Air Force disaster response: Haiti experience.
After the devastating earthquake in Haiti, the United States Air Force deployed multiple medical units as part of the disaster response. Air Force Special Operations Command medical teams provided initial medical response and assisted in the organization of medical assets. A small portable expeditionary aeromedical rapid response team with the assistance of a mobile aeromedical staging facility team stabilized patients for flight and coordinated air evacuation to the United States. An expeditionary medical support hospital was set up and assisted in patient movement to and from the USNS Comfort hospital ship. These units were able to adapt to the unique circumstances in Haiti and provide great patient care. The lessons learned from these experiences may help the United States better respond to future disasters.


A brief, standardized tool for measuring HIV-related stigma among health facility staff: results of field testing in China, Dominica, Egypt, Kenya, Puerto Rico and St. Christopher & Nevis.
Within healthcare settings, HIV-related stigma is a recognized barrier to access of HIV prevention and treatment services and yet, few efforts have been made to scale-up stigma reduction programs in service delivery. This is in part due to the lack of a brief, simple, standardized tool for measuring stigma among all levels of health facility staff that works across diverse HIV prevalence, language and healthcare settings. In response, an international consortium led by the Health Policy Project, has developed and field tested a stigma measurement tool for use with health facility staff. Experts participated in a content-development workshop to review an item pool of existing measures, identify gaps and prioritize questions. The resulting questionnaire was field tested in six diverse sites (China, Dominica, Egypt, Kenya, Puerto Rico and St. Christopher & Nevis). Respondents included clinical and non-clinical staff. Questionnaires were self- or interviewer-administered. Analysis of item performance across sites examined both psychometric properties and contextual issues. The key outcome of the process was a substantially reduced questionnaire. Eighteen core questions measure three programmatically actionable drivers of stigma within health facilities (worry about HIV transmission, attitudes towards people living with HIV (PLHIV), and health facility environment, including policies), and enacted stigma. The questionnaire also includes one short scale for attitudes towards PLHIV (5-item scale, α=0.78). Stigma-reduction programmes in healthcare facilities are urgently needed to improve the quality of care provided, uphold the human right to healthcare, increase access to health services, and maximize investments in HIV prevention and treatment. This brief, standardized tool will facilitate inclusion of stigma measurement in research studies and in routine facility data collection, allowing for the monitoring of stigma within healthcare facilities and evaluation of stigma-reduction programmes. There is potential for wide use of the tool either as a stand-alone survey or integrated within other studies of health facility staff.


Trends in Nonoperative Treatment Modalities Prior to Cervical Surgery and Impact on Patient-Derived Outcomes: Two-Year Analysis of 1522 Patients From the Prospective Spine Treatment Outcome Study.
Effects of nonoperative treatments on surgical outcomes for patients who failed conservative management for cervical spine pathologies remain unknown. The objective is to describe conservative modality use in patients indicated for surgery for degenerative cervical spine conditions and its impact on perioperative outcomes. The current study comprises a retrospective review of a prospective multicenter database. A total of 1522 patients with 1- to 2-level degenerative cervical pathology who were undergoing surgical intervention were included. Outcome measures used were health-related quality-of-life scores, length of hospitalization, estimated blood loss, length of surgery, and return-to-work status at 2 weeks, 6 months, 1 year, and 2 years postoperatively. Patients were grouped by diagnosis (radiculopathy vs. myelopathy), then divided based on epidural injection(s), physical therapy (PT), or opioid use prior to enrollment. Univariate t-tests and χ2 tests were performed to determine differences between groups and impact on outcomes. Among 1319 radiculopathy patients, 25.7% received preoperative epidural injections, 35.3% received PT, and 35.5% received opioids. Radiculopathy patients who received epidurals and PT had higher 1-year postoperative return-to-work rates (P < .05). Radiculopathy patients without preoperative PT had longer hospitalization times, whereas those who received PT had higher 36-Item Short Form Health Survey (SF-36) physical functioning and physical component scores, lower 2-year visual analog scale (VAS) neck/arm pain scores, and higher 2-year return-to-work incidence (P < .05). Of myelopathy patients (n = 203), 14.8% received epidural injections, 25.1% received opioids, and 41.5% received PT. Myelopathy patients with preoperative PT had worse VAS arm pain scores 2 years postoperatively (P < .05). Patients receiving opioids were younger and had greater baseline-2-year Neck Disability Index improvement (P < .05). Radiculopathy patients receiving epidurals returned to work after 1 year more frequently. PT was associated with shorter hospitalizations, greater SF-36 bodily pain norm and physical component score improvements, and increased return-to-work rates after 1 and 2 years. No statistically significant nonoperative treatment was associated with return-to-work rate in myelopathy patients. These findings suggest certain preoperative conservative treatment modalities are associated with improved outcomes in radiculopathy patients.


Epidemiology of central nervous system infectious diseases: a meta-analysis and systematic review with implications for neurosurgeons worldwide.
Central nervous system (CNS) infections cause significant morbidity and mortality and often require neurosurgical intervention for proper diagnosis and treatment. However, neither the international burden of CNS infection, nor the current capacity of the neurosurgical workforce to treat these diseases is well characterized. The objective of this study was to elucidate the global incidence of surgically relevant CNS infection, highlighting geographic areas for targeted improvement in neurosurgical capacity. A systematic literature review and meta-analysis were performed to capture studies published between 1990 and 2016. PubMed, EMBASE, and Cochrane databases were searched using variations of terms relating to CNS infection and epidemiology (incidence, prevalence, burden, case fatality, etc.). To deliver a geographic breakdown of disease, results were pooled using the random-effects model and stratified by WHO region and national income status for the different CNS infection types. The search yielded 10,906 studies, 154 of which were used in the final qualitative analysis. A meta-analysis was performed to compute disease incidence by using data extracted from 71 of the 154 studies. The remaining 83 studies were excluded from the quantitative analysis because they did not report incidence. A total of 508,078 cases of CNS infections across all studies were included, with a total sample size of 130,681,681 individuals. Mean patient age was 35.8 years (range: newborn to 95 years), and the male/female ratio was 1:1.74. Among the 71 studies with incidence data, 39 were based in high-income countries, 25 in middle-income countries, and 7 in low-income countries. The pooled incidence of studied CNS infections was consistently highest in low-income countries, followed by middle- and then high-income countries. Regarding WHO regions, Africa had the highest pooled incidence of bacterial meningitis (65 cases/100,000 people), neurocysticercosis (650/100,000), and tuberculous spondylodiscitis (55/100,000), whereas Southeast Asia had the highest pooled incidence of intracranial abscess (49/100,000), and Europe had the highest pooled incidence of nontuberculous vertebral spondylodiscitis (5/100,000). Overall, few articles reported data on deaths associated with infection. The limited case fatality data revealed the highest case fatality for tuberculous meningitis/spondylodiscitis (21.1%) and the lowest for neurocysticercosis (5.5%). In all five disease categories, funnel plots assessing for publication bias were asymmetrical and suggested that the results may underestimate the incidence of disease. This systematic review and meta-analysis approximates the global incidence of neurosurgically relevant infectious diseases. These results underscore the disproportionate burden of CNS infections in the developing world, where there is a tremendous demand to provide training and resources for high-quality neurosurgical care.


Analysis of the population genetic structure of the malaria vector Anopheles sinensis in South Korea based on mitochondrial sequences.
The population genetics of Anopheles sinensis, a major malaria vector in South Korea, was studied based on the nucleotide sequences of a 238-bp variable region of the mitochondrial control region. Three features of genetic variance were observed. First, the Taebaek and Sobaek mountain ranges may function as genetic barriers between the Northern Group (NG) and the Southern Group (SG). These mountain ranges are associated with the subdivision of the population, and significant and unique population differentiation was observed in the examined area. Second, the genetic cohesiveness observed within each group may have been caused by a recent expansion in the population rather than recurrent gene flow. Third, a marked dissimilarity in the genetic diversity between the two groups may also have resulted from several factors that caused a difference in the effective population sizes.


Deep anterior lamellar keratoplasty versus penetrating keratoplasty for treating keratoconus.
Keratoconus is an ectatic (weakening) disease of the cornea, which is the clear surface at the front of the eye. Approximately 10% to 15% of patients diagnosed with keratoconus require corneal transplantation. This may be full-thickness (penetrating) or partial-thickness (lamellar). To compare visual outcomes after deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty for keratoconus, and to compare additional outcomes relating to factors which may contribute to poor visual outcomes (e.g. astigmatism, graft rejection and failure). We searched a number of electronic databases including CENTRAL, PubMed and EMBASE without using any date or language restrictions. We last searched the electronic databases on 31 October 2013. We also handsearched the proceedings of several international ophthalmic conferences. We included all randomised controlled trials (RCTs) comparing the outcomes of DALK and penetrating keratoplasty in the treatment of keratoconus. Two authors assessed trial quality and extracted data independently. For dichotomous data (graft failure, rejection, achievement of functional vision) results were expressed as odds ratios (ORs) and 95% confidence intervals (CIs). For continuous data (postoperative best corrected visual acuity (BCVA), uncorrected visual acuity (UCVA), keratometric astigmatism and spherical equivalent) results were expressed as mean differences (MDs) and 95% CIs. We identified two completed studies, with a total of 111 participants (n = 30 and n = 81), both conducted in Iran, that met our inclusion criteria. Participants had moderate to severe keratoconus pre-operatively and were randomly allocated to receive either DALK or penetrating keratoplasty. Only one eye of each participant was treated as part of the trials. The smaller study had 12 month follow-up data for all participants. For the larger study, four DALK surgeries had to be abandoned due to technical failure and visual and refractive outcomes were not measured in these participants. Follow-up length for the remaining 77 participants ranged from 6.8 to 36.4 months, with all 77 followed for at least three months post-suture removal. Details of the randomisation procedure were unavailable for the smaller study and so sensitivity analyses were conducted to determine if the results from this study had affected the overall results of the review.Neither of the included studies reported a difference between groups on any of the measures of post-graft visual achievement, keratometric astigmatism or spherical equivalent. A single case of graft failure in a penetrating keratoplasty was reported. No postoperative graft failures were reported in the DALK group of either study.Instances of graft rejection were reported in both groups, in both studies. The majority of these cases were successfully treated with steroids. The data, which related to all cases in each study - given that the four cases that did not go ahead as planned had already technically failed without presence of rejection - showed that rejection was less likely to occur in DALK (odds ratio (OR): 0.33, 95% confidence interval (CI) 0.14 to 0.81, GRADE rating: moderate).Results of the sensitivity analysis indicated that inclusion of the Razmju 2011 study did not bias the results with regards to rejection episodes. While sensitivity analysis showed altered results with regards to failure rates, the data available from the Javadi 2010 study alone had a very wide 95% CI, suggesting an imprecise estimate. Therefore, even after removal of the Razmju 2011 data, it is still difficult to draw conclusions regarding superiority of one technique over another with regards to graft failure.DALK was unable to be completed as planned in four cases and in a further three cases, complications during dissection required further intervention. Other adverse events, of varying severity, were reported in both intervention groups with similar frequency. For both types of surgery, these included postoperative astigmatism, steroid induced ocular hypertension and persistent epithelial defects. In recipients of DALK, one participant had interface neovascularisation (a proliferation of blood vessels where the host and donor cornea come together) and one had wrinkling of Descemet's membrane, the basement membrane separating the corneal stroma from the corneal endothelium. In the penetrating keratoplasty groups, one participant required graft resuturing and one had an atonic pupil, a condition in which the pupil dilates and is non-reactive.Overall, the quality of the evidence was rated as very low to moderate, with methodological limitations, incomplete data analysis and imprecision of findings, as well as high risk of bias in several areas for both studies. We found no evidence to support a difference in outcomes with regards to BCVA at three months post-graft or at any of the other time points analysed (GRADE rating: very low). We also found no evidence of a difference in outcomes with regards to graft survival, final UCVA or keratometric outcomes. We found some evidence that rejection is more likely to occur following penetrating keratoplasty than DALK (GRADE rating: moderate). The small number of studies included in the review and methodological issues relating to the two, mean that the overall quality of the evidence in this review is low. There is currently insufficient evidence to determine which technique may offer better overall outcomes - final visual acuity and time to attain this, keratometric stabilisation, risk of rejection or failure, or both, and risk of other adverse events - for patients with keratoconus. Large randomised trials comparing the outcomes of penetrating keratoplasty and DALK in the treatment of keratoconus are needed.


Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA.
Tumor genotyping using cell-free plasma DNA (cfDNA) has the potential to allow noninvasive assessment of tumor biology, yet many existing assays are cumbersome and vulnerable to false-positive results. We sought to determine whether droplet digital PCR (ddPCR) of cfDNA would allow highly specific and quantitative assessment of tumor genotype. ddPCR assays for EGFR, KRAS, and BRAF mutations were developed using plasma collected from patients with advanced lung cancer or melanoma of a known tumor genotype. Sensitivity and specificity were determined using cancers with nonoverlapping genotypes as positive and negative controls. Serial assessment of response and resistance was studied in patients with EGFR-mutant lung cancer on a prospective trial of erlotinib. We identified a reference range for EGFR L858R and exon 19 deletions in specimens from KRAS-mutant lung cancer, allowing identification of candidate thresholds with high sensitivity and 100% specificity. Received operative characteristic curve analysis of four assays demonstrated an area under the curve in the range of 0.80 to 0.94. Sensitivity improved in specimens with optimal cfDNA concentrations. Serial plasma genotyping of EGFR-mutant lung cancer on erlotinib demonstrated pretreatment detection of EGFR mutations, complete plasma response in most cases, and increasing levels of EGFR T790M emerging before objective progression. Noninvasive genotyping of cfDNA using ddPCR demonstrates assay qualities that could allow effective translation into a clinical diagnostic. Serial quantification of plasma genotype allows noninvasive assessment of response and resistance, including detection of resistance mutations up to 16 weeks before radiographic progression.


Examining the Overlap between Autism Spectrum Disorder and 22q11.2 Deletion Syndrome.
22q11.2 deletion syndrome (22q11.2DS) is a genomic disorder reported to associate with autism spectrum disorders (ASDs) in 15-50% of cases; however, others suggest that individuals with 22q11.2DS present psychiatric or behavioral features associated with ASDs, but do not meet full criteria for ASD diagnoses. Such wide variability in findings may arise in part due to methodological differences across studies. Our study sought to determine whether individuals with 22q11.2DS meet strict ASD diagnostic criteria using research-based guidelines from the Collaborative Programs of Excellence in Autism (CPEA), which required a gathering of information from three sources: the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic Observational Schedule (ADOS), and a clinician's best-estimate diagnosis. Our study examined a cohort of children, adolescents, and young adults (n = 56) with 22q11.2DS, who were ascertained irrespective of parents' behavioral or developmental concerns, and found that 17.9% (n = 10) of the participants met CPEA criteria for an ASD diagnosis, and that a majority showed some level of social-communication impairment or the presence of repetitive behaviors. We conclude that strictly defined ASDs occur in a substantial proportion of individuals with 22q11.2DS, and recommend that all individuals with 22q11.2DS be screened for ASDs during early childhood.


Health profile and disease determinants among asylum seekers: a cross-sectional retrospective study from an Italian reception centre.
Data on diseases' determinants and health status of asylum seekers (ASs) are limited. We performed a cross-sectional retrospective study in a large ASs centre in Italy. Data were collected during a 1-year period. Descriptive statistics were calculated. A χ(2) test was used to assess the association between socio-demographics characteristics of ASs and screening test results. A multiple logistic regression analysis was performed to identify diseases' predictors by using ICD-10 diagnoses classification as outcome variable, socio-demographic characteristics as independent variable and visits' number as confounding variable. Overall, data on 792 ASs (mean age 27 years, 80% males, 58% from Africa) were assessed, 43% underwent voluntary infectious diseases screening and 2843 diagnoses were recorded. The most frequent diagnoses were: respiratory diseases, symptoms/signs not elsewhere classified, digestive diseases and infectious diseases. Gender was the most frequent predictor of ICD-10 diagnoses, while African origin, civil status and education were, respectively, predictive of cardiovascular and infectious diseases, genitourinary diseases and pregnancy-related disorders. Higher mean age was associated with syphilis, HIV and HCV infection and African origin with HIV infection. Communicable diseases were not prevalent in the ASs population we analysed. A stronger cultural mediation support is needed to facilitate prevention, access and continuity of care for ASs.


Clinical Outcomes Of Descemet Membrane Endothelial Keratoplasty Using The Bonfadini-Todd Injector For Graft Insertion.
To evaluate the clinical outcomes of using an Alcon intraocular lens (IOL) B cartridge for graft insertion during Descemet membrane endothelial keratoplasty (DMEK). We retrospectively reviewed medical charts of patients who underwent DMEK using the Bonfadini-Todd injector, composed of an Alcon IOL B cartridge connected to plastic tubing and a syringe, for graft insertion between May 2016 and August 2018. Patient demographics, diagnoses, donor information, visual acuity, intraocular pressure (IOP), graft position and attachment status, pachymetry, and postoperative complications were recorded. Twenty-four eyes of 23 patients with an average age of 72.8 ± 10.0 years (range, 48-87 years) were included. Mean follow-up duration was 13.3 ± 6.6 months (range, 3-26 months). Twenty-one (87.5%) patients had a primary diagnosis of Fuchs endothelial dystrophy, two (8.3%) patients had bullous keratopathy and one (4.2%) had Peter's anomaly. Sixteen (66.7%) cases combined phacoemulsification and IOL implantation. Best-corrected visual acuity improved from a median of 0.398 logMAR preoperatively to 0.097 logMAR (P <0.001) at last follow-up examination, and central corneal thickness decreased from a median of 651 μm to 533.5 μm (P <0.001). Nine of 24 patients (37.5%) required re-bubbling due to partial graft detachment with a mean time of 12.1 ± 9.2 days (range, 5-35 days). One patient (4.2%) developed graft failure after re-bubbling and underwent Descemet stripping endothelial keratoplasty. The Alcon IOL B cartridge for DMEK graft insertion is safe and simple.


Trans-heteroclinic bifurcation: a novel type of catastrophic shift.
Global and local bifurcations are extremely important since they govern the transitions between different qualitative regimes in dynamical systems. These transitions or tipping points, which are ubiquitous in nature, can be smooth or catastrophic. Smooth transitions involve a continuous change in the steady state of the system until the bifurcation value is crossed, giving place to a second-order phase transition. Catastrophic transitions involve a discontinuity of the steady state at the bifurcation value, giving place to first-order phase transitions. Examples of catastrophic shifts can be found in ecosystems, climate, economic or social systems. Here we report a new type of global bifurcation responsible for a catastrophic shift. This bifurcation, identified in a family of quasi-species equations and named as trans-heteroclinic bifurcation, involves an exchange of stability between two distant and heteroclinically connected fixed points. Since the two fixed points interchange the stability without colliding, a catastrophic shift takes place. We provide an exhaustive description of this new bifurcation, also detailing the structure of the replication-mutation matrix of the quasi-species equation giving place to this bifurcation. A perturbation analysis is provided around the bifurcation value. At this value the heteroclinic connection is replaced by a line of fixed points in the quasi-species model. But it is shown that, if the replication-mutation matrix satisfies suitable conditions, then, under a small perturbation, the exchange of heteroclinic connections is preserved, except on a tiny range around the bifurcation value whose size is of the order of magnitude of the perturbation. The results presented here can help to understand better novel mechanisms behind catastrophic shifts and contribute to a finer identification of such transitions in theoretical models in evolutionary biology and other dynamical systems.


A database of geopositioned onchocerciasis prevalence data.
Onchocerciasis is a neglected tropical disease with numerous symptoms and side effects, and when left untreated can lead to permanent blindness or skin disease. This database is an attempt to combine onchocerciasis prevalence data from peer-reviewed publications into a single open-source dataset. The process followed to extract and format the information has been detailed in this paper. A total of 14,043 unique location, diagnostic, age and sex-specific records from 1975-2017 have been collected, organized and marked for collapse where a single geo-position is shared between multiple records. The locations vary from single villages up to smaller administrative units and onchocerciasis control program-defined foci. This resulting database can be used to by the global health community to advance understanding of the distribution of onchocerciasis infection and disease.


Development of haemostatic decontaminants for the treatment of wounds contaminated with chemical warfare agents. 2: evaluation of in vitro topical decontamination efficacy using undamaged skin.
The risk of penetrating, traumatic injury occurring in a chemically contaminated environment cannot be discounted. Should a traumatic injury be contaminated with a chemical warfare (CW) agent, it is likely that standard haemostatic treatment options would be complicated by the need to decontaminate the wound milieu. Thus, there is a need to develop haemostatic products that can simultaneously arrest haemorrhage and decontaminate CW agents. The purpose of this study was to evaluate a number of candidate haemostats for efficacy as skin decontaminants against three CW agents (soman, VX and sulphur mustard) using an in vitro diffusion cell containing undamaged pig skin. One haemostatic product (WoundStat™) was shown to be as effective as the standard military decontaminants Fuller's earth and M291 for the decontamination of all three CW agents. The most effective haemostatic agents were powder-based and use fluid absorption as a mechanism of action to sequester CW agent (akin to the decontaminant Fuller's earth). The envisaged use of haemostatic decontaminants would be to decontaminate from within wounds and from damaged skin. Therefore, WoundStat™ should be subject to further evaluation using an in vitro model of damaged skin.


Regulation of sialoadhesin expression on rat macrophages. Induction by glucocorticoids and enhancement by IFN-beta, IFN-gamma, IL-4, and lipopolysaccharide.
Sialoadhesin is a macrophage-restricted member of the Ig superfamily that mediates adhesion with lymphoid and myeloid cells. It is expressed on a subpopulation of macrophages in lymphoid tissues and in chronic inflammation (e.g., during autoimmune diseases). We have studied the regulation of sialoadhesin expression in vitro and show that glucocorticoids (GC) induce sialoadhesin expression on freshly isolated rat macrophages and the rat macrophage cell line R2. The cytokines IFN-beta, IFN-gamma, IL-4, and LPS, although unable to induce sialoadhesin expression by themselves, were able to enhance GC-mediated induction of sialoadhesin. Sialoadhesin expression was functional as shown by cell adhesion assays with human RBCs. Northern blotting experiments indicated that regulation predominantly occurred at the mRNA level. Comparison of the different combinations of GC and cytokines/LPS revealed differences in the level of GC-dependent enhancement of sialoadhesin expression, with IFN-beta and IL-4 being more potent than IFN-gamma and LPS. Moreover, the effects of IFN-gamma and LPS could be reproduced by priming, whereas IFN-beta and IL-4 were required simultaneously with GC. The regulation of sialoadhesin expression was mediated by the GC receptor, and not by mineralocorticoid receptor, as shown by inhibition experiments with specific antagonists. Finally, it is demonstrated that macrophages in the adrenal gland, the major site of endogenous GC production, express sialoadhesin. This study demonstrates that GC act as a primary inducer of sialoadhesin expression on rat macrophages, and that the response can be enhanced by IFN-beta, T cell-derived cytokines, or LPS.


Reconstructing the diet, trophic level and migration pattern of mysticete whales based on baleen isotopic composition.
Baleen from mysticete whales is a well-preserved proteinaceous material that can be used to identify migrations and feeding habits for species whose migration pathways are unknown. Analysis of δ13C and δ15N values from bulk baleen have been used to infer migration patterns for individuals. However, this approach has fallen short of identifying migrations between regions as it is difficult to determine variations in isotopic shifts without temporal sampling of prey items. Here, we apply analysis of δ15N values of amino acids to five baleen plates belonging to three species, revealing novel insights on trophic position, metabolic state and migration between regions. Humpback and minke whales had higher reconstructed trophic levels than fin whales (3.7-3.8 versus 3-3.2, respectively) as expected due to different feeding specialization. Isotopic niche areas between baleen minima and maxima were well separated, indicating regional resource use for individuals during migration that aligned with isotopic gradients in Atlantic Ocean particulate organic matter. Phenylanine δ15N values confirmed regional separation between the niche areas for two fin whales as migrations occurred and elevated glycine and threonine δ15N values suggested physiological changes due to fasting. Simultaneous resolution of trophic level and physiological changes allow for identification of regional migrations in mysticetes.


beta(1-3)Glucanosyltransferase Gel4p is essential for Aspergillus fumigatus.
The beta(1-3)glucanosyltransferase GEL family of Aspergillus fumigatus contains 7 genes, among which only 3 are expressed during mycelial growth. The role of the GEL4 gene was investigated in this study. Like the other Gelps, it encodes a glycosylphosphatidylinositol (GPI)-anchored protein. In contrast to the other beta(1-3)glucanosyltransferases analyzed to date, it is essential for this fungal species.


Patient-ventilator asynchronies: types, outcomes and nursing detection skills.
Mechanical ventilation is often employed as partial ventilatory support where both the patient and the ventilator work together. The ventilator settings should be adjusted to maintain a harmonious patient-ventilator interaction. However, this balance is often altered by many factors able to generate a patient ventilator asynchrony (PVA). The aims of this review were: to identify PVAs, their typologies and classifications; to describe how and to what extent their occurrence can affect the patients' outcomes; to investigate the levels of nursing skill in detecting PVAs. Literature review performed on Cochrane Library, Medline and CINAHL databases. 1610 records were identified; 43 records were included after double blind screening. PVAs have been classified with respect to the phase of the respiratory cycle or based on the circumstance of occurrence. There is agreement on the existence of 7 types of PVAs: ineffective effort, double trigger, premature cycling, delayed cycling, reverse triggering, flow starvation and auto-cycling. PVAs can be identified through the ventilator graphics monitoring of pressure and flow waveforms. The influence on patient outcomes varies greatly among studies but PVAs are mostly associated with poorer outcomes. Adequately trained nurses can learn and retain how to correctly detect PVAs. Since its challenging interpretation and the potential advantages of its implementation, ventilator graphics monitoring can be classified as an advanced competence for ICU nurses. The knowledge and skills to adequately manage PVAs should be provided by specific post-graduate university courses.


Synthesis and biological evaluation of NAS-21 and NAS-91 analogues as potential inhibitors of the mycobacterial FAS-II dehydratase enzyme Rv0636.
The identification of potential new anti-tubercular chemotherapeutics is paramount due to the recent emergence of extensively drug-resistant strains of Mycobacterium tuberculosis (XDR-TB). Libraries of NAS-21 and NAS-91 analogues were synthesized and evaluated for their whole-cell activity against Mycobacterium bovis BCG. NAS-21 analogues 1 and 2 demonstrated enhanced whole-cell activity in comparison to the parental compound, and an M. bovis BCG strain overexpressing the dehydratase enzyme Rv0636 was resistant to these analogues. NAS-91 analogues with ortho-modifications gave enhanced whole-cell activity. However, extension with biphenyl modifications compromised the whole-cell activities of both NAS-21 and NAS-91 analogues. Interestingly, both libraries demonstrated in vitro activity against fatty acid synthase II (FAS-II) but not FAS-I in cell-free extracts. In in vitro assays of FAS-II inhibition, NAS-21 analogues 4 and 5 had IC(50) values of 28 and 19 mug ml(-1), respectively, for the control M. bovis strain, and the M. bovis BCG strain overexpressing Rv0636 showed a marked increase in resistance. In contrast, NAS-91 analogues demonstrated moderate in vitro activity, although increased resistance was again observed in FAS-II activity assays with the Rv0636-overexpressing strain. Fatty acid methyl ester (FAME) and mycolic acid methyl ester (MAME) analysis of M. bovis BCG and the Rv0636-overexpressing strain revealed that the effect of the drug was relieved in the overexpressing strain, further implicating and potentially identifying Rv0636 as the target for these known FabZ dehydratase inhibitors. This study has identified candidates for further development as drug therapeutics against the mycobacterial FAS-II dehydratase enzyme.


An international perspective on youth gambling prevalence studies.
In the wake of rapid expansion of legal gambling internationally, studies of adolescent gambling involvement and problem gambling prevalence have been carried out in numerous jurisdictions. This paper reviews adolescent gambling prevalence studies that have been carried out in North America, Europe, and Oceania. Based on this review, work is clearly needed to assess the impact of survey methods on identified prevalence rates and to improve the measurement of problem gambling among adolescents. From a substantive perspective, several clear demographic and behavioral characteristics are associated with gambling involvement and problem gambling among youth. However, early assumptions about youth gambling and problem gambling must give way to more nuanced understandings of how these phenomena change in response to changes in the social and cultural environment. We may have traveled some distance down the road toward understanding the determinants as well as the distribution of youth gambling and problem gambling, but we still have a long way to go.


Tissue factor-specific ultra-bright SERRS nanostars for Raman detection of pulmonary micrometastases.
Here we demonstrate a novel application of 'surface enhanced resonance Raman scattering nanoparticles' (SERRS NPs) for imaging breast cancer lung metastases with much higher precision than currently feasible. A breast cancer lung metastasis mouse model was established by intravenous injection of LM2 cells. These mice were intravenously administered SERRS NPs conjugated with ALT-836, an anti-tissue factor (TF) monoclonal antibody, and subjected to Raman imaging to visualize the expression of TF both in vivo and ex vivo. Raman imaging indicated marked uptake of αTF-SERRS-NPs by the lung metastases compared to isotype and blocking controls. Conversely, little uptake of αTF-SERRS-NPs was observed in the lungs of healthy mice. Successful detection and delineation of pulmonary micrometastatic lesions as small as 200 μm, corroborated by histology, immunohistochemistry, and bioluminescence imaging confirmed the suitability of both TF as a target and αTF-SERRS-NPs as an effective contrast agent for imaging breast cancer lung metastases. Further advancements of this technique in the form of Raman endoscopes coupled with ultrabright SERRS NPs developed in this work could lead to minimally invasive detection and resection of lung metastases.


Lysosome-related genes are regulated in the orbital fat of patients with graves' ophthalmopathy.
The molecular mechanism involved in the hypertrophy of the orbital fat in patients with Graves' ophthalmopathy or thyroid eye disease (TED) remains unclear. Comparison of genome-wide expression profiles may help in the search for the gene sets involved in TED. Twenty-five orbital adipose tissue specimens were obtained, from which the RNA was isolated. Four of the tissue specimens (from four individuals, two with TED and two control subjects) were subjected to cDNA microarray analysis. The data were analyzed by the gene set enrichment analysis (GSEA) to survey the biological pathways involved in the pathogenesis of TED. Messenger RNA levels of some top-ranked genes in GSEA-selected pathways are validated by quantitative PCR (QPCR). The expression of specific gene sets related to lytic vacuoles, lysosomes, and vacuoles were different between the specimens obtained from patients with TED and control subjects (P < 0.001). These three gene sets overlapped. For QPCR, four top-ranked genes were selected from these overlapping gene sets and another one that related to visual failure, using 21 independent samples of patients with TED (n = 15) and control subjects (n = 6). The results showed that ceroid-lipofuscinosis, neuronal 2, late infantile (CLN2; P = 0.044) and ceroid-lipofuscinosis, neuronal 3, juvenile (CLN3, which related to visual failure; P = 0.012) were significantly downregulated in the orbital fat of patients with TED. The expression of the beta subunit of hexosaminidase A (HEXB) was reduced as well, but the change did not reach statistical significance (P = 0.058). Lysosome-related genes, such as CLN2, CLN3, and HEXB, may be involved in the pathogenesis of adipose tissue hypertrophy in TED.


Cell Cycle Regulation of the Pdx1 Transcription Factor in Developing Pancreas and Insulin-Producing β-Cells.
Current evidence indicates that proliferating β-cells express lower levels of some functional cell identity genes, suggesting that proliferating cells are not optimally functional. Pdx1 is important for β-cell specification, function, and proliferation and is mutated in monogenic forms of diabetes. However, its regulation during the cell cycle is unknown. Here we examined Pdx1 protein expression in immortalized β-cells, maternal mouse islets during pregnancy, and mouse embryonic pancreas. We demonstrate that Pdx1 localization and protein levels are highly dynamic. In nonmitotic cells, Pdx1 is not observed in constitutive heterochromatin, nucleoli, or most areas containing repressive epigenetic marks. At prophase, Pdx1 is enriched around the chromosomes before Ki67 coating of the chromosome surface. Pdx1 uniformly localizes in the cytoplasm at prometaphase and becomes enriched around the chromosomes again at the end of cell division, before nuclear envelope formation. Cells in S phase have lower Pdx1 levels than cells at earlier cell cycle stages, and overexpression of Pdx1 in INS-1 cells prevents progression toward G2, suggesting that cell cycle-dependent regulation of Pdx1 is required for completion of mitosis. Together, we find that Pdx1 localization and protein levels are tightly regulated throughout the cell cycle. This dynamic regulation has implications for the dichotomous role of Pdx1 in β-cell function and proliferation.


Neuroligin 1 modulates striatal glutamatergic neurotransmission in a pathway and NMDAR subunit-specific manner.
Together with its presynaptic partner Neurexin 1 (Nxn1), Neuroligin 1 (NL1) participates in synapse specification and synapse maintenance. We and others have shown that NL1 can also modulate glutamatergic synaptic function in the central nervous system of rodent models. These molecular/cellular changes can translate into altered animal behaviors that are thought to be analogous to symptomatology of neuropsychiatric disorders. For example, in dorsal striatum of NL1 deletion mice, we previously reported that the ratio N-methyl-D-aspartate receptor (NMDAR) mediated synaptic currents to α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) mediated synaptic currents (NMDA/AMPA) is reduced in medium spiny neuron (MSNs). Importantly, this reduction in NMDA/AMPA ratio correlated with increased repetitive grooming. The striatum is the input nucleus of the basal ganglia (BG). Classical models of this circuitry imply that there are two principal pathways that render distinct and somewhat opposite striatal outputs critical to the function of these nuclei in modulating motor behavior. Thus, we set out to better characterize the effects of NL1 deletion on direct and indirect pathways of the dorsal striatum by genetically labeling MSNs participating in the direct and indirect pathways. We demonstrate that a decrease in NMDAR-mediated currents is limited to MSNs of the direct pathway. Furthermore, the decrease in NMDAR-mediated currents is largely due to a reduction in function of NMDARs containing the GluN2A subunit. In contrast, indirect pathway MSNs in NL1 knockout (KO) mice showed a reduction in the frequency of miniature excitatory neurotransmission not observed in the direct pathway. Thus, NL1 deletion differentially affects direct and indirect pathway MSNs in dorsal striatum. These findings have potential implications for striatal function in NL1 KO mice.


eIF4A3 Phosphorylation by CDKs Affects NMD during the Cell Cycle.
Exon junction complexes (EJCs) loaded onto spliced mRNAs during splicing serve as molecular markers for various post-transcriptional gene-regulatory processes, including nonsense-mediated mRNA decay (NMD). Although the composition and structure of EJCs are well characterized, the mechanism regulating EJC deposition remains unknown. Here we find that threonine 163 (T163) within the RNA-binding motif of eIF4A3 (a core EJC component) is phosphorylated by cyclin-dependent protein kinases 1 and 2 in a cell cycle-dependent manner. T163 phosphorylation hinders binding of eIF4A3 to spliced mRNAs and other EJC components. Instead, it promotes association of eIF4A3 with CWC22, which guides eIF4A3 to an active spliceosome. These molecular events ensure the fidelity of specific deposition of the EJC ∼20-24 nt upstream of an exon-exon junction. Accordingly, NMD is affected by T163 phosphorylation. Collectively, our data provide evidence that T163 phosphorylation affects EJC formation and, consequently, NMD efficiency in a cell cycle-dependent manner.


A disease-related epitope of Torpedo acetylcholine receptor. Residues involved in I-Ab binding, self-nonself discrimination, and TCR antagonism.
Residues 146-162 of the Torpedo californica acetylcholine receptor alpha-subunit contain the immunodominant T cell epitope for experimental autoimmune myasthenia gravis-susceptible C57BL/6 mice. To develop potential therapeutic peptides, a detailed analysis of the epitope was undertaken. Truncated and substituted synthetic peptides were tested as stimulators of T cell clones and immune lymph node cells. Critical residues spanned positions 151-159. Y151 and V156 were critical for MHC binding. The results indicated a general motif for binding to I-Ab to be an aromatic or hydrophobic residue (preferentially Y or F) at position i followed by an uncharged residue at position (i + 5). Lysine was not tolerated at position (i + 8). Residues D152, K155, S157, and I158 were important T cell contact residues. A peptide corresponding to the murine 146-162 sequence, which differs from the Torpedo sequence at 5 residues, bound to I-Ab but was nonimmunogenic, consistent with the assigned TCR and I-Ab contact residues. These results suggest that tolerance is responsible for the lack of T cell cross-reactivity with the murine acetylcholine receptor. Substituted peptides were tested for the inhibition of T cell clone responses and for TCR antagonism. Although peptides substituted at residues 157 and 158 inhibited most clones, no single peptide could completely inhibit all clones or primed lymph node cells. These findings indicate that antagonist peptides may be useful in inhibiting T cell responses to complex Ag displaying a single immunodominant epitope. Multiple antagonists used in combination may be required for maximum inhibition of the response.


The emerging periplasm-localized subclass of AroQ chorismate mutases, exemplified by those from Salmonella typhimurium and Pseudomonas aeruginosa.
Chorismate mutases of the AroQ homology class are widespread in the Bacteria and the Archaea. Many of these exist as domains that are fused with other aromatic-pathway catalytic domains. Among the monofunctional AroQ proteins, that from Erwinia herbicola was previously shown to have a cleavable signal peptide and located in the periplasmic compartment. Whether or not this might be unique to E. herbicola was unknown. The gene coding for the AroQ protein was cloned from Salmonella typhimurium, and the AroQ protein purified from both S. typhimurium and Pseudomonas aeruginosa was shown to have a periplasmic location. The periplasmic chorismate mutases (denoted *AroQ) are shown to be a distinct subclass of AroQ, being about twice the size of cytoplasmic AroQ proteins. The increased size is due to a carboxy-terminal extension of unknown function. In addition, a so-far novel aromatic aminotransferase was shown to be present in the periplasm of P. aeruginosa. Our analysis has detected a number of additional *aroQ genes. The joint presence of *AroQ, cyclohexadienyl dehydratase and aromatic aminotransferase in the periplasmic compartment of P. aeruginosa comprises a complete chorismate-to-phenylalanine pathway and accounts for the "hidden overflow pathway" to phenylalanine described previously.


Evaluation of breathing pattern: comparison of a Manual Assessment of Respiratory Motion (MARM) and respiratory induction plethysmography.
Altered breathing pattern is an aspect of dysfunctional breathing but few standardised techniques exist to evaluate it. This study investigates a technique for evaluating and quantifying breathing pattern, called the Manual Assessment of Respiratory Motion (MARM) and compares it to measures performed with Respiratory Induction Plethysmography (RIP). About 12 subjects altered their breathing and posture while 2 examiners assessed their breathing using the MARM. Simultaneous measurements with RIP were taken. Inter-examiner agreement and agreement between MARM and RIP were assessed. The ability of the measurement methods to differentiate between diverse breathing and postural patterns was compared. High levels of agreement between examiners were found with the MARM for measures of the upper rib cage relative to lower rib cage/abdomen motion during breathing but not for measures of volume. The measures of upper rib cage dominance during breathing correlated with similar measures obtained from RIP. Both RIP and MARM measures methods were able to differentiate between abdominal and thoracic breathing patterns, but only MARM was able to differentiate between breathing changes occurring as result of slumped versus erect sitting posture. This study suggests that the MARM is a reliable clinical tool for assessing breathing pattern.


Producing physician-scientists: a survey of graduates from the Harvard--MIT Program in Health Sciences and Technology.
The Harvard-MIT Program in Health Sciences and Technology (HST) is a flexible, preclinical curriculum, taught by members of the faculties of both Harvard University and the Massachusetts Institute of Technology, that stresses a rigorous, scientific, quantitative approach, small classes (usually fewer than 50 students), and student-faculty interaction. The program is aimed at students with strong backgrounds in quantitative and biological sciences who are interested in careers as physician-scientists. The first 234 students of the program, who graduated between 1975 and 1985, were asked to participate in a 1990 follow-up study by completing a four-page questionnaire and submitting curricula vitae and lists of publications, if available. Data were analyzed quantitatively and qualitatively. Of the 234 graduates, 211 (90%) responded. Sixty-three (30%) had received both MD and PhD degrees. The graduates were twice as likely to describe their primary professional roles as academic than as clinical practice; 94 held full-time faculty positions at 50 medical schools. The 154 (73%) in research spent an average of 51% of their time on this activity. According to the 179 graduates (85%) who stated that they would choose HST again, the most frequently mentioned reasons were the quantitative approach that emphasized integration of basic science and clinical practice (49%) and the small class size (37%). The HST MD curriculum, with its emphasis on basic science and research experience, has been successful in preparing carefully selected students for careers as physician-scientists, without necessarily requiring the completion of a PhD degree.


Impact of antiretroviral therapy on serum lipoprotein levels and dyslipidemias: a systematic review and meta-analysis.
Antiretroviral drugs increase biosynthesis and reduce hepatic clearance of serum cholesterol. It is thus important to evaluate the impact of antiretroviral treatment on serum lipoprotein levels and the risk of dyslipidemia. We searched EMBASE and PubMed for articles comparing lipid profiles between HIV-infected adult patients naïve and exposed to antiretroviral therapy (ART). Eligible studies were pooled by performing random-effects meta-analyses of mean serum lipoprotein levels and prevalence estimates of dyslipidemias. 51 observational studies comprising 37,110 patients were included in the meta-analyses. ART-exposed patients had significantly higher concentrations of total cholesterol (45 studies, mean difference [MD]=29.4mg/dL, 95% confidence interval [CI] 26.5 to 32.4, I(2)=82.2%), low density lipoprotein-cholesterol (37 studies, MD=14.9mg/dL, 95% CI 11.2 to 18.5, I(2)=86.1%), and triglycerides (43 studies, MD=46.8mg/dL, 95% CI 37.8 to 55.8, I(2)=97.1%), compared with ART-naïve patients. The risks of hypercholesterolemia (25 studies, pooled odds ratio [OR] 3.8, 95% CI 3.1 to 4.7, I(2)=60.0%) and hypertriglyceridemia (21 studies, OR 2.2, 95% CI 1.7 to 2.9, I(2)=81.7%) were also significantly higher among ART-exposed patients, compared with ART-naïve patients. Antiretroviral therapy is significantly associated with increase in serum lipid levels and increased risk of dyslipidemia. Whether or not these associations are causal should be investigated by future studies.


Polarization independent enhanced optical transmission in one-dimensional gratings and device applications.
A review and analysis is performed of various resonance effects associated with subwavelength one-dimensional (1-D) metal gratings for transverse electric (TE) and transverse magnetic (TM) polarized incident radiation. It is shown that by tuning the structural geometry (especially the groove width) and material composition of the 1-D gratings, polarization independent enhanced optical transmission (EOT) can be achieved. Three different cases of EOT have been studied for 1-D metal gratings: a) EOT for TM-polarized incident radiation b) EOT for TE-polarized incident radiation, and most importantly c) EOT for un-polarized incident light. Potential uses of these results in the design and improvement of various optoelectronic devices, such as polarizers, photodetectors and wavelength filters are discussed.


Lateral weight transference exercises following acute stroke: a preliminary study of clinical effectiveness.
To evaluate a training programme aimed at improving lateral weight transference in patients following acute stroke to determine main treatment effects, if any, to inform the design of future studies. A single-blind randomized controlled trial. The Stroke Unit at The James Cook University Hospital, Middlesbrough, UK. Thirty-five patients with an acute stroke. All subjects received their usual care, including physiotherapy. The treatment group (n = 17) received 12 additional therapy sessions (over four weeks) comprising exercises aimed at improving lateral weight transference in sitting delivered by trained physiotherapy assistants. Measures of dynamic reaching, sitting and standing, and static standing balance were undertaken by a blind independent observer. Specific measures of weight displacement in standing and reaching, and timed standing up and sitting down did not detect any differences over time regardless of group. Neither were there any significant changes over time, except for sway during static standing (p < 0.01) and time to return to their original position during dynamic reaching (p = 0.01). A training programme aimed at improving lateral weight transference did not appear to enhance the rehabilitation of acute stroke patients. Improvements observed in postural control in standing and sitting may be attributable to usual care or natural recovery.


Are Some Countries More Honest than Others? Evidence from a Tax Compliance Experiment in Sweden and Italy.
This study examines cultural differences in ordinary dishonesty between Italy and Sweden, two countries with different reputations for trustworthiness and probity. Exploiting a set of cross-cultural tax compliance experiments, we find that the average level of tax evasion (as a measure of ordinary dishonesty) does not differ significantly between Swedes and Italians. However, we also uncover differences in national "styles" of dishonesty. Specifically, while Swedes are more likely to be either completely honest or completely dishonest in their fiscal declarations, Italians are more prone to fudging (i.e., cheating by a small amount). We discuss the implications of these findings for the evolution and enforcement of honesty norms.


The child as econometrician: a rational model of preference understanding in children.
Recent work has shown that young children can learn about preferences by observing the choices and emotional reactions of other people, but there is no unified account of how this learning occurs. We show that a rational model, built on ideas from economics and computer science, explains the behavior of children in several experiments, and offers new predictions as well. First, we demonstrate that when children use statistical information to learn about preferences, their inferences match the predictions of a simple econometric model. Next, we show that this same model can explain children's ability to learn that other people have preferences similar to or different from their own and use that knowledge to reason about the desirability of hidden objects. Finally, we use the model to explain a developmental shift in preference understanding.


COVID-19 and the environment: A critical review and research agenda.
The current Coronavirus infection (COVID-19) outbreak has had a substantial impact on many aspects of general life. Although a number of studies have been published on the topic already, there has not been a critical review of studies on the impacts of COVID-19 by and on environmental factors. The current study fills this gap by presenting a critical analysis of 57 studies on the nexus between COVID-19 and the environment, published in nine journals up to May 2020. Majority of the studies in our sample are published in Science of the Total Environment (74%), and studies used mostly descriptive statistics and regression as research methods. We identified four underlying research clusters based on a systematic content analysis of the studies. The clusters are: (1) COVID-19 and environmental degradation, (2) COVID-19 and air pollution, (3) COVID-19 and climate/metrological factors and (4) COVID-19 and temperature. Besides a critical analysis of the studies in each cluster, we propose research questions to guide future research on the relationship between COVID-19 and the environment.


Note of Caution for the Aqueous Behaviour of Metal-Based Drug Candidates.
Poor aqueous solubility is one of the recurrent drawbacks of many compounds in medicinal chemistry. To overcome this limitation, the dilution of drug candidates from stock solutions of an organic solvent is common practice. However, the precise characterisation of these compounds in aqueous solutions is often neglected, leading to some uncertainties regarding the nature of the actual active species. In this communication, we demonstrate that two ruthenium complexes previously reported by our group for their chemotherapeutic potential against cancer, namely [Ru(DIP)2 (sq)](PF6 ) and [Ru(DIP)2 (3-methoxysq)](PF6 ), where DIP is 4,7-diphenyl-1,10-phenanthroline, sq=semiquinonate and 3-methoxysq=3-methoxysemiquinonate, form colloids in water-DMSO (1 % v/v) mixtures that are invisible to the naked eyes. [Ru(DIP)2 (3-methoxysq)](PF6 ) was found to form a highly stable and monodispersed colloid with nanoaggregates of ∼25 nm. In contrast, [Ru(DIP)2 (sq)](PF6 ) was found to form large reticulates of mostly spherical aggregates which size was found to increase over time. The difference in size and shape distribution of drug candidates is of tremendous significance as the study of their biological activity might be severely affected. Overall, we strongly believe that these observations should be taken into account by the scientific community working on the development of metal-based drugs with poor water solubility.


Percutaneous Endoscopic Gastrostomy in a Patient With Continuous Intrathecal Baclofen Infusion Therapy.
Percutaneous endoscopic gastrostomy (PEG) is the method of choice in patients requiring long-term enteral tube feeding. In patients with intrathecal baclofen infusion therapy (IBT) pump implantation, infection via the skin and soft tissue may be an issue of concern. The introducer technique for gastrostomy tube insertion may be useful in reducing the risk of peristomal infection. Although the presence of a PEG tube has been reported as a risk factor for implantation site infection (for newly inserted IBT pumps), whether existing IBT pumps are at risk for infection during or after the placement of a PEG tube is not clear. We report a case where PEG was successfully performed using the introducer technique on a patient with an IBT pump implant.


Galactosyltransferase associated with tumor in patients with ovarian cancer: factors involved in elevation of serum galactosyltransferase.
The serum level of beta1,4-galactosyltransferase (beta1,4-GalT) is increased in both malignancy and benign diseases. Galactosyltransferase associated with tumor (GAT) is one of the soluble forms of beta1,4-GalT, and is a marker of ovarian cancer with a high specificity. GAT and normal soluble beta1,4-GalT are both derived from the same membrane-bound form of the enzyme. This study investigated the mechanism of GAT elevation in patients with ovarian cancer. The serum levels of GAT and normal beta1,4-GalT were measured using specific monoclonal antibodies. In addition, nude mice bearing human ovarian cancer were used to assess the kinetics of tumor-derived enzymes. GAT and normal beta1,4-GalT were both detected in ovarian cancer patients, but only GAT reflected the tumor status. In tumor-bearing nude mice, both soluble forms of beta1,4-GalT were released from tumor cells, but the half-life of GAT was far shorter than that of normal beta1,4-GalT. Addition of serum from healthy women to colostrum (which has a high GAT content) reduced the GAT level, while adding patient serum caused a significantly smaller reduction of GAT. Addition of the serum from mouse which includes no human beta1,4-GalT to colostrum also reduced the GAT level with no significant change of total soluble beta1,4-GalT. These findings indicate that human serum contains certain factors that decrease the GAT level, but these factors are inhibited in ovarian cancer patients so that a high GAT level persists. It seems that the decrease of GAT occurs as a result of conversion into normal beta1,4-GalT.


Improving tuberculosis case detection rate with a lay informant questionnaire: an experience from the Lao People's Democratic Republic.
In many countries, the tuberculosis (TB) annual case detection rate is below the target of 70%. In the Lao People's Democratic Republic in 2005, it did not exceed 55% The DOTS strategy promotes passive case detection of TB. In order to increase the detection rate, we validated a questionnaire targeting lay informants at village level to notify patients with chronic cough and assessed the relevance for TB case-finding. A three-item questionnaire was sent through the district health departments to all villages in six districts in six provinces. The village headmen were asked to notify chronic cough patients. Answers were validated in a door-to-door survey (20 villages/district). In a sub-sample (four villages/district) all confirmed patients were screened for TB and paragonimiasis. Attapeu, Luang Namtha, Luang Prabang, Saravane, Savanakhet and Vientiane provinces in the Lao People's Democratic Republic. Lay informant questionnaires sent from district health offices to villages are cost-effective and foster interaction between the health services and remote and underserved communities. Although the correct detection of patients is highly dependent on direct respondents, a substantial number of new TB and paragonimiasis cases were consistently diagnosed in chronic cough patients. Out of 456 questionnaires, 295 were returned (65%). Return rates were highly variable between districts (48-87%), questionnaires' sensitivity (56-98%), positive predictive value (34-88%) and correlation between number of notified and confirmed patients (r: 0.26-0.78). In sub-sampled villages (13,541 population) 19 (5.1%) TB and 26 (7.0%) paragonimiasis cases were detected in 374 chronic cough patients. This quick questionnaire approach proved motivating for district authorities and village key informants, although no incentives were provided. The highly operator-dependent approach yielded a consistent detection rate of TB and paragonimiasis cases. This approach brings health services and populations in need in close contact, which is particularly crucial in remote and underserved areas.


Fatal cerebroembolism from nonbacterial thrombotic endocarditis in a trauma patient: case report and review.
Nonbacterial thrombotic endocarditis (NBTE) is a rare condition that may result in an unexpected and usually fatal cerebroembolism. It occurs in a variety of clinical situations, including malignancy, immune disorders, and sepsis, but it has rarely been reported after trauma. The formation of NBTE appears to require a hypercoagulable state and changes in valvular morphology, e.g., during a hyperdynamic state. Patients with disseminated intravascular coagulation have a 21% incidence of NBTE. Although NBTE is usually found at autopsy, premorbid detection by echocardiography is currently possible and feasible. Untreated patients have a high incidence of embolic events, but anticoagulation with heparin may be life-saving. A lethal case of NBTE in a severely injured patient is reported here with the purpose of increasing awareness among medical personnel caring for trauma patients. Recommendations have been made for surveillance echocardiography in high-risk patients, e.g., critically ill patients with sepsis or disseminated intravascular coagulation.


Compact method for optical induction of proximal probe heating and elongation.
A tapered, metal-coated, optical fiber probe will elongate when heated by light input through a fiber. The induced motion can be used for data storage or nanostructuring of a surface. The elongation produced by this alignment-free system is measured with force feedback in a near-field scanning optical microscope (NSOM). The input light intensity controls the elongation magnitude, which ranges from a few nanometers to more than 100 nm. A 0.5-mW input energy yields approximately 20 nm of probe elongation. The elongation quantified here can create artifacts in any experiment using pulsed laser light with a NSOM or an atomic force microscope.


Extra- and intracellular formation of reactive oxygen species by human neutrophils in the presence of pheniramine, chlorpheniramine and brompheniramine.
Allergic inflammation was found to be accompanied by activation of neutrophils. Since this resulted in increased formation of reactive oxygen species, the antioxidative activity of antiallergic drugs was considered to decrease the risk of tissue damage. However, if the drug-induced inhibition of radical formation occurred intracellularly, it could disturb regulation of neutrophil functions and decrease bactericidal activity of these cells. Separate analysis of extra- and intracellular activity of antioxidative drugs is thus of particular importance. To differentiate the effects of three antiallergic H1-antihistamine drugs (pheniramine, chlor- and brompheniramine) on radical formation outside and inside human neutrophils. Formation of reactive oxygen species was determined in vitro using the chemiluminescence method. The chemiluminescence signal, initiated by phorbol-12-myristate-13-acetate, was enhanced either with isoluminol (extracellular) or with luminol in the presence of extracellular scavengers, superoxide dismutase and catalase (intracellular). The antihistamines tested displayed dual activity - they inhibited the extracellular and potentiated the intracellular chemiluminescence. Chlor- and brompheniramine were found to be more effective than pheniramine. Compared to other H1-antihistamines (such as dithiaden or loratadine, active both extra- and intracellularly), the observed inhibition caused by the pheniramines tested was unique since it occurred selectively outside neutrophils. This might indicate the ability of these drugs to minimise toxic effects of extracellular radicals without affecting intracellular oxidant production involved in regulation of neutrophil functions and in microbial killing.


Sex differences in plaque characteristics by intravascular imaging in patients with coronary artery disease.
We aimed to study sex differences in coronary plaque burden and plaque composition in patients with coronary artery disease (CAD). Virtual histology intravascular ultrasound (VH-IVUS) and near-infrared spectroscopy (NIRS) imaging of a non-culprit coronary artery was performed in 178 (23.5%) women and 581 (76.5%) men who underwent invasive management of stable angina pectoris (SAP) or acute coronary syndrome (ACS). Women were older and had a worse cardiovascular risk profile than men, but less extended angiographic coronary disease. Irrespective of the presenting diagnosis, women had lower VH-IVUS-derived plaque burden than men (38.1% vs. 40.5% in SAP, and 35.9% vs. 38.8% in ACS). Standardised (mean 211 vs. 263 mm3 in SAP, and 199 vs. 245 mm3 in ACS) total plaque volume was lower in women. Volumes of fibrous tissue, fibro-fatty tissue, necrotic core and dense calcium were also lower in women. NIRS-derived lipid core burden index (LCBI) was lower in women, in particular in SAP (mean LCBI in the worst 4 mm 220 vs. 240). The observed differences remained significant after adjustment for clinical characteristics. Women had more favourable plaque characteristics than men, despite their worse risk profile. Long-term follow-up studies are required to evaluate the clinical consequences.


In vitro inhibition of Plasmodium falciparum rosette formation by Curdlan sulfate.
Spontaneous binding of infected erythrocytes to uninfected erythrocytes to form rosettes is a property of some strains of Plasmodium falciparum that is linked to severe complications of malaria. Curdlan sulfate (CRDS) is a sulfated glycoconjugate compound that is chemically similar to known rosette-inhibiting drugs such as heparin. CRDS has previously been shown to have antimalarial activity in vitro and is safe for clinical use. Here we show that CRDS at therapeutic levels (10 to 100 microg/ml) significantly reduces rosette formation in vitro in seven P. falciparum laboratory strains and in a group of 18 African clinical isolates. The strong ability to inhibit rosetting suggests that CRDS has the potential to reduce the severe complications and mortality rates from P. falciparum malaria among African children. Our data support further clinical trials of CRDS.


Tuberculosis drug discovery in the post-post-genomic era.
The expectation that genomics would result in new therapeutic interventions for infectious diseases remains unfulfilled. In the post-genomic era, the decade immediately following the availability of the genome sequence of Mycobacterium tuberculosis, tuberculosis (TB) drug discovery relied heavily on the target-based approach but this proved unsuccessful leading to a return to whole cell screening. Genomics underpinned screening by providing knowledge and many enabling technologies, most importantly whole genome resequencing to find resistance mutations and targets, and this resulted in a selection of leads and new TB drug candidates that are reviewed here. Unexpectedly, many new targets were found to be 'promiscuous' as they were inhibited by a variety of different compounds. In the post-post-genomics era, more advanced technologies have been implemented and these include high-content screening, screening for inhibitors of latency, the use of conditional knock-down mutants for validated targets and siRNA screens. In addition, immunomodulation and pharmacological manipulation of host functions are being explored in an attempt to widen our therapeutic options.


Nanotherapy delivery of c-myc inhibitor targets Protumor Macrophages and preserves Antitumor Macrophages in Breast Cancer.
Tumor-associated macrophages (TAMs) enhance tumor growth in mice and are correlated with a worse prognosis for breast cancer patients. While early therapies sought to deplete all macrophages, current therapeutics aim to reprogram pro-tumor macrophages (M2) and preserve those necessary for anti-tumor immune responses (M1). Recent studies have shown that c-MYC (MYC) is induced in M2 macrophages in vitro and in vivo where it regulates the expression of tumor-promoting genes. In a myeloid lineage MYC KO mouse model, MYC had important roles in macrophage maturation and function leading to reduced tumor growth. We therefore hypothesized that targeted delivery of a MYC inhibitor to established M2 TAMs could reduce polarization toward an M2 phenotype in breast cancer models. Methods: In this study, we developed a MYC inhibitor prodrug (MI3-PD) for encapsulation within perfluorocarbon nanoparticles, which can deliver drugs directly to the cytosol of the target cell through a phagocytosis independent mechanism. We have previously shown that M2-like TAMs express significant levels of the vitronectin receptor, integrin β3, and in vivo targeting and therapeutic potential was evaluated using αvβ3 integrin targeted rhodamine-labeled nanoparticles (NP) or integrin αvβ3-MI3-PD nanoparticles. Results: We observed that rhodamine, delivered by αvβ3-rhodamine NP, was incorporated into M2 tumor promoting macrophages through both phagocytosis-independent and dependent mechanisms, while NP uptake in tumor suppressing M1 macrophages was almost exclusively through phagocytosis. In a mouse model of breast cancer (4T1-GFP-FL), M2-like TAMs were significantly reduced with αvβ3-MI3-PD NP treatment. To validate this effect was independent of drug delivery to tumor cells and was specific to the MYC inhibitor, mice with integrin β3 knock out tumors (PyMT-Bo1 β3KO) were treated with αvβ3-NP or αvβ3-MI3-PD NP. M2 macrophages were significantly reduced with αvβ3-MI3-PD nanoparticle therapy but not αvβ3-NP treatment. Conclusion: These data suggest αvβ3-NP-mediated drug delivery of a c-MYC inhibitor can reduce protumor M2-like macrophages while preserving antitumor M1-like macrophages in breast cancer.


Practical applications of topical therapy for allergic, infectious, and seborrheic disorders.
Topical therapy is extremely important in the management of allergic, infectious, and seborrheic disorders. It can be used as a sole therapy or adjunctive therapy for these disorders, often minimizing the need for systemic therapy. In allergic diseases, pruritus can be decreased by removing allergen, desensitizing the skin or other antipruritic effects. Many agents can also maintain or replace moisture to the skin and have emollient effects. When used for infectious conditions, topical therapy can decrease microbial counts and reduce surface colonization of microbes and help to prevent relapses. Antiseborrheic products function by normalizing keratinocyte turnover rates by reducing epidermal division (keratoplastic), normalizing keratinization, and increasing desquamation (keratolytic). There are many different topical vehicles and modes of application: shampoos, whirlpools, soaks, rinses, sprays, lotions, gels, creams, and ointments. Shampoos are often the most practical and effective. The practitioner needs to become familiar with many active ingredients to learn what products are indicated for specific diseases.


Actinomycetoma in SE Asia: the first case from Laos and a review of the literature.
Mycetoma is a chronic, localized, slowly progressing infection of the cutaneous and subcutaneous tissues caused either by fungi (eumycetoma or implantation mycosis) or by aerobic actinomycetes (actinomycetoma). It is acquired by traumatic implantation, most commonly in the tropics and subtropics, especially in rural agricultural communities. Although well recognized elsewhere in Asia, it has not been reported from the Lao People's Democratic Republic (Laos). A 30 year-old female elementary school teacher and rice farmer from northeast Laos was admitted to Mahosot Hospital, Vientiane, with a massive growth on her left foot, without a history of trauma. The swelling had progressed slowly but painlessly over 5 years and multiple draining sinuses had developed. Ten days before admission the foot had increased considerably in size and became very painful, with multiple sinuses and discharge, preventing her from walking. Gram stain and bacterial culture of tissue biopsies revealed a branching filamentous Gram-positive bacterium that was subsequently identified as Actinomadura madurae by 16S rRNA gene amplification and sequencing. She was treated with long-term co-trimoxazole and multiple 3-week cycles of amikacin with a good therapeutic response. We report the first patient with actinomycetoma from Laos. The disease should be considered in the differential diagnosis of chronic skin and bone infections in patients from rural SE Asia.


Spatial and body-size dependent response of marine pelagic communities to projected global climate change.
Temperature, oxygen, and food availability directly affect marine life. Climate models project a global warming of the ocean's surface (~+3 °C), a de-oxygenation of the ocean's interior (~-3%) and a decrease in total marine net primary production (~-8%) under the 'business as usual' climate change scenario (RCP8.5). We estimated the effects of these changes on biological communities using a coupled biogeochemical (PISCES)--ecosystems (APECOSM) model forced by the physical outputs of the last generation of the IPSL-CM Earth System Model. The APECOSM model is a size-structured bio-energetic model that simulates the 3D dynamical distributions of three interactive pelagic communities (epipelagic, mesopelagic, and migratory) under the effects of multiple environmental factors. The PISCES-APECOSM model ran from 1850 to 2100 under historical forcing followed by RCP8.5. Our RCP8.5 simulation highlights significant changes in the spatial distribution, biomass, and maximum body-size of the simulated pelagic communities. Biomass and maximum body-size increase at high latitude over the course of the century, reflecting the capacity of marine organisms to respond to new suitable environment. At low- and midlatitude, biomass and maximum body-size strongly decrease. In those regions, large organisms cannot maintain their high metabolic needs because of limited and declining food availability. This resource reduction enhances the competition and modifies the biomass distribution among and within the three communities: the proportion of small organisms increases in the three communities and the migrant community that initially comprised a higher proportion of small organisms is favored. The greater resilience of small body-size organisms resides in their capacity to fulfill their metabolic needs under reduced energy supply and is further favored by the release of predation pressure due to the decline of large organisms. These results suggest that small body-size organisms might be more resilient to climate change than large ones.


Association of Mediterranean diet, dietary supplements and alcohol consumption with breast density among women in South Germany: a cross-sectional study.
Effects of dietary factors, such as adherence to Mediterranean diet, multivitamin-multimineral supplements use and alcohol consumption on mammographic breast density, an important biomarker of breast cancer risk, are not sufficiently consistent to elaborate preventive recommendations. This study aims to investigate the association between current diet and mammographic density. We performed a cross-sectional study in 424 pre- and post-menopausal women aged 21 to 84 years. Current Mediterranean dietary pattern, multivitamin-multimineral supplements use, alcohol consumption and potential confounders were assessed with a self-administered questionnaire in the University Hospital Ulm (2007-2008). Radiologists evaluated mammographic density according to the American College of Radiology (ACR) classification, which was summarized in low = ACR1/2 and high = ACR3/4 mammographic density. Logistic regression models were used to assess the association between current diet and mammographic density. Adherance to Mediterranean dietary pattern was inversely associated with mammographic density in the models adjusted for age and BMI (per 1 unit increase of score OR 0.95; 95%CI 0.90-0.997). Current use of multivitamin-multimineral supplements was also inversely associated with mammographic density (OR 0.53; 95%CI 0.34-0.83). Further adjustment revealed similar point estimates but the associations were no longer statistically significant. Compared to non-drinkers, excessive alcohol consumption (<10 g/d) was positively associated with mammographic density (OR 1.47; 95%CI 0.82-2.63). Our results show that dietary factors are associated with mammographic density. Adherence to Mediterranean diet and current use of multivitamin-multimineral supplements could be inversely associated with mammographic density and may suggest a protective effect against breast cancer, whereas high alcohol consumption was associated with increased mammographic density.


Roles of neutrophils in the regulation of the extent of human inflammation through delivery of IL-1 and clearance of chemokines.
This study examined the establishment of neutrophilic inflammation in humans. We tested the hypotheses that neutrophil recruitment was associated with local CXCL8 production and that neutrophils themselves might contribute to the regulation of the size of the inflammatory response. Humans were challenged i.d. with endotoxin. Biopsies of these sites were examined for cytokine production and leukocyte recruitment by qPCR and IHC. Additional in vitro models of inflammation examined the ability of neutrophils to produce and sequester cytokines relevant to neutrophilic inflammation. i.d. challenge with 15 ng of a TLR4-selective endotoxin caused a local inflammatory response, in which 1% of the total biopsy area stained positive for neutrophils at 6 h, correlating with 100-fold up-regulation in local CXCL8 mRNA generation. Neutrophils themselves were the major source of the early cytokine IL-1β. In vitro, neutrophils mediated CXCL8 but not IL-1β clearance (>90% clearance of ≤2 nM CXCL8 over 24 h). CXCL8 clearance was at least partially receptor-dependent and modified by inflammatory context, preserved in models of viral infection but reduced in models of bacterial infection. In conclusion, in a human inflammatory model, neutrophils are rapidly recruited and may regulate the size and outcome of the inflammatory response through the uptake and release of cytokines and chemokines in patterns dependent on the underlying inflammatory stimulus.


Stem cell factor-activated bone marrow ameliorates amyotrophic lateral sclerosis by promoting protective microglial migration.
Amyotrophic lateral sclerosis (ALS) is a progressive disease associated with motor neuron death. Several experimental treatments, including cell therapy using hematopoietic or neuronal stem cells, have been tested in ALS animal models, but therapeutic benefits have been modest. Here we used a new therapeutic strategy, bone marrow transplantation (BMT) with stem cell factor (SCF)- or FMS-like tyrosine kinase 3 (flt3)-activated bone marrow (BM) cells for the treatment of hSOD1(G93A) transgenic mice. Motor function and survival showed greater improvement in the SCF group than in the group receiving BM cells that had not been activated (BMT alone group), although no improvement was shown in the flt3 group. In addition, larger numbers of BM-derived cells that expressed the microglia marker Iba1 migrated to the spinal cords of recipient mice compared with the BMT alone group. Moreover, after SCF activation, but not flt3 activation or no activation, the migrating microglia expressed glutamate transporter-1 (GLT-1). In spinal cords in the SCF group, inflammatory cytokines tumor necrosis factor-α and interleukin-1β were suppressed and the neuroprotective molecule insulin-like growth factor-1 increased relative to nontreatment hSOD1(G93A) transgenic mice. Therefore, SCF activation changed the character of the migrating donor BM cells, which resulted in neuroprotective effects. These studies have identified SCF-activated BM cells as a potential new therapeutic agent for the treatment of ALS.


Long-Term Outcomes Associated with Traumatic Brain Injury in Childhood and Adolescence: A Nationwide Swedish Cohort Study of a Wide Range of Medical and Social Outcomes.
Traumatic brain injury (TBI) is the leading cause of disability and mortality in children and young adults worldwide. It remains unclear, however, how TBI in childhood and adolescence is associated with adult mortality, psychiatric morbidity, and social outcomes. In a Swedish birth cohort between 1973 and 1985 of 1,143,470 individuals, we identified all those who had sustained at least one TBI (n = 104,290 or 9.1%) up to age 25 y and their unaffected siblings (n = 68,268) using patient registers. We subsequently assessed these individuals for the following outcomes using multiple national registries: disability pension, specialist diagnoses of psychiatric disorders and psychiatric inpatient hospitalisation, premature mortality (before age 41 y), low educational attainment (not having achieved secondary school qualifications), and receiving means-tested welfare benefits. We used logistic and Cox regression models to quantify the association between TBI and specified adverse outcomes on the individual level. We further estimated population attributable fractions (PAF) for each outcome measure. We also compared differentially exposed siblings to account for unobserved genetic and environmental confounding. In addition to relative risk estimates, we examined absolute risks by calculating prevalence and Kaplan-Meier estimates. In complementary analyses, we tested whether the findings were moderated by injury severity, recurrence, and age at first injury (ages 0-4, 5-9, 6-10, 15-19, and 20-24 y). TBI exposure was associated with elevated risks of impaired adult functioning across all outcome measures. After a median follow-up period of 8 y from age 26 y, we found that TBI contributed to absolute risks of over 10% for specialist diagnoses of psychiatric disorders and low educational attainment, approximately 5% for disability pension, and 2% for premature mortality. The highest relative risks, adjusted for sex, birth year, and birth order, were found for psychiatric inpatient hospitalisation (adjusted relative risk [aRR] = 2.0; 95% CI: 1.9-2.0; 6,632 versus 37,095 events), disability pension (aRR = 1.8; 95% CI: 1.7-1.8; 4,691 versus 29,778 events), and premature mortality (aRR = 1.7; 95% CI: 1.6-1.9; 799 versus 4,695 events). These risks were only marginally attenuated when the comparisons were made with their unaffected siblings, which implies that the effects of TBI were consistent with a causal inference. A dose-response relationship was observed with injury severity. Injury recurrence was also associated with higher risks-in particular, for disability pension we found that recurrent TBI was associated with a 3-fold risk increase (aRR = 2.6; 95% CI: 2.4-2.8) compared to a single-episode TBI. Higher risks for all outcomes were observed for those who had sustained their first injury at an older age (ages 20-24 y) with more than 25% increase in relative risk across all outcomes compared to the youngest age group (ages 0-4 y). On the population level, TBI explained between 2%-6% of the variance in the examined outcomes. Using hospital data underestimates milder forms of TBI, but such misclassification bias suggests that the reported estimates are likely conservative. The sibling-comparison design accounts for unmeasured familial confounders shared by siblings, including half of their genes. Thus, residual genetic confounding remains a possibility but will unlikely alter our main findings, as associations were only marginally attenuated within families. Given our findings, which indicate potentially causal effects between TBI exposure in childhood and later impairments across a range of health and social outcomes, age-sensitive clinical guidelines should be considered and preventive strategies should be targeted at children and adolescents.


Modeling resting-state functional networks when the cortex falls asleep: local and global changes.
The transition from wakefulness to sleep represents the most conspicuous change in behavior and the level of consciousness occurring in the healthy brain. It is accompanied by similarly conspicuous changes in neural dynamics, traditionally exemplified by the change from "desynchronized" electroencephalogram activity in wake to globally synchronized slow wave activity of early sleep. However, unit and local field recordings indicate that the transition is more gradual than it might appear: On one hand, local slow waves already appear during wake; on the other hand, slow sleep waves are only rarely global. Studies with functional magnetic resonance imaging also reveal changes in resting-state functional connectivity (FC) between wake and slow wave sleep. However, it remains unclear how resting-state networks may change during this transition period. Here, we employ large-scale modeling of the human cortico-cortical anatomical connectivity to evaluate changes in resting-state FC when the model "falls asleep" due to the progressive decrease in arousal-promoting neuromodulation. When cholinergic neuromodulation is parametrically decreased, local slow waves appear, while the overall organization of resting-state networks does not change. Furthermore, we show that these local slow waves are structured macroscopically in networks that resemble the resting-state networks. In contrast, when the neuromodulator decrease further to very low levels, slow waves become global and resting-state networks merge into a single undifferentiated, broadly synchronized network.


Effect of exercise intensity on the postexercise sweating threshold.
The hypothesis that the magnitude of the postexercise onset threshold for sweating is increased by the intensity of exercise was tested in eight subjects. Esophageal temperature was monitored as an index of core temperature while sweat rate was measured by using a ventilated capsule placed on the upper back. Subjects remained seated resting for 15 min (no exercise) or performed 15 min of treadmill running at either 55, 70, or 85% of peak oxygen consumption (V(o2 peak)) followed by a 20-min seated recovery. Subjects then donned a liquid-conditioned suit used to regulate mean skin temperature. The suit was first perfused with 20 degrees C water to control and stabilize skin and core temperature before whole body heating. Subsequently, the skin was heated ( approximately 4.0 degrees C/h) until sweating occurred. Exercise resulted in an increase in the onset threshold for sweating of 0.11 +/- 0.02, 0.23 +/- 0.01, and 0.33 +/- 0.02 degrees C above that measured for the no-exercise resting values (P < 0.05) for the 55, 70, and 85% of V(o2 peak) exercise conditions, respectively. We did note that there was a greater postexercise hypotension as a function of exercise intensity as measured at the end of the 20-min exercise recovery. Thus it is plausible that the increase in postexercise threshold may be related to postexercise hypotension. It is concluded that the sweating response during upright recovery is significantly modified by exercise intensity and may likely be influenced by the nonthermal baroreceptor reflex adjustments postexercise.


Systematic technology transfer from biology to engineering.
Solutions to problems move only very slowly between different disciplines. Transfer can be greatly speeded up with suitable abstraction and classification of problems. Russian researchers working on the TRIZ (Teoriya Resheniya Izobretatelskikh Zadatch) method for inventive problem solving have identified systematic means of transferring knowledge between different scientific and engineering disciplines. With over 1500 person years of effort behind it, TRIZ represents the biggest study of human creativity ever conducted, whose aim has been to establish a system into which all known solutions can be placed, classified in terms of function. At present, the functional classification structure covers nearly 3 000 000 of the world's successful patents and large proportions of the known physical, chemical and mathematical knowledge-base. Additional tools are the identification of factors which prevent the attainment of new technology, leading directly to a system of inventive principles which will resolve the impasse, a series of evolutionary trends of development, and to a system of methods for effecting change in a system (Su-fields). As yet, the database contains little biological knowledge despite early recognition by the instigator of TRIZ (Genrich Altshuller) that one day it should. This is illustrated by natural systems evolved for thermal stability and the maintenance of cleanliness.


Proteomic analysis of cell lines to identify the irinotecan resistance proteins.
Chemotherapeutic drug resistance is a frequent cause of treatment failure in colon cancer patients. Several mechanisms have been implicated in drug resistance. However, they are not sufficient to exhaustively account for this resistance emergence. In this study, two-dimensional gel electrophoresis (2-DE) and the PDQuest software analysis were applied to compare the differential expression of irinotecan-resistance-associated protein in human colon adenocarcinoma LoVo cells and irinotecan-resistant LoVo cells (LoVo/irinotecan). The differential protein dots were excised and analysed by ESI-Q-TOF mass spectrometry (MS). Fifteen proteins were identified, including eight proteins with decreased expression and seven proteins with increased expression. The identified known proteins included those that function in diverse biological processes such as cellular transcription, cell apoptosis, electron transport/redox regulation, cell proliferation/differentiation and retinol metabolism pathways. Identification of such proteins could allow improved understanding of the mechanisms leading to the acquisition of chemoresistance.


Targeting the IL-6 dependent phenotype can identify novel therapies for cholangiocarcinoma.
The need for new therapies for cholangiocarcinoma is highlighted by their poor prognosis and refractoriness to chemotherapy. Increased production of Interleukin-6 promotes cholangiocarcinoma growth and contributes to chemoresistance by activating cell survival mechanisms. We sought to identify biologically active compounds capable of ameliorating the phenotypic effects of IL-6 expression and to explore their potential therapeutic use for cholangiocarcinoma. A genomic signature associated with Interleukin-6 expression in Mz-ChA-1 human malignant cholangiocytes was derived. Computational bioinformatics analysis was performed to identify compounds that induced inverse gene changes to the signature. The effect of these compounds on cholangiocarcinoma growth was then experimentally verified in vitro and in vivo. Interactions with other therapeutic agents were evaluated using median effects analysis. A group of structurally related compounds, nitrendipine, nifedipine and felodipine was identified. All three compounds were cytotoxic to Mz-ChA-1 cells with an IC50 for felodipine of 26 µM, nitrendipine, 44 µM and nifedipine, 15 µM. Similar results were observed in KMCH-1, CC-LP-1 and TFK-1 cholangiocarcinoma cell lines. At a fractional effect of 0.5, all three agents were synergistic with either camptothecin or gemcitabine in Mz-ChA-1 cells in vitro. Co-administration of felodipine and gemcitabine decreased the growth of Mz-ChA-1 cell xenografts in nude athymic mice. Computational bioinformatics analysis of phenotype-based genomic expression can be used to identify therapeutic agents. Using this drug discovery approach based on targeting a defined tumor associated phenotype, we identified compounds with the potential for therapeutic use in cholangiocarcinoma.


Helical computed tomographic angiography of the normal canine pancreas.
Helical abdominal computed tomography (CT) was performed in nine normal beagle-mix dogs. Following cephalic vein injection of ionic iodinated contrast medium via power injector (rate 5 ml/s) dual-phase CT was performed in all dogs. A delayed scan was performed in five dogs between 5 and 13 min after the contrast medium injection. The median time of appearance of contrast medium in the aorta and gastroduodenal artery was 6.3 and 7 s, post start injection and 12 and 12.2 s in the gastroduodenal and portal vein, resulting in a purely arterial pancreatic time window of 5-6s. Pancreatic veins and parenchyma remained enhanced until the end of the dynamic scan (40s). The pancreatic parenchyma showed heterogeneous arterial and homogenous venous contrast enhancement which was slightly hypoattenuating compared to the liver. Delayed scans provided best delineation of the pancreas from the liver. The common bile duct could be identified ventral and to the right of the portal vein joining the dorsomedial aspect of proximal duodenum. Because of the very short time window and variable onset of pure arterial enhancement careful planning of dual-phase studies with previous dynamic CT is recommended. Dual-phase CT angiography enables assessment of the arterial supply, parenchymal perfusion and venous drainage of the canine pancreas.


PSRR: A Web Server for Predicting the Regulation of miRNAs Expression by Small Molecules.
Background: MicroRNAs (miRNAs) play key roles in a variety of pathological processes by interacting with their specific target mRNAs for translation repression and may function as oncogenes (oncomiRs) or tumor suppressors (TSmiRs). Therefore, a web server that could predict the regulation relations between miRNAs and small molecules is expected to achieve implications for identifying potential therapeutic targets for anti-tumor drug development. Methods: Upon obtaining positive/known small molecule-miRNA regulation pairs from SM2miR, we generated a multitude of high-quality negative/unknown pairs by leveraging similarities between the small molecule structures. Using the pool of the positive and negative pairs, we created the Dataset1 and Dataset2 datasets specific to up-regulation and down-regulation pairs, respectively. Manifold machine learning algorithms were then employed to construct models of predicting up-regulation and down-regulation pairs on the training portion of pairs in Dataset1 and Dataset2, respectively. Prediction abilities of the resulting models were further examined by discovering potential small molecules to regulate oncogenic miRNAs identified from miRNA sequencing data of endometrial carcinoma samples. Results: The random forest algorithm outperformed four machine-learning algorithms by achieving the highest AUC values of 0.911 for the up-regulation model and 0.896 for the down-regulation model on the testing datasets. Moreover, the down-regulation and up-regulation models yielded the accuracy values of 0.91 and 0.90 on independent validation pairs, respectively. In a case study, our model showed highly-reliable results by confirming all top 10 predicted regulation pairs as experimentally validated pairs. Finally, our predicted binding affinities of oncogenic miRNAs and small molecules bore a close resemblance to the lowest binding energy profiles using molecular docking. Predictions of the final model are freely accessible through the PSRR web server at https://rnadrug.shinyapps.io/PSRR/. Conclusion: Our study provides a novel web server that could effectively predict the regulation of miRNAs expression by small molecules.