and downregulation of tetraspanin-2 in both, murine and human ECs, was induced. In summary, a higher incidence of BM was associated with prior taxane treatment in both a patient cohort and a murine mouse model. We could identify tubulin family members and tetraspanin-2 as potential contributors for the destabilization of the blood-brain barrier. Further analyses are needed to decipher the exact role of those alterations on tumor metastatic processes in the brain.


Incidence, diagnosis and treatment of popliteal artery entrapment syndrome in current vascular practice in Japan.
Few data regarding popliteal artery entrapment syndrome (PAES) is available in Japan. In this study, we investigated incidence, diagnosis and treatment of PAES in current vascular practice. A retrospective analysis of all patients with PAES visiting 31 participating institutes between 2003 and 2015 was conducted. Thirty-five limbs (28 patients) were identified during the 13-year study period, and the incidence of PAES was 0.12% of all peripheral artery disease cases revascularized. Mean age was 32.0 ± 16.9 years old, and 60 and more years old was 10.7%. Also, 92.9% were male and 39.3% were athletes. Most frequent initial symptoms were intermittent claudication in 23 limbs (65.7%); 4 limbs (11.4%) had chronic limb-threatening ischemia. CT scan was most frequently (94.3%) used for the diagnostic imaging followed by MRI (45.7%) and duplex ultrasound (45.7%). Stress test such as dorsal flexion during duplex ultrasound was used only in 28.6%. Thirty-two limbs (91.4%) received surgical treatment, including 23 arterial reconstructions (71.9%); there were no major perioperative complications. All patients achieved improvement of their symptoms, and the average ankle brachial index increased from 0.69 ± 0.22 to 1.00 ± 0.14 post-surgery. The average postoperative follow-up period was 26.0 months with only one reintervention during the follow-up. In conclusion, PAES was a rare condition and traditional surgical treatment was solid. However, given a broad spectrum of clinical feature of PAES and less usage of diagnostic duplex ultrasound with stress test, there might be a miss- or delayed diagnosis of PAES even in the current vascular practice.


Molecular analysis of prokaryotic diversity in the deep subsurface of the former Homestake gold mine, South Dakota, USA.
A culture-independent molecular phylogenetic analysis was carried out to study the prokaryotic diversity in two soil samples collected from the subsurface (1.34 km depth) of the former Homestake gold mine, Lead, South Dakota, USA at two sites, the Ross shaft and number 6 Winze. Microbial community analyses were performed by cloning and sequencing of 16S rRNA genes retrieved directly from soil samples. Geochemical characterization of soils revealed high amount of toxic metals such as As, Cd, Co, Cr, Cu, Ni, Pb, Zn, and U at both the sites. Phylogenetic analyses showed that soil samples were predominantly composed of phylotypes related to phylum Proteobacteria. Other phyla detected in libraries were Acidobacteria, Actinobacteria, Bacteroidetes, Chloroflexi, Chlorobi, Firmicutes, Gemmatimonadetes, Nitrospirae, Planctomycetes, Verrucomicrobia, and candidate divisions OP10 and TM7. The majority (>95%) of the phylotypes retrieved in the libraries were most closely related to environmental sequences from yet-uncultured bacteria representing a hitherto unidentified diversity. The archaeal communities at both the sites exhibited lower diversity and were most closely affiliated to uncultivated species within the Crenarchaeota. Results showed the existence of diverse microbial populations in deep subsurface environment of the Homestake gold mine. Statistical analyses demonstrated that each site harbored phylogenetically distinct microbial populations that were more diverse at Ross site compare to winze site.


Direct interaction between a myosin V motor and the Rab GTPases Ypt31/32 is required for polarized secretion.
Rab GTPases recruit myosin motors to endocytic compartments, which in turn are required for their motility. However, no Ypt/Rab GTPase has been shown to regulate the motility of exocytic compartments. In yeast, the Ypt31/32 functional pair is required for the formation of trans-Golgi vesicles. The myosin V motor Myo2 attaches to these vesicles through its globular-tail domain (GTD) and mediates their polarized delivery to sites of cell growth. Here, we identify Myo2 as an effector of Ypt31/32 and show that the Ypt31/32-Myo2 interaction is required for polarized secretion. Using the yeast-two hybrid system and coprecipitation of recombinant proteins, we show that Ypt31/32 in their guanosine triphosphate (GTP)-bound form interact directly with Myo2-GTD. The physiological relevance of this interaction is shown by colocalization of the proteins, genetic interactions between their genes, and rescue of the lethality caused by a mutation in the Ypt31/32-binding site of Myo2-GTD through fusion with Ypt32. Furthermore, microscopic analyses show a defective Myo2 intracellular localization in ypt31Delta/32ts and in Ypt31/32-interaction-deficient myo2 mutant cells, as well as accumulation of unpolarized secretory vesicles in the latter mutant cells. Together, these results indicate that Ypt31/32 play roles in both the formation of trans-Golgi vesicles and their subsequent Myo2-dependent motility.


Gender-dependent pharmacokinetics of topotecan in adult patients.
Gender-dependent differences in the clinical pharmacokinetic behavior of various drugs have been documented previously. Most commonly, these differences are associated with differences in body composition, renal elimination, drug absorption or hepatic metabolism. Gender-dependent differences in the pharmacokinetics of topotecan (Hycamtin) have not yet been described. In this report, pharmacokinetic data of the lactone and carboxylate forms of topotecan were derived from clinical studies in which topotecan was administered either orally or i.v. to a total of 55 males and 37 females. A significant difference (p=0.0082) of 38% was found between the apparent clearance of topotecan lactone after oral administration in males (237+/-105 l/h) and females (163+/-62.5 l/h). When adjusted for body surface area, this difference remained significant (p=0.031). Similarly, differences were noted in the percentage of topotecan in the lactone form (37.1+/-5.32 versus 41.7+/-6.51%, p=0.0076). Statistical analysis revealed that individual hematocrit values, which were consistently lower in females (p<0.023), were a significant predictor of the apparent topotecan lactone clearance. This was confirmed experimentally in in vitro incubation studies in whole blood using artificially altered hematocrit values and in blood samples from both male and female volunteers. Topotecan is thus subject to significant gender-dependent differences in pharmacokinetics that arise as a result of a physiological difference in hematocrit values between males and females. This finding may have significant implications for the interpretation of the relationships between pharmacokinetics and pharmacodynamic outcome of topotecan treatment, and may provide a basis for the development and refinement of future clinical protocols.


Consensus on the Definition of Control and Remission in Chronic Urticaria.
The terms control and remission and other key terms used in chronic urticaria (CU) such as flare-up, relapse, exacerbation, and recurrence have not been fully defined in the literature. Disease monitoring and treatment goals in clinical practice are not well established. After a qualitative appraisal of available evidence, we aimed to find a consensus definition of control and remission, clarify key terminology, provide guidance on how to monitor the disease, and establish treatment goals in clinical practice. A modified Delphi consensus approach was used. Based on a literature review, a scientific committee provided 137 statements addressing controversial definitions and terms, available patient-reported outcomes (PROs), and recommendations on how to measure therapeutic objectives in CU. The questionnaire was evaluated by 138 expert allergists and dermatologists. A consensus was reached on 105 out of the 137 proposed items (76.6%). The experts agreed that complete control and remission of CU could be defined as the absence of signs or symptoms while on treatment and in the absence of treatment, respectively. Consensus was not reached on the definition of other key terms such as flare-up, exacerbation, and recurrence. The panel agreed that the objective of therapy in CU should be to achieve complete control. PROs that define the degree of control (complete, good, partial, or absence) were established. An algorithm for disease assessment is provided. In conclusion, this work offers consensus definitions and tools that may be useful in the management of patients with CU.


