[A case of sigmoid colon cancer with liver and ovarian metastases effectively treated by panitumumab after acquiring resistance to prior chemotherapy regimens].
A 44-year-old female was referred to our hospital with a complaint of abdominal fullness. Computed tomography(CT) showed multiple liver masses and a huge ovarian tumor. Colonoscopy revealed a type 4 advanced cancer in the sigmoid colon. She was diagnosed with unresectable liver and ovarian metastases from advanced sigmoid colon cancer, for which we were obliged to select chemotherapy. As the first line, FOLFOX was applied and performed for 6 cycles, followed by FOLFOX plus bevacizumab(BV)for 5 cycles. While no deterioration of liver and ovarian metastases was observed during the course of those chemotherapy regimens, the patient developed a considerable level of acute sensorimotor neuropathic symptoms associated with oxaliplatin-induced peripheral neurotoxicity, forcing us to replace FOLFOX plus BV with FOLFIRI plus BV. Three cycles of FOLFIRI plus BV, however, turned out to be progressive disease with deterioration of liver and ovarian metastases. Since her oxaliplatin-induced neurotoxicity was improved, a regimen of FOLFOX plus BV was once again applied to her for 3 cycles, which failed to prevent her from having a progressive disease. The sequencing of K-RAS genes from the biopsy specimens of sigmoid colon cancer revealed an expression of a wild-type K-RAS. Thus, an addition of panitumumab to FOLFOX was made. Surprisingly, after 3 cycles of the chemotherapy regimen over 3 months, a significant reduction in the size of liver and ovarian metastases was observed. Her sense of abdominal fullness was apparently reduced and was even lower than what it was at admission. Panitumumab has great potential for effective treatment of patients with unresectable stage IV colorectal cancer, even after having acquired resistance to prior chemotherapy regimens.


Light and intermittent smoking among California Black, Hispanic/Latino, and non-Hispanic White men and women.
The prevalence of light and intermittent smoking (LITS) is increasing as the prevalence of heavier smoking continues to fall. The purpose of this study was to examine changes in LITS over time among Blacks, Hispanic/Latinos (Latinos) and non-Hispanic Whites (Whites). Data from the California Tobacco Surveys from 1990, 1992, and 1996 (Time 1 [T1]) were combined and compared to combined data from 1999, 2002, 2005, and 2008 (Time 2 [T2]). T1 participants (N = 50,424) included Blacks (n = 3,029), Latinos (n = 7,910), and Whites (n = 39,485). T2 participants (N = 53,005) included Blacks (n = 5,460), Latinos (n = 14,273), and Whites (n = 33,246). LITS increased by a factor of 12.9% to a rate of 79.6% (76.0-83.2) among Latinos, by 19.4% to a rate of 74.4% (70.9-77.9) among Blacks, and by 51.7% to a rate of 48.9% (47.5-50.3) among Whites. In unadjusted analyses at T1, females were more likely to be LITS than males across ethnic groups. At T2, this sex difference was maintained among Whites, but not Blacks and Latinos. Females were significantly more likely to be LITS than males when controlling for demographic variables. The present study found that LITS rates increased over time for male and female Black, Latino and White adults. There is a need for increased tobacco control attention to LITS across all ethnic groups, but with additional focus on Blacks, Latinos, and women who have the highest rates of LITS.


Prevention of dental erosion of a sports drink by nano-sized hydroxyapatite in situ study.
To evaluate the inhibitory effects of the sports drink containing nano-sized hydroxyapatite (nano-HA) on dental erosion in situ. The study had a single-blind, two-treatment crossover design. The two treatment groups were a control group (CG; Powerade only) and an experimental group (EG; 0.25% wt/vol nano-HA was added to Powerade). Ten subjects wore removable palatal appliances containing bovine enamel specimens. The appliances were immersed in each drink for 10 mins, 4 times a day for 10 days. The tooth surface microhardness (SMH) was tested, and the erosion depth and the morphology of the tooth surface were observed. The data were analysed by repeated measures anova and t-test. Between the baseline and the 10th day, SMH was decreased by 80% in the specimens of the CG (P < 0.001), whereas there was only a 6% decrease in the SMH of the specimens in the EG. An erosion depth of 12.70 ± 4.66 μm and an irregular tooth surface were observed on the 10th day in the specimens of the CG. No dental erosions, however, was observed in the specimens of the EG. The sports drink containing 0.25% nano-HA was effective in preventing dental erosion in situ.


Conserved cysteine residues of GidA are essential for biogenesis of 5-carboxymethylaminomethyluridine at tRNA anticodon.
The 5-carboxymethylaminomethyl modification of uridine (cmnm(5)U) at the anticodon first position occurs in tRNAs that read split codon boxes ending with purine. This modification is crucial for correct translation, by restricting codon-anticodon wobbling. Two conserved enzymes, GidA and MnmE, participate in the cmnm(5)U modification process. Here we determined the crystal structure of Aquifex aeolicus GidA at 2.3 A resolution. The structure revealed the tight interaction of GidA with FAD. Structure-based mutation analyses allowed us to identify two conserved Cys residues in the vicinity of the FAD-binding site that are essential for the cmnm(5)U modification in vivo. Together with mutational analysis of MnmE, we propose a mechanism for the cmnm(5)U modification process where GidA, but not MnmE, attacks the C6 atom of uridine by a mechanism analogous to that of thymidylate synthase. We also present a tRNA-docking model that provides structural insights into the tRNA recognition mechanism for efficient modification.


Increased follistatin levels after oral contraceptive treatment in obese and non-obese women with polycystic ovary syndrome.
Follistatin levels have recently been considered as a marker for inflammation. Our objective was to evaluate the level of circulating follistatin and high-sensitivity C-reactive protein (hsCRP) in women with polycystic ovary syndrome (PCOS) after oral contraceptive (OC) treatment. A total of 56 Taiwanese women with PCOS were enrolled in this prospective observational study in which they were treated for 3 months with OCs (ethinyl estradiol-cyproterone acetate). Blood samples were taken at baseline after treatment during the withdrawal bleed. Body mass index (BMI), lipid profiles, plasma follistatin, hsCRP, fasting glucose, insulin for the homeostasis model assessment of insulin resistance (HOMA-IR) and hormone profiles were measured and analyzed. Total testosterone, free androgen index (FAI), dehydroepiandrosterone sulfate (DHEAS), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol levels were significantly lower, but total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, circulating follistatin and hsCRP were significantly higher than baseline in women with PCOS after treatment with OCs. An elevation of fasting insulin, HOMA-IR and hsCRP after OC treatment was more evident in non-obese than obese women, whereas the elevation of follistatin was significant in both obese and non-obese women. Follistatin and hsCRP levels all showed significant correlations with each other at baseline and after treatment. The differences in follistatin and hsCRP levels from baseline to after OC treatment were significantly associated with the difference in triglyceride levels. Both hsCRP and follistatin levels increase after OC treatment in women with PCOS. Follistatin seems more sensitive than hsCRP alone to represent the aggravated low-grade inflammatory status after OC treatment in obese and non-obese women with PCOS.


A long-period, violently variable X-ray source in a young supernova remnant.
Observations with the Newton X-ray Multimirror Mission satellite show a strong periodic modulation at 6.67 +/- 0.03 hours of the x-ray source at the center of the 2000-year-old supernova remnant RCW 103. No fast pulsations are visible. If genetically tied to the supernova remnant, the source could either be an x-ray binary, composed of a compact object and a low-mass star in an eccentric orbit, or an isolated neutron star. In the latter case, the combination of its age and period would indicate that it is a peculiar magnetar, dramatically slowed down, possibly by a supernova debris disc. Both scenarios require nonstandard assumptions about the formation and evolution of compact objects in supernova explosions.


Determination of Primary Spectral Bands for Remote Sensing of Aquatic Environments.
About 30 years ago, NASA launched the first ocean-color observing satellite:the Coastal Zone Color Scanner. CZCS had 5 bands in the visible-infrared domain with anobjective to detect changes of phytoplankton (measured by concentration of chlorophyll) inthe oceans. Twenty years later, for the same objective but with advanced technology, theSea-viewing Wide Field-of-view Sensor (SeaWiFS, 7 bands), the Moderate-ResolutionImaging Spectrometer (MODIS, 8 bands), and the Medium Resolution ImagingSpectrometer (MERIS, 12 bands) were launched. The selection of the number of bands andtheir positions was based on experimental and theoretical results achieved before thedesign of these satellite sensors. Recently, Lee and Carder (2002) demonstrated that foradequate derivation of major properties (phytoplankton biomass, colored dissolved organicmatter, suspended sediments, and bottom properties) in both oceanic and coastalenvironments from observation of water color, it is better for a sensor to have ~15 bands inthe 400 - 800 nm range. In that study, however, it did not provide detailed analysesregarding the spectral locations of the 15 bands. Here, from nearly 400 hyperspectral (~ 3-nm resolution) measurements of remote-sensing reflectance (a measure of water color)taken in both coastal and oceanic waters covering both optically deep and optically shallowwaters, first- and second-order derivatives were calculated after interpolating themeasurements to 1-nm resolution. From these derivatives, the frequency of zero values foreach wavelength was accounted for, and the distribution spectrum of such frequencies wasobtained. Furthermore, the wavelengths that have the highest appearance of zeros wereidentified. Because these spectral locations indicate extrema (a local maximum orminimum) of the reflectance spectrum or inflections of the spectral curvature, placing the bands of a sensor at these wavelengths maximizes the potential of capturing (and then restoring) the spectral curve, and thus maximizes the potential of accurately deriving properties of the water column and/or bottom of various aquatic environments with a multi-band sensor.


Modulation of Auxin Levels in Pollen Grains Affects Stamen Development and Anther Dehiscence in Arabidopsis.
Auxin regulates diverse aspects of flower development in plants, such as differentiation of the apical meristem, elongation of the stamen, and maturation of anthers and pollen. It is known that auxin accumulates in pollen, but little information regarding the biological relevance of auxin in this tissue at different times of development is available. In this work, we manipulated the amount of free auxin specifically in developing pollen, using transgenic Arabidopsis lines that express the bacterial indole-3-acetic acid-lysine synthetase (iaaL) gene driven by a collection of pollen-specific promoters. The iaaL gene codes for an indole-3-acetic acid-lysine synthetase that catalyzes the conversion of free auxin into inactive indole-3-acetyl-l-lysine. The transgenic lines showed several abnormalities, including the absence of short stamina, a diminished seed set, aberrant pollen tubes, and perturbations in the synchronization of anther dehiscence and stamina development. This article describes the importance of auxin accumulation in pollen and its role in stamina and anther development.


Constitutive expression of pregnancy-associated plasma protein-A in arterial smooth muscle reduces the vascular response to injury in vivo.
Pregnancy-associated plasma protein-A (PAPP-A) functions to increase local IGF-I bioactivity. In this study, we used transgenic mice that constitutively express human PAPP-A in arterial smooth muscle to test the hypothesis that overexpression of PAPP-A enhances vascular smooth muscle cell (SMC) response to IGF-I in vivo. PAPP-A transgenic (Tg) and wild-type (WT) mice underwent unilateral carotid ligation, a model of injury-induced SMC hyperplasia and neointimal formation. In both WT and PAPP-A Tg mice, endogenous PAPP-A mRNA expression showed peak elevation 5 days after carotid ligation. However, PAPP-A Tg mice had 70-75% less neointima than WT at 5 and 10 days postligation, with a significant reduction in occlusion of the ligated artery. WT and PAPP-A Tg mice had equivalent increases in medial area and vessel remodeling postligation. There was little change in medial area and no evidence of neointima in the contralateral carotid of WT or PAPP-A Tg mice. Both WT and PAPP-A Tg carotids exhibited signs of dedifferentiation of SMC, which precedes the increase in proliferation and migration that results in neointimal formation. However, the number of proliferating cells in the media and neointima of the ligated PAPP-A Tg artery was reduced by 90% on day 5 postsurgery compared with WT. This decrease was associated with a significant decrease in an in vivo marker of IGF-I bioactivity and reduced IGF-I-stimulated receptor phosphorylation ex vivo. These data suggest differential effects of chronic (transgenic) and transient (endogenous) PAPP-A expression on neointimal formation following vascular injury that may be due in part to the differential impact on IGF-I signaling.


Invasive interval cancers in the Ostergötland Mammographic Screening Programme: radiological analysis.
The aim of this study was to find out by radiological analysis whether it is possible to prevent interval cancers in screening programmes without a concomitant increase in false positives. Re-scrutiny of all mammograms of 544 interval cancers was implemented. Blinded re-scrutiny of screening mammograms of 390 interval cancers mixed with other cases (prevalence of detectable cases 37 %) by two outside radiologists was also carried out. True interval cancers constituted 49 %, missed tumours 25 %, occult tumours 10 % and unclassifiable cases 16 %. There were no significant differences in survival between true interval cancers, overlooked or misinterpreted cancers, and mammographically occult cancers. In the blinded re-scrutiny both examiners reached a positive predictive value for malignancy of 67 %, and a sensitivity of 69 % and 81 %, respectively. In a screening programme such as this, it was estimated that 100-400 additional women would have to be recalled from screening for further workup in order to detect each additional cancer which would otherwise emerge as an interval cancer. The occurrence of interval cancer increased with age and was influenced by the design of screening. The proportion of patients with potential iatrogenic delay in diagnosis (overlooked and misinterpreted cancers) was equivalent to figures from other studies. There were no significant differences in survival between the various categories of interval cancer. The study confirmed the association of criteria for referral for further investigation with the number of false positives. Efforts to reduce the number of interval cancers by lowering the threshold for recall are likely to be counterproductive.


Toxicosis in horses after ingestion of hoary alyssum.
Fever, limb edema, and laminitis were observed in horses 18 to 36 hours after they consumed hoary alyssum (Berteroa incana) under field and experimental conditions. Clinical signs were not observed in all horses that had ingested the plant. Diagnosis in the field cases was limited to observation of clinical signs and evidence of plant ingestion in hay or on pasture. In most cases, clinical remission was observed 2 to 4 days after empirical treatment, removal of the plant source, or both.


Off-Pump Versus On-Pump Bypass Surgery for Left Main Coronary Artery Disease.
Concerns remain for a greater risk of incomplete revascularization and reduced survival with off-pump coronary artery bypass grafting (CABG) surgery compared with on-pump surgery particularly in patients with left main disease and extensive underlying myocardial ischemia. This study sought to compare outcomes following off-pump versus on-pump surgery for left main disease by performing a post hoc analysis from the multicenter, randomized EXCEL (Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial. The EXCEL trial was designed to compare percutaneous coronary intervention with everolimus-eluting stents versus CABG in patients with left main disease. CABG was performed with or without cardiopulmonary bypass (on-pump vs. off-pump surgery) according to the discretion of the operator. The 3-year outcomes in the off-pump and on-pump groups were compared using inverse probability of treatment weighting (IPTW) for treatment effect estimation. Among 923 CABG patients, 652 and 271 patients underwent on-pump and off-pump surgery, respectively. Despite a similar extent of disease, off-pump surgery was associated with a lower rate of revascularization of the left circumflex coronary artery (84.1% vs. 90.0%; p = 0.01) and right coronary artery (31.1% vs. 40.6%; p = 0.007). After IPTW adjustment for baseline differences, off-pump surgery was associated with a significantly increased risk of 3-year all-cause death (8.8% vs. 4.5%; hazard ratio: 1.94; 95% confidence interval: 1.10 to 3.41; p = 0.02) and a nonsignificant difference in the risk for the composite endpoint of death, myocardial infarction, or stroke (11.8% vs. 9.2%; hazard ratio: 1.28; 95% confidence interval: 0.82 to 2.00; p = 0.28). Among patients with left main disease treated with CABG in the EXCEL trial, off-pump surgery was associated with a lower rate of revascularization of the coronary arteries supplying the inferolateral wall and an increased risk of 3-year all-cause death compared with on-pump surgery.


Methods to detect low quality data and its implication for psychological research.
Web-based data collection methods such as Amazon's Mechanical Turk (AMT) are an appealing option to recruit participants quickly and cheaply for psychological research. While concerns regarding data quality have emerged with AMT, several studies have exhibited that data collected via AMT are as reliable as traditional college samples and are often more diverse and representative of noncollege populations. The development of methods to screen for low quality data, however, has been less explored. Omitting participants based on simple screening methods in isolation, such as response time or attention checks may not be adequate identification methods, with an inability to delineate between high or low effort participants. Additionally, problematic survey responses may arise from survey automation techniques such as survey bots or automated form fillers. The current project developed low quality data detection methods while overcoming previous screening limitations. Multiple checks were employed, such as page response times, distribution of survey responses, the number of utilized choices from a given range of scale options, click counts, and manipulation checks. This method was tested on a survey taken with an easily available plug-in survey bot, as well as compared to data collected by human participants providing both high effort and randomized, or low effort, answers. Identified cases can then be used as part of sensitivity analyses to warrant exclusion from further analyses. This algorithm can be a promising tool to identify low quality or automated data via AMT or other online data collection platforms.


Local learning algorithm for optical neural networks.
An anti-Hebbian local learning algorithm for two-layer optical neural networks is introduced. With this learning rule, the weight update for a certain connection depends only on the input and output of that connection and a global, scalar error signal. Therefore the backpropagation of error signals through the network, as required by the commonly used back error propagation algorithm, is avoided. It still guarantees, however, that the synaptic weights are updated in the error descent direction. With the apparent advantage of simpler optical implementation this learning rule is also shown by simulations to be computationally effective.


Devaluation of Safe Sex by Delay or Uncertainty: A Within-Subjects Study of Mechanisms Underlying Sexual Risk Behavior.
The value of safe sex may be discounted based on contextual factors associated with an opportunity for sex. College students in a within-subjects study selected hypothetical sexual partners from a set of pictures and classified them based on attractiveness and estimated chance of having an sexually transmitted infection (STI). In the Sexual Delay Discounting (SDD) task, participants rated their likelihood (0-100 %) of waiting for some period of time (e.g., 3 h) to have protected sex with their selected partners, when they could have immediate sex without protection. In the Sexual Probability Discounting (SPD) task, participants rated their likelihood of having protected sex if the opportunity was uncertain (e.g., 50 %), when they could have unprotected sex for sure (100 %). All participants included in the final analyses were aware of and had a positive attitude towards protection against STIs as they were likely to have immediate (or certain) protected sex. Results from 432 delay data in the SDD task and 488 probability data in the SPD task showed that participants' preference for safe sex systematically decreased as the delay to and odds against having safe sex increased. However, this preference was altered by the participants' perception of their partner's attractiveness and STI risk.


Synthesis and incorporation of an advanced lipid peroxidation end-product building block into collagen mimetic peptides.
Advanced lipid peroxidation end-products (ALEs) accumulate with ageing and oxidative stress-related diseases. Despite their potential therapeutic value, there are no suitably protected ALE building blocks reported in the literature to enable their site-specific incorporation into synthetic peptides. The synthesis of an Fmoc-protected ALE building block, N∈-(3-methylpyridinium)lysine (MP-lysine) and its incorporation into collagen model peptides is reported.


Sleep, immunity and inflammation in gastrointestinal disorders.
Sleep disorders have become a global issue, and discovering their causes and consequences are the focus of many research endeavors. An estimated 70 million Americans suffer from some form of sleep disorder. Certain sleep disorders have been shown to cause neurocognitive impairment such as decreased cognitive ability, slower response times and performance detriments. Recent research suggests that individuals with sleep abnormalities are also at greater risk of serious adverse health, economic consequences, and most importantly increased all-cause mortality. Several research studies support the associations among sleep, immune function and inflammation. Here, we review the current research linking sleep, immune function, and gastrointestinal diseases and discuss the interdependent relationship between sleep and these gastrointestinal disorders. Different physiologic processes including immune system and inflammatory cytokines help regulate the sleep. The inflammatory cytokines such as tumor necrosis factor, interleukin-1 (IL-1), and IL-6 have been shown to be a significant contributor of sleep disturbances. On the other hand, sleep disturbances such