DFG-based mid-IR generation using a compact dual-wavelength all-fiber amplifier for laser spectroscopy applications.
We demonstrate a compact mid-infrared (mid-IR) radiation source based on difference frequency generation (DFG) in periodically poled lithium niobate (PPLN) crystal. The system incorporates a dual-wavelength master oscillator power amplifier (MOPA) source capable of simultaneous amplification of 1064 nm and 1548 nm signals in a common active fiber co-doped with erbium and ytterbium ions. Two low-power seed lasers were amplified by a factor of 14.4 dB and 23.7 dB for 1064 nm and 1548 nm, respectively and used in a nonlinear DFG setup to generate 1.14 mW of radiation centered at 3.4 μm. The system allowed for open-path detection of methane (CH(4)) in ambient air with estimated minimum detectable concentration at a level of 26 ppbv.


Filipino domestic workers in Hong Kong: health related behaviors, health locus of control and social support.
A total of 290 female Filipino domestic helpers residing in Hong Kong completed a concurrent cross sectional survey designed to provide an initial report of basic data which measured mental health symptoms, health-related behaviors, health locus of control and social support. The four top ranking symptoms of mental distress reported included waking in the early hours, loneliness, worry and taking a long time to get to sleep. In general, the level of health related behaviors was high, with a satisfactory diet and low rates of alcohol, nicotine and coffee consumption. However, few women surveyed had previously had a Pap smear. There were also low scores for other preventive health practices. Reinforcement for health behaviors was seen as either a matter of chance or being influenced by powerful others for two thirds of the women. The conclusion highlights the intersection between gender, immigration and social class by drawing attention to issues of acceptance and accessibility of healthcare services for immigrant within host countries. In addition, cultural directions for immigrant health education are outlined.


Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data.
Genome-wide expression profiling is a powerful tool for implicating novel gene ensembles in cellular mechanisms of health and disease. The most popular platform for genome-wide expression profiling is the Affymetrix GeneChip. However, its selection of probes relied on earlier genome and transcriptome annotation which is significantly different from current knowledge. The resultant informatics problems have a profound impact on analysis and interpretation the data. Here, we address these critical issues and offer a solution. We identified several classes of problems at the individual probe level in the existing annotation, under the assumption that current genome and transcriptome databases are more accurate than those used for GeneChip design. We then reorganized probes on more than a dozen popular GeneChips into gene-, transcript- and exon-specific probe sets in light of up-to-date genome, cDNA/EST clustering and single nucleotide polymorphism information. Comparing analysis results between the original and the redefined probe sets reveals approximately 30-50% discrepancy in the genes previously identified as differentially expressed, regardless of analysis method. Our results demonstrate that the original Affymetrix probe set definitions are inaccurate, and many conclusions derived from past GeneChip analyses may be significantly flawed. It will be beneficial to re-analyze existing GeneChip data with updated probe set definitions.


[Does ultraclean air in the operating room provide greater safety?].
The Dutch quality control plan for climatisation of the operating room (OR), which was published in 2005, describes the management and maintenance of the air conditioning system. This management plan proposes a standard for air quality in class 1 ORs. This has been adopted by the Dutch Orthopaedic Society, but not by other surgical societies. The British study which underlies the proposed norm for air quality in class 1 ORs, a study on the infection preventive effect of ultraclean air, dates from 1982 and is inadequately controlled for prophylactic use of antibiotics. Antibiotic prophylaxis in itself already reduces the number of surgical site infections.-More recent studies fail to show an infection preventive effect of ultraclean air in the OR. The Dutch Working Party for Infection Prevention (WIP) ought to take the initiative, together with the medical Scientific Societies and the Society of Infection Prevention and Control in the health care setting (VHIG), to establish enforceable norms for microbiological air quality and to set criteria as to which types of operations are allowed to be performed in which class of OR.


Effects of gum arabic on lipase interfacial binding and activity.
We investigated the surface behavior of gum Arabic (GA) as well as its effects on the lipolytic activity of human pancreatic lipase (HPL) and Humicola lanuginosa lipase (HLL), using emulsions of triacylglycerols (TAG) with various chain lengths. The effects of GA on the interfacial binding of HPL were also investigated. In the presence of 4 mM sodium taurodeoxycholate (NaTDC), GA (3% w/v, final concentration) had no effect on the HPL activity measured in the presence of colipase, whatever the type of TAG used. However, in the absence of bile salts or at low bile salt concentrations, GA inhibited the HPL activity when trioctanoin (TC8) and purified soybean oil (PSO) were used as substrates. At 3% (w/v, final concentration), GA strongly desorbed pure HPL from the TC8 interface and the classical anchoring effect of colipase was clearly observed. Both crude and dialyzed GA solutions were found to be highly tensioactive at the air-water as well as the oil-water interface using the drop technique. In conclusion, GA, or a putative contaminant present in GA, was found to be surface active and to have similar effects to those of bile salts on the interfacial binding and activity of HPL.


Adolescent PR3-ANCA-positive hypertrophic pachymeningitis: A case report and review of the literature.
Hypertrophic pachymeningitis (HP) is an uncommon, life-threatening disease that is seen in elderly patients with antineutrophil cytoplasmic antibody (ANCA) positivity. Proteinase-3 (PR3)-ANCA-positive HP has not been reported in adolescents. Here, we report the first case of adolescent PR3-ANCA-positive HP successfully treated with immunosuppressive therapy. A 14-year-old female presented with fullness and pain in her right ear unresponsive to antibiotics. Laboratory tests showed an elevated C-reactive protein and PR3-ANCA positivity. Computed tomography and magnetic resonance imaging revealed mastoiditis in the right temporal bone. Surgical biopsy revealed severe fibrosis and prominent inflammatory-cell infiltration. She received prednisolone and methotrexate therapy, and then underwent a right mastoidectomy. Five months later, she developed headache, dysarthria, and multiple cranial nerve palsies. Further imaging revealed enhancement and thickening of the right hemispheric dura. PR3-ANCA-positive HP. She was successfully treated with steroid pulse therapy for 3 days, followed by high doses of prednisolone and intravenous cyclophosphamide. The treatment resulted in significant improvement of her symptoms, laboratory data, and radiologic findings. PR3-ANCA-positive HP can present not only in the elderly, but also in adolescence, and prompt diagnosis and treatment with immunosuppressive therapy is vital.


Shoulder pain and repetition strain injury to the supraspinatus muscle: etiology and manipulative treatment.
Chronic inflammation and degenerative tendonitis of the supraspinatus muscle is an important cause of intrinsic shoulder pain. Injury to this muscle is usually caused, not by a single event, but by slight to moderate trauma repeatedly to the same anatomic area. The term repetition strain injury is used to describe this form of microtrauma. Repetition strain injury of the supraspinatus muscle is not an isolated event, but rather a form of microtrauma that affects the entire shoulder girdle. This functional unit must be evaluated and considered in the treatment plan. The authors discuss the diagnosis of this pain syndrome, which is based on the patient's work history, motion and strength testing, and palpation for trigger points. They also provide instruction in treatment involving manipulation with functional and counterstrain techniques combined with home exercise and modification of work posture.


The Stomach-Derived Hormone Ghrelin Increases Impulsive Behavior.
Impulsivity, defined as impaired decision making, is associated with many psychiatric and behavioral disorders, such as attention-deficit/hyperactivity disorder as well as eating disorders. Recent data indicate that there is a strong positive correlation between food reward behavior and impulsivity, but the mechanisms behind this relationship remain unknown. Here we hypothesize that ghrelin, an orexigenic hormone produced by the stomach and known to increase food reward behavior, also increases impulsivity. In order to assess the impact of ghrelin on impulsivity, rats were trained in three complementary tests of impulsive behavior and choice: differential reinforcement of low rate (DRL), go/no-go, and delay discounting. Ghrelin injection into the lateral ventricle increased impulsive behavior, as indicated by reduced efficiency of performance in the DRL test, and increased lever pressing during the no-go periods of the go/no-go test. Central ghrelin stimulation also increased impulsive choice, as evidenced by the reduced choice for large rewards when delivered with a delay in the delay discounting test. In order to determine whether signaling at the central ghrelin receptors is necessary for maintenance of normal levels of impulsive behavior, DRL performance was assessed following ghrelin receptor blockade with central infusion of a ghrelin receptor antagonist. Central ghrelin receptor blockade reduced impulsive behavior, as reflected by increased efficiency of performance in the DRL task. To further investigate the neurobiological substrate underlying the impulsivity effect of ghrelin, we microinjected ghrelin into the ventral tegmental area, an area harboring dopaminergic cell bodies. Ghrelin receptor stimulation within the VTA was sufficient to increase impulsive behavior. We further evaluated the impact of ghrelin on dopamine-related gene expression and dopamine turnover in brain areas key in impulsive behavior control. This study provides the first demonstration that the stomach-produced hormone ghrelin increases impulsivity and also indicates that ghrelin can change two major components of impulsivity-motor and choice impulsivity.


Asymmetry in voltage-dependent movements of isolated outer hair cells from the organ of Corti.
The electrically induced movements of outer hair cells (OHC) were studied using the whole-cell voltage-clamp technique and video analysis. Cell shortening occurs during depolarization and elongation occurs during hyperpolarization from holding potentials near -70 mV. However, a marked asymmetry in response magnitude exists such that depolarization produces larger cell length changes than do comparable levels of hyperpolarization. The response is such that at normal resting potentials in vivo, displacements are about 2 nm/mV, but increase to about 15 nm/mV as the cell is depolarized. This mechanical rectification in the depolarizing direction manifests itself during symmetrical sinusoidal voltage stimulation as a "DC" reduction in cell length superimposed upon "AC" length changes. The observed OHC mechanical rectification may be involved in the reported production of "DC" basilar membrane displacements during suprathreshold acoustic stimulation (LePage, 1987). Estimates of the magnitude of OHC movements at acoustic threshold levels induced by receptor potentials in the high-frequency region of the cochlea indicate a disparity between basilar membrane and OHC movements on the order of 21 dB. Thus, it appears questionable whether OHC mechanical movements solely underlie the "active process" thought to be responsible for the high degree of neural tuning at sound pressures near 0 dB.


Narrowband photon pair source for quantum networks.
We demonstrate a compact photon pair source based on a periodically poled lithium niobate nonlinear crystal in a short cavity. This approach provides efficient, low-loss, mode selection that is compatible with standard telecommunication networks. Photons with a coherence time of 8.6 ns (116 MHz) are produced and their purity is demonstrated. A source brightness of 134 pairs (s. mW. MHz)(-1) is reported. The cavity parameters are chosen such that the photon pair modes emitted can be matched to telecom ultra dense wavelength division multiplexing (U-DWDM) channel spacings. The high level of purity and compatibility with standard telecom networks is of great importance for complex quantum communication networks.


Prp22 and spliceosome components regulate chromatin dynamics in germ-line polyploid cells.
During Drosophila oogenesis, the endopolyploid nuclei of germ-line nurse cells undergo a dramatic shift in morphology as oogenesis progresses; the easily-visible chromosomes are initially polytenic during the early stages of oogenesis before they transiently condense into a distinct '5-blob' configuration, with subsequent dispersal into a diffuse state. Mutations in many genes, with diverse cellular functions, can affect the ability of nurse cells to fully decondense their chromatin, resulting in a '5-blob arrest' phenotype that is maintained throughout the later stages of oogenesis. However, the mechanisms and significance of nurse-cell (NC) chromatin dispersal remain poorly understood. Here, we report that a screen for modifiers of the 5-blob phenotype in the germ line isolated the spliceosomal gene peanuts, the Drosophila Prp22. We demonstrate that reduction of spliceosomal activity through loss of peanuts promotes decondensation defects in NC nuclei during mid-oogenesis. We also show that the Prp38 spliceosomal protein accumulates in the nucleoplasm of nurse cells with impaired peanuts function, suggesting that spliceosomal recycling is impaired. Finally, we reveal that loss of additional spliceosomal proteins impairs the full decondensation of NC chromatin during later stages of oogenesis, suggesting that individual spliceosomal subcomplexes modulate expression of the distinct subset of genes that are required for correct morphology in endopolyploid nurse cells.


Automated Selection of Hotspots (ASH): enhanced automated segmentation and adaptive step finding for Ki67 hotspot detection in adrenal cortical cancer.
In prognosis and therapeutics of adrenal cortical carcinoma (ACC), the selection of the most active areas in proliferative rate (hotspots) within a slide and objective quantification of immunohistochemical Ki67 Labelling Index (LI) are of critical importance. In addition to intratumoral heterogeneity in proliferative rate i.e. levels of Ki67 expression within a given ACC, lack of uniformity and reproducibility in the method of quantification of Ki67 LI may confound an accurate assessment of Ki67 LI. We have implemented an open source toolset, Automated Selection of Hotspots (ASH), for automated hotspot detection and quantification of Ki67 LI. ASH utilizes NanoZoomer Digital Pathology Image (NDPI) splitter to convert the specific NDPI format digital slide scanned from the Hamamatsu instrument into a conventional tiff or jpeg format image for automated segmentation and adaptive step finding hotspots detection algorithm. Quantitative hotspot ranking is provided by the functionality from the open source application ImmunoRatio as part of the ASH protocol. The output is a ranked set of hotspots with concomitant quantitative values based on whole slide ranking. We have implemented an open source automated detection quantitative ranking of hotspots to support histopathologists in selecting the 'hottest' hotspot areas in adrenocortical carcinoma. To provide wider community easy access to ASH we implemented a Galaxy virtual machine (VM) of ASH which is available from http://bioinformatics.erasmusmc.nl/wiki/Automated_Selection_of_Hotspots . The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_216.


Effect of diagnostic criteria on the prevalence of peripheral arterial disease. The San Luis Valley Diabetes Study.
The ankle/brachial systolic blood pressure index (ABI), a noninvasive measure of peripheral arterial disease (PAD), is widely used in epidemiological studies. However, the normal ranges of the ABI in healthy populations and ABI criteria for the diagnosis of PAD in large population studies have not been critically evaluated. The San Luis Valley Diabetes Study (SLVDS) was designed to evaluate the prevalence and complications of non-insulin-dependent diabetes mellitus (NIDDM) in a biethnic population. The present study was conducted as part of the SLVDS to assess the prevalence of vascular disease in 1280 nondiabetic control subjects and 430 patients with NIDDM. The ABI criteria for PAD were developed in 403 healthy individuals with a low risk for cardiovascular disease. In these low-risk subjects, the average resting ABI value was 0.07 lower in women than in men. In both sexes, the dorsalis pedis ABI was 0.04 lower than in the posterior tibial artery, and the left leg ABI was 0.02 lower than the right leg ABI (all differences, P < .05). In the low-risk subjects, ABI values were lower after exercise than at rest and had similar differences by sex and leg as observed at rest. Using specific abnormal cutoff points for the ABI, we evaluated three criteria for PAD in the overall population: two abnormal vessels in the same leg at rest (both dorsalis pedis and posterior tibial arteries), one abnormal vessel per leg at rest, and an ABI abnormality only after exercise. Subjects classified with PAD by the two-vessel criterion had a higher frequency of claudication and the physical finding of an absent pulse compared with subjects without PAD or patients with PAD defined by the one-vessel or exercise criterion. Use of the two-vessel criterion identified an increased risk of PAD with increasing age, NIDDM, smoking, hypertension, and elevated cholesterol levels. In contrast, the one-vessel PAD criterion was associated only with increasing age and smoking, and exercise-diagnosed PAD was not associated with any cardiovascular risk factor except for male sex. In low-risk subjects, the normal distribution and lower abnormal cutoff point values of the ABI differed by type of test, sex, ankle vessel, and leg. When these specific abnormal cutoff points were applied to the SLVDS population, the two-vessel abnormal criterion described patients with typical clinical characteristics of PAD and the expected associations of PAD with cardiovascular risk factors. These clinical characteristics and cardiovascular risk factor associations were less evident with PAD diagnosed by the one-vessel or exercise criterion. Therefore, an abnormal dorsalis pedis and posterior tibial ABI in the same leg at rest should be used for the diagnosis of PAD in epidemiological studies.


Contemporary management of acute coronary syndromes: does the practice match the evidence? The global registry of acute coronary events (GRACE).
To determine to what extent evidence based guidelines are followed in the management of acute coronary syndromes (ACS) in the UK, elsewhere in Europe, and multinationally, and what the outcomes are. Multinational, prospective, observational registry (GRACE, global registry of acute coronary events) with six months' follow up. Patients presenting to a cluster of hospitals. The study was designed to collect data representative of the full spectrum of ACS in specific geographic populations. Patients admitted with a working diagnosis of unstable angina or suspected myocardial infarction (MI). Death during hospitalisation and at six months' follow up (adjusted for baseline risks). In ST elevation MI, reperfusion was applied more often in the UK (71%) than in Europe (65%) and multinationally (59%) (p < 0.01). However, this was almost entirely by lytic treatment, in contrast with elsewhere (primary percutaneous coronary intervention 1%, 29%, 16%, respectively). Statins were applied more frequently in the UK for all classes of patients with ACS (p < 0.0001). In contrast there was lower use of revascularisation procedures in non-ST MI (20% v 37% v 28%, respectively) and glycoprotein IIb/IIIa antagonists (6% v 25% v 26%, respectively). In-hospital death rates, adjusted for baseline risk, were not significantly different but six month death rates were higher in the UK for ST elevation MI (7.2% UK, 4.3% Europe, 5.3% multinationally; p < 0.0001) and non-ST elevation MI (7.5%, 6.2%, and 6.7%, respectively; p = 0.012, UK v Europe). Current management of ACS in the UK more closely follows the recommendations of the National Service Framework than British or European guidelines. Differences in practice may account for the observed higher event rates in the UK after hospital discharge.


Omega 3 fatty acids chemosensitize multidrug resistant colon cancer cells by down-regulating cholesterol synthesis and altering detergent resistant membranes composition.
The activity of P-glycoprotein (Pgp) and multidrug resistance related protein 1 (MRP1), two membrane transporters involved in multidrug resistance of colon cancer, is increased by high amounts of cholesterol in plasma membrane and detergent resistant membranes (DRMs). It has never been investigated whether omega 3 polyunsatured fatty acids (PUFAs), which modulate cholesterol homeostasis in dyslipidemic syndromes and have chemopreventive effects in colon cancer, may affect the response to chemotherapy in multidrug resistant (MDR) tumors. We studied the effect of omega 3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in human chemosensitive colon cancer HT29 cells and in their MDR counterpart, HT29-dx cells. MDR cells, which overexpressed Pgp and MRP1, had a dysregulated cholesterol metabolism, due to the lower expression of ubiquitin E3 ligase Trc8: this produced lower ubiquitination rate of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCoAR), higher cholesterol synthesis, higher cholesterol content in MDR cells. We found that DHA and EPA re-activated Trc8 E3 ligase in MDR cells, restored the ubiquitination rate of HMGCoAR to levels comparable with chemosensitive cells, reduced the cholesterol synthesis and incorporation in DRMs. Omega 3 PUFAs were incorporated in whole lipids as well as in DRMs of MDR cells, and altered the lipid composition of these compartments. They reduced the amount of Pgp and MRP1 contained in DRMs, decreased the transporters activity, restored the antitumor effects of different chemotherapeutic drugs, restored a proper tumor-immune system recognition in response to chemotherapy in MDR cells. Our work describes a new biochemical effect of omega 3 PUFAs, which can be useful to overcome chemoresistance in MDR colon cancer cells.


Reorganization of mental health services: from institutional to community-based models of care.
Mental health services in the Eastern Mediterranean Region are predominantly centralized and institutionalized, relying on scarce specialist manpower. This creates a major treatment gap for patients with common and disabling mental disorders and places an unnecessary burden on the individual, their family and society. Six steps for reorganization of mental health services in the Region can be outlined: (1) integrate delivery of interventions for priority mental disorders into primary health care and existing priority programmes; (2) systematically strengthen the capacity of non-specialized health personnel for providing mental health care; (3) scale up community-based services (community outreach teams for defined catchment, supported residential facilities, supported employment and family support); (4) establish mental health services in general hospitals for outpatient and acute inpatient care; (5) progressively reduce the number of long-stay beds in mental hospitals through restricting new admissions; and (6) provide transitional/bridge funding over a period of time to scale up community-based services and downsize mental institutions in parallel.


Topology of outer membrane porins in pathogenic Neisseria spp.
In Escherichia coli, membrane-spanning amphipathic beta-sheet structures are characteristic of many outer membrane proteins. By applying the principles that have been recognized for them to the four classes of neisserial porins, we have constructed a model for the topology of the porins within the outer membrane. This model predicts eight surface-exposed loops, both in the meningococcal class 1 and 2 proteins and in the gonococcal PIA and PIB proteins. The transmembrane sequences are highly conserved among these porins and are able to form an amphipathic beta-sheet structure. The surface-exposed hydrophilic loops show extensive variation in both length and sequence. Experimental evidence in support of this model has been obtained by using antisera against synthetic peptides which correspond to surface-exposed loops in class 1 and 2 proteins. Thus, binding to the cell surface was observed with antibodies against loops 1, 4, and 5 of class 1 and loops 1 and 5 of class 2. In class 1, these loops are the longest ones and show the highest sequence diversity among strains of different subtypes. Mapping of epitopes recognized by monoclonal antibodies with bactericidal activity has also provided strong support for the model. The epitopes are located in loops 1 and 4 of class 1 protein, loop 5 of PIB, and loop 6 of PIA. A nonbactericidal antibody that binds only weakly to whole cells was shown to recognize loop 3 of PIB. These results suggest that the longest loops are immunodominant, provide the binding sites for bactericidal antibodies, and display the greatest variation among different strains.


Neural mechanisms of saccadic suppression.
In normal vision our gaze leaps from detail to detail, resulting in rapid image motion across the retina. Yet we are unaware of such motion, a phenomenon known as saccadic suppression. We recorded neural activity in the middle temporal and middle superior temporal cortical areas during saccades and identical image motion under passive viewing conditions. Some neurons were selectively silenced during saccadic image motion, but responded well to identical external image motion. In addition, a subpopulation of neurons reversed their preferred direction of motion during saccades. Consequently, oppositely directed motion signals annul one another, and motion percepts are suppressed.


Can cytoplasmic nucleophosmin be detected by immunocytochemical staining of cell smears in acute myeloid leukemia?
Mutations in the C-terminal region of nucleophosmin in acute myeloid leukemia (AML) result in aberrant cytoplasmic nucleophosmin (cNPM) in leukemic blast cells which is detectable by immunocytochemistry in bone marrow trephine (BMT) biopsy sections. We tested whether cNPM is detectable by immunocytochemistry in air-dried smears of AML with nucleophosmin1 (NPM1) mutations. An immunoalkaline phosphatase method was developed using the OCI-AML3 cell line, known to have mutated NPM1, and assessed on blood and marrow smears of 60 AML cases. NPM was detectable in all blast cell nucleoli and cNPM in 21 of 31 of NPM1 mutated and 15 of 29 wild-type cases. Paired air-dried smears and BMT biopsies from the same case (mutated and wild-type) gave discrepancies in cNPM expression and there was no correlation in 10 of 22 cases. Due to the high false positive and negative rates for cNPM in cell smears, this method should not be used as a surrogate for NPM1 mutations in AML.


Systematic review of influenza resistance to the neuraminidase inhibitors.
Antivirals play a critical role in the prevention and the management of influenza. One class of antivirals, neuraminidase inhibitors (NAIs), is effective against all human influenza viruses. Currently there are two NAI drugs which are licensed worldwide: oseltamivir (Tamiflu®) and zanamivir (Relenza®); and two drugs which have received recent approval in Japan: peramivir and laninamivir. Until recently, the prevalence of antiviral resistance has been relatively low. However, almost all seasonal H1N1 strains that circulated in 2008-09 were resistant to oseltamivir whereas about 1% of tested 2009 pandemic H1N1 viruses were found to be resistant to oseltamivir. To date, no studies have demonstrated widespread resistance to zanamivir. It seems likely that the literature on antiviral resistance associated with oseltamivir as well as zanamivir is now sufficiently comprehensive to warrant a systematic review.The primary objectives were to systematically review the literature to determine the incidence of resistance to oseltamivir, zanamivir, and peramivir in different population groups as well as assess the clinical consequences of antiviral resistance. We searched MEDLINE and EMBASE without language restrictions in September 2010 to identify studies reporting incidence of resistance to oseltamivir, zanamivir, and peramivir. We used forest plots and meta-analysis of incidence of antiviral resistance associated with the three NAIs. Subgroup analyses were done across a number of population groups. Meta-analysis was also performed to evaluate associations between antiviral resistance and clinical complications and symptoms. We identified 19 studies reporting incidence of antiviral resistance. Meta-analysis of 15 studies yielded a pooled incidence rate for oseltamivir resistance of 2.6% (95%CI 0.7% to 5.5%). The incidence rate for all zanamivir resistance studies was 0%. Only one study measured incidence of antiviral resistance among subjects given peramivir and was reported to be 0%. Subgroup analyses detected higher incidence rates among influenza A patients, especially for H1N1 subtype influenza. Considerable heterogeneity between studies precluded definite inferences about subgroup results for immunocompromised patients, in-patients, and children. A meta-analysis of 4 studies reporting association between oseltamivir-resistance and pneumonia yielded a statistically significant risk ratio of 4.2 (95% CI 1.3 to 13.1, p = 0.02). Oseltamivir-resistance was not statistically significantly associated with other clinical complications and symptoms. Our results demonstrate that that a substantial number of patients may become oseltamivir-resistant as a result of oseltamivir use, and that oseltamivir resistance may be significantly associated with pneumonia. In contrast, zanamivir resistance has been rarely reported to date.


The subjective visual vertical in benign paroxysmal positional vertigo. A preliminary study.
In Benign Paroxysmal Positional Vertigo (BPPV), the existence of otoconial debris in the cupula or canal explains most of the symptoms and signs characteristic of this common inner ear disorder. We have studied the ability of patients with BPPV to correctly determine the subjective visual vertical, as this is a good test to evaluate utricular function. Only 1 of 10 patients with BPPV displayed a clearly abnormal response, and there was no correlation between the side of the lesion and the perceived tilt. This might imply that the limited damage induced by the dislodged otoconia does not disrupt utricular function or that the saccule is the source of the problem.


Sandwich mixer-reactor: influence of the diffusion coefficient and flow rate ratios.
A sandwich mixer consists of mixing two solutions in a channel, one central laminar flow being sandwiched between two outer flow solutions. The present numerical study considers the convection-diffusion of two reacting species A and B, provided respectively by the two incoming solutions. The simulations show how the diffusion coefficient, flow rate and species concentration ratios influence, via the transversal diffusion length and reaction kinetics, the reaction extent at the end of the sandwich mixer. First, this extent can be enhanced up to 60% if the species with the lowest diffusion coefficient is located in the outer solutions where the flow velocity is small compared to that of the central part (higher residence time). Secondly, decreasing the outer flow rates (to confine the reaction close to the walls) and increasing the local concentration to keep the same flux ratio improve the extent by 300%. Comparison with a bi-lamination passive mixer, with an ideal mixer and an electro-osmotic driven flow mixer is presented. These conclusions are also demonstrated for consecutive reactions, showing an amplification of the effects described above. The results are also presented versus the residence time in the mixer-reactor to show the time window for which the gain is appreciable.


A prospective study of HIV-seropositive asymptomatic women of childbearing age in a developing country.
An observational study of 140 HIV-seropositive asymptomatic women of childbearing age was conducted in Haiti from 1984 to 1992 as part of a larger natural history study. Forty-four women were pregnant or became pregnant during the study period. The progression to HIV-related disease, AIDS, and mortality from AIDS was compared in the pregnant and nonpregnant cohorts. The mean follow-up time was 44 months. Overall, 32 of the 140 women (38%) developed AIDS, and 26 (19%) died from AIDS during the study period, with a cumulative AIDS incidence rate of 16% at 3 years after study entry. There was a trend toward earlier manifestation of HIV-related symptoms among the pregnant cohort, but no significant difference was observed in the rate of progression to AIDS or death between the pregnant and nonpregnant women.


Comparison of FilmArray and Quantitative Real-Time Reverse Transcriptase PCR for Detection of Zaire Ebolavirus from Contrived and Clinical Specimens.
Rapid, reliable, and easy-to-use diagnostic assays for detection of Zaire ebolavirus (ZEBOV) are urgently needed. The goal of this study was to examine the agreement among emergency use authorization (EUA) tests for the detection of ZEBOV nucleic acids, including the BioFire FilmArray BioThreat (BT) panel, the FilmArray BT-E panel, and the NP2 and VP40 quantitative real-time reverse transcriptase (qRT) PCR assays from the Centers for Disease Control and Prevention (CDC). Specimens used in this study included whole blood spiked with inactivated ZEBOV at known titers and whole-blood, plasma, and urine clinical specimens collected from persons diagnosed with Ebola virus disease (EVD). The agreement for FilmArray and qRT-PCR results using contrived whole-blood specimens was 100% (6/6 specimens) for each ZEBOV dilution from 4 × 10(7) to 4 × 10(2) 50% tissue culture infective dose (TCID50)/ml, as well as the no-virus negative-control sample. The limit of detection for FilmArray and qRT-PCR assays with inactivated ZEBOV, based on duplicate positive results, was determined to be 4 × 10(2) TCID50/ml. Rates of agreement between FilmArray and qRT-PCR results for clinical specimens from patients with EVD were 85% (23/27 specimens) for whole-blood specimens, 90% (18/20 specimens) for whole-blood specimens tested by FilmArray testing and matched plasma specimens tested by qRT-PCR testing, and 85% (11/13 specimens) for urine specimens. Among 60 specimens, eight discordant results were noted, with ZEBOV nucleic acids being detected only by FilmArray testing in four specimens and only by qRT-PCR testing in the remaining four specimens. These findings demonstrate that the rapid and easy-to-use FilmArray panels are effective tests for evaluating patients with EVD.


Objective physical activity accumulation in bouts and nonbouts and relation to markers of obesity in US adults.
Little is known about the relation between duration of physical activity and obesity. The objective of this study was to compare the effects of physical activity in bouts (> or = 10 minutes) to the effects of physical activity in nonbouts (<10 minutes) on markers of obesity. We used data from the 2003-2004 National Health and Nutrition Examination Survey on body mass index, waist circumference, and objectively determined physical activity levels for 3,250 adults aged 18 years or older. After controlling for relevant confounding variables, we performed multiple linear regression analyses to predict body mass index and waist circumference for bout and nonbout minutes of moderate- to vigorous-intensity physical activity (MVPA) and for bout and nonbout accelerometer counts of physical activity. MVPA bout minutes and MVPA nonbout minutes are independently associated with body mass index and waist circumference, after controlling for confounding variables. The strength of the association between lower body mass index and MVPA bout minutes (beta = -0.04, P <.001) was nearly 4 times greater than for MVPA nonbout minutes (beta = -0.01, P = .06). For smaller waist circumference the association was nearly 3 times greater for MVPA bout minutes (beta = -0.09, P <.001) than for MVPA nonbout minutes (beta = -0.03, P = .01). Bout minutes of physical activity were at a higher intensity of activity compared with nonbout minutes of physical activity. Accumulating MVPA in nonbouts may be a beneficial starting point for individuals to increase physical activity levels and decrease body mass index and waist circumference. However, bouts of physical activity lasting > or = 10 minutes may be a more time-efficient strategy to decrease body mass index and waist circumference.


Surgery-related posttraumatic stress disorder in parents of children undergoing cardiopulmonary bypass surgery: a prospective cohort study.
We aimed at evaluating surgery-related posttraumatic stress disorder (PTSD) in parents of children undergoing cardiopulmonary bypass surgery. Risk factors for parental PTSD symptoms were explored. A prospective cohort study was performed assessing PTSD symptoms immediately after discharge and 6 months after cardiopulmonary bypass surgery. Recruitment took place at a tertiary pediatric medical center in Switzerland. German-speaking parents of children with congenital heart defects aged between 0 and 16 yrs undergoing cardiopulmonary bypass surgery were eligible (n = 228). After child discharge, 135 mothers and 98 fathers of 139 children (response rate 61.0%) participated. Six months after surgery, 121 mothers and 92 fathers of 128 children (response rate, 56.1%) took part in the study. Assessment via a screening instrument and self-rating scale, and extraction of data from charts. The Posttraumatic Diagnostic Scale was applied to estimate self-reported symptoms of PTSD. Following discharge, 16.4% of mothers and 13.3% of fathers met diagnostic criteria for acute PTSD. Another 15.7% of mothers and 13.3% of fathers experienced significant symptoms of posttraumatic stress. Six months after surgery, PTSD rates were 14.9% and 9.5%, respectively. Mothers experienced more severe symptoms of PTSD, but gender differences were not detected with regard to the frequency of PTSD at either time. After controlling for socioeconomic status and child preoperative morbidity, PTSD symptom severity after discharge remained the only significant predictor of PTSD severity at 6 months. Pre-, peri-, and postoperative factors did not predict parental PTSD. Parents of children undergoing cardiopulmonary bypass surgery are at increased risk for intermediate and long-term psychological malfunctioning. Acute symptoms of PTSD in parents shortly after discharge of their child are a major risk factor for the development of chronic PTSD. Clinicians need to identify parents at risk at an early stage to provide them with systematic support.


Drug Interactions of Clinical Importance with Antihyperglycaemic Agents : An Update.
Because management of type 2 diabetes mellitus usually involves combined pharmacological therapy to obtain adequate glucose control and treatment of concurrent pathologies (especially dyslipidaemia and arterial hypertension), drugdrug interactions must be carefully considered with antihyperglycaemic drugs. Additive glucose-lowering effects have been extensively reported when combining sulphonylureas (or the new insulin secretagogues, meglitinide derivatives, i.e. nateglinide and repaglinide) with metformin, sulphonylureas (or meglitinide derivatives) with thiazolidinediones (also called glitazones) and the biguanide compound metformin with thiazolidinediones. Interest in combining α-glucosidase inhibitors with either sulphonylureas (or meglitinide derivatives), metformin or thiazolidinediones has also been demonstrated. These combinations result in lower glycosylated haemoglobin (HbA1c), fasting glucose and postprandial glucose levels than with either monotherapy. Even if modest pharmacokinetic interferences have been reported with some combinations, they do not appear to have important clinical consequences. No significant adverse effects, except a higher risk of hypoglycaemic episodes that may be attributed to better glycaemic control, occur with any combination. Challenging the classical dual therapy with sulphonylurea plus metformin, there is a recent trend to use alternative dual combinations (sulphonylurea plus thiazolidinedione or metformin plus thiazolidinedione). In addition, triple therapy with the addition of a thiazolidinedione to the metformin-sulphonylurea combination has been recently evaluated and allows glucose targets to be reached before insulin therapy is considered. This triple therapy appears to be safe, with no deleterious drug-drug interactions being reported so far.Potential interferences may also occur between glucose-lowering agents and other drugs, and such drug-drug interactions may have important clinical implications. Relevant pharmacological agents are those that are widely coadministered in diabetic patients (e.g. lipid-lowering agents, antihypertensive agents); those that have a narrow efficacy/toxicity ratio (e.g. digoxin, warfarin); or those that are known to induce (rifampicin [rifampin]) or inhibit (fluconazole) the cytochrome P450 (CYP) system. Metformin is currently a key compound in the pharmacological management of type 2 diabetes, used either alone or in combination with other antihyperglycaemics. There are no clinically relevant metabolic interactions with metformin, because this compound is not metabolised and does not inhibit the metabolism of other drugs. In contrast, sulphonylureas, meglitinide derivatives and thiazolidinediones are extensively metabolised in the liver via the CYP system and thus, may be subject to drug-drug metabolic interactions. Many HMGCoA reductase inhibitors (statins) are also metabolised via the CYP system. Even if modest pharmacokinetic interactions may occur, it is not clear whether drugdrug interactions between oral antihyperglycaemic agents and statins may have clinical consequences regarding both efficacy and safety. In contrast, a marked pharmacokinetic interference has been reported between gemfibrozil and repaglinide and, to a lesser extent, between gemfibrozil and rosiglitazone. This leads to a drastic increase in plasma concentrations of each antihyperglycaemic agent when they are coadministered with the fibric acid derivative, and an increased risk of adverse effects.Some antihypertensive agents may favour hypoglycaemic episodes when coprescribed with sulphonylureas or meglitinide derivatives, especially ACE inhibitors, but this effect seems to result from a pharmacodynamic drug-drug interaction rather than from a pharmacokinetic drug-drug interaction. No, or only modest, interferences have been described with glucose-lowering agents and other pharmacological compounds such as digoxin or warfarin. The effects of inducers or inhibitors of CYP isoenzymes on the metabolism and pharmacokinetics of the glucose-lowering agents of each pharmacological class has been tested. Significantly increased (with CYP inhibitors) or decreased (with CYP inducers) plasma levels of sulphonylureas, meglitinide derivatives and thiazolidinediones have been reported in healthy volunteers, and these pharmacokinetic changes may lead to enhanced or reduced glucose-lowering action, and thus hypoglycaemia or worsening of metabolic control, respectively. In addition, some case reports have evidenced potential drug-drug interactions with various antihyperglycaemic agents that are usually associated with a higher risk of hypoglycaemia.


Deep learning for cardiovascular medicine: a practical primer.
Deep learning (DL) is a branch of machine learning (ML) showing increasing promise in medicine, to assist in data classification, novel disease phenotyping and complex decision making. Deep learning is a form of ML typically implemented via multi-layered neural networks. Deep learning has accelerated by recent advances in computer hardware and algorithms and is increasingly applied in e-commerce, finance, and voice and image recognition to learn and classify complex datasets. The current medical literature shows both strengths and limitations of DL. Strengths of DL include its ability to automate medical image interpretation, enhance clinical decision-making, identify novel phenotypes, and select better treatment pathways in complex diseases. Deep learning may be well-suited to cardiovascular medicine in which haemodynamic and electrophysiological indices are increasingly captured on a continuous basis by wearable devices as well as image segmentation in cardiac imaging. However, DL also has significant weaknesses including difficulties in interpreting its models (the 'black-box' criticism), its need for extensive adjudicated ('labelled') data in training, lack of standardization in design, lack of data-efficiency in training, limited applicability to clinical trials, and other factors. Thus, the optimal clinical application of DL requires careful formulation of solvable problems, selection of most appropriate DL algorithms and data, and balanced interpretation of results. This review synthesizes the current state of DL for cardiovascular clinicians and investigators, and provides technical context to appreciate the promise, pitfalls, near-term challenges, and opportunities for this exciting new area.


LAT, the linker for activation of T cells: a bridge between T cell-specific and general signaling pathways.
A key event in the regulation of the adaptive immune response is the binding of major histocompatibility complex-bound foreign peptides to T cell antigen receptors (TCRs) that are present on the cell surface of T lymphocytes. Recognition of the presence of cognate antigen in the host animal induces a series of biochemical changes within the T cell; these changes, in the context of additional signals from other surface receptors, ultimately result in massive proliferation of receptor-engaged T cells and the acquisition of effector and memory functions. Early studies established the importance of the activation of the enzymes phospholipase C-gamma1 (PLC-gamma1) and phosphatidylinositol 3-kinase (PI3K), as well as the small molecular weight heterotrimeric guanine nucleotide binding protein (G protein) Ras, in this process. These biochemical events are dependent on the activity of several protein tyrosine kinases that become activated immediately upon TCR engagement. An unresolved question in the field has been which molecules and what sequence of events tie together the early tyrosine phosphorylation events with the activation of these downstream signaling molecules. A likely candidate for linking the proximal and distal portions of the TCR signaling pathway is the recently described protein, LAT. LAT is a 36-kD transmembrane protein that becomes rapidly tyrosine-phosphorylated after TCR engagement. Phosphorylation of LAT creates binding sites for the Src homology 2 (SH2) domains of other proteins, including PLC-gamma1, Grb2, Gads, Grap, 3BP2, and Shb, and indirectly binds SOS, c-Cbl, Vav, SLP-76, and Itk. LAT is localized to the glycolipid-enriched membrane (GEM) subdomains of the plasma membrane by virtue of palmitoylation of two cysteine residues positioned near the endofacial side of the plasma membrane. Notably, in the absence of LAT, TCR engagement does not lead to activation of distal signaling events. This review examines the circumstances surrounding the discovery of LAT and our current understanding of its properties, and discusses current models for how LAT may be functioning to support the transduction of TCR-initiated, T cell-specific signaling events to the distal, general signaling machinery.


Renewable energy targets and unintended storage cycling: Implications for energy modeling.
To decarbonize the economy, many governments have set targets for the use of renewable energy sources. These are often formulated as relative shares of electricity demand or supply. Implementing respective constraints in energy models is a surprisingly delicate issue. They may cause a modeling artifact of excessive electricity storage use. We introduce this phenomenon as "unintended storage cycling", which can be detected in case of simultaneous storage charging and discharging. In this paper, we provide an analytical representation of different approaches for implementing minimum renewable share constraints in energy models, and show how these may lead to unintended storage cycling. Using a parsimonious optimization model, we quantify related distortions of optimal dispatch and investment decisions as well as market prices, and identify important drivers of the phenomenon. Finally, we provide recommendations on how to avoid the distorting effects of unintended storage cycling in energy modeling.


Scientists and religious leaders compete for cultural authority of science.
Measurement of public trust in sources of information about science primarily examines whether the public turns to the "science communication industry" for information about science. Research posits, however, that scientists are not the singular cultural authority on science. Here, we examine the extent to which people turn to religion and religious individuals for information about science. Drawing on a nationally representative survey of US adults, we examine what factors-when individuals have a question about science-shape respondent's likelihood of turning to science-based versus religion-based sources. Results show that religiosity is a strong positive predictor of looking to religious sources for scientific information, but it does not deter seeking out scientific sources. The results also show that interest in science has a positive influence on the likelihood of turning to a religious source.


Transcriptional regulatory circuits: predicting numbers from alphabets.
Transcriptional regulatory circuits govern how cis and trans factors transform signals into messenger RNA (mRNA) expression levels. With advances in quantitative and high-throughput technologies that allow measurement of gene expression state in different conditions, data that can be used to build and test models of transcriptional regulation is being generated at a rapid pace. Here, we review experimental and computational methods used to derive detailed quantitative circuit models on a small scale and cruder, genome-wide models on a large scale. We discuss the potential of combining small- and large-scale approaches to understand the working and wiring of transcriptional regulatory circuits.


Targeting HIV interventions for adolescent girls and young women in Southern Africa: use of the PLACE methodology in Hwange District, Zimbabwe.
This paper addresses the issue of how to target interventions to girls 15-19 and young women 20-24 in a resource poor setting of Hwange District, Zimbabwe. The Priorities for Local AIDS Control efforts methodology was used to understand where these young people socialize and also to understand whether age disparate relationships were a common occurrence. Findings indicated prevention efforts for those 15-19 would need to focus on "everyday" sites as these are the places where the majority of girls socialized. However, the girls 15-19 with the riskiest sexual behaviors were found at venues affiliated with alcohol. Prevention efforts for those 20-24 would also need to largely focus on venues affiliated with alcohol. Women at such sites generally reported more risky behaviors than women in other types of venues. Reporting of a partner 5 or more years older was common across age groups and across venues. Tackling HIV in Zimbabwe will take a multifaceted approach targeted towards the places girls 15-19 and young women 20-24 are meeting new partners.


Collective behavior in the spatial spreading of obesity.
Obesity prevalence is increasing in many countries at alarming levels. A difficulty in the conception of policies to reverse these trends is the identification of the drivers behind the obesity epidemics. Here, we implement a spatial spreading analysis to investigate whether obesity shows spatial correlations, revealing the effect of collective and global factors acting above individual choices. We find a regularity in the spatial fluctuations of their prevalence revealed by a pattern of scale-free long-range correlations. The fluctuations are anomalous, deviating in a fundamental way from the weaker correlations found in the underlying population distribution indicating the presence of collective behavior, i.e., individual habits may have negligible influence in shaping the patterns of spreading. Interestingly, we find the same scale-free correlations in economic activities associated with food production. These results motivate future interventions to investigate the causality of this relation providing guidance for the implementation of preventive health policies.


Clinical, laboratory and pathological findings in cats experimentally infected with Aelurostrongylus abstrusus.
Aelurostrongylus abstrusus parasitizes the respiratory tract and can heavily affect the breathing and general condition of cats. Experimental infections of six cats were initiated by intragastric administration with 100 or 800 third-stage larvae (L3) obtained from the terrestrial snail Helix aspersa. First-stage larvae were isolated from faecal samples after 35-41 days post infection (dpi) in five animals and until end of study (84 dpi) in two cats. Cough and respiratory sounds were observed starting from 28 to 41 dpi and dyspnoea and panting starting from 52 dpi. All cats had enlarged lymph nodes and, starting from 56 dpi, reduced body weight, and four cats showed intermittent reduced general condition with apathia and anorexia. Eosinophilia and leucocytosis partially with massive lymphocytosis, and occasional basophilia and monocytosis were observed. Mild anaemia was present in five cats, while alterations in coagulation parameters suggested stimulation of the coagulation cascade with increased consumption of coagulation factors (delayed PT, hypofibrinogenemia). Adult A. abstrusus specimens were isolated from the five patent cats at necropsy and all six cats showed pathological changes in the lungs, including disseminated inflammatory cell infiltrates, often associated with incorporated larvae and eggs. There was some degree of overlap between the severity and the inoculation doses. Infections starting from 100 L3 of A. abstrusus had an impact on the lung tissues and on the health of the cats, despite the presence of only mild haematological abnormalities. Due to the worldwide occurrence of feline lung worms, parasitic infections should be considered in the differential diagnosis of lung diseases regardless of the presence of clinical signs and larval excretion.


Postsurgical inflammatory neuropathy.
Perioperative nerve injuries are devastating complications that are commonly attributed to a variety of patient, surgical, or anesthetic factors. Well-documented causes of postsurgical neuropathy include nerve compression, stretch, contusion, or transection, which can occur following surgical trauma or patient positioning. Potential anesthetic causes of perioperative nerve injury include mechanical trauma, local anesthetic toxicity, and ischemic injury. We present a case of a diffuse, bilateral neurologic deficit of unclear etiology in a patient who underwent a combined neuraxial-general anesthetic for bilateral total hip arthroplasty. A 17-year old boy with end-stage Legg-Perthes disease presented with severe lower-extremity neuropathy of both legs following bilateral total hip arthroplasty under combined epidural-general anesthesia. A thorough workup excluded potentially devastating and treatable causes, including epidural hematoma or abscess and surgical bleeding or trauma. A neurology consultation and further testing (electromyography, nerve biopsy) resulted in a diagnosis of postsurgical inflammatory neuropathy. Treatment with prolonged, high-dose corticosteroids was undertaken, and although the patient's symptoms improved, he continues to have significant neurologic deficits 8 months after surgery. Perioperative nerve deficits not readily explained by direct surgical or anesthesia-related causes should prompt early neurologic consultation to seek alternative etiologies such as postsurgical inflammatory neuropathy. Although this condition is poorly understood, it is believed to be an idiopathic immune-mediated response to a physiologic stress (eg, surgery, regional block) and is treated with prolonged, high-dose corticosteroids. Because suppression of the immune system with high-dose steroids may result in improved neurologic outcome, it is essential that surgeons and anesthesiologists are aware of this condition so that treatment is not delayed.


Role of budget impact in drug reimbursement decisions.
There are three known criteria that underlie drug reimbursement decisions: therapeutic value, cost-effectiveness, and burden of disease. However, evidence from recent reimbursement decisions in several jurisdictions points to residual, unexplained variables, among which is budget impact. Budget impact refers to the total costs that drug reimbursement and use entail with respect to one part of the health care system, pharmaceutical care, or to the entire health care system, taking into account the possible reallocation of resources across budgets or sectors of the health care system. The economic and equity rationale for carrying out budget impact analyses is opportunity cost, or benefits forgone, measured in terms of utility or equitable distribution, by using resources in one way rather than another. In other words, by choosing to draw down the budget in one way, decision makers forgo other opportunities to use the same resources. Under a set of unrealistic assumptions, cost-effectiveness analysis accounts for opportunity cost while conveying to the decision maker the price of maximizing health gains, subject to a budget or resource constraint. However, the underlying assumptions are implausible, particularly in the context of pharmaceutical care. Moreover, budget impact analysis is more useful to the decision maker than cost-effectiveness analysis if the objective is not to maximize health gains subject to a budget or resource constraint, but to reduce variance in health gains. With respect to equitable distribution, budget impact analyses lay bare the individuals or groups who lose out - those who bear the opportunity cost of spending resources in accordance with one decision rule rather than another.


An unusual effect of interferential therapy.
In this report, a patient with severe shoulder pain was treated with interferential currents, a commonly used modality in physiotherapy for the management of pain. He reported loss of concentration, drowsiness, decreased alertness and gait disturbance, along with analgaesia, for 4-5 h after each treatment. He was regularly taking tramadol HCl for pain relief. Endogenous opioids produced in response to interferential therapy may be excessive or may interact with the tramadol HCl and potentiate its effect. There is no published report of interferential-induced symptoms, as described above, in the authors' knowledge. The clinician using interferential currents should be aware of this possible effect.


Paired Trial Classification: A Novel Deep Learning Technique for MVPA.
Many recent developments in machine learning have come from the field of "deep learning," or the use of advanced neural network architectures and techniques. While these methods have produced state-of-the-art results and dominated research focus in many fields, such as image classification and natural language processing, they have not gained as much ground over standard multivariate pattern analysis (MVPA) techniques in the classification of electroencephalography (EEG) or other human neuroscience datasets. The high dimensionality and large amounts of noise present in EEG data, coupled with the relatively low number of examples (trials) that can be reasonably obtained from a sample of human subjects, lead to difficulty training deep learning models. Even when a model successfully converges in training, significant overfitting can occur despite the presence of regularization techniques. To help alleviate these problems, we present a new method of "paired trial classification" that involves classifying pairs of EEG recordings as coming from the same class or different classes. This allows us to drastically increase the number of training examples, in a manner akin to but distinct from traditional data augmentation approaches, through the combinatorics of pairing trials. Moreover, paired trial classification still allows us to determine the true class of a novel example (trial) via a "dictionary" approach: compare the novel example to a group of known examples from each class, and determine the final class via summing the same/different decision values within each class. Since individual trials are noisy, this approach can be further improved by comparing a novel individual example with a "dictionary" in which each entry is an average of several examples (trials). Even further improvements can be realized in situations where multiple samples from a single unknown class can be averaged, thus permitting averaged signals to be compared with averaged signals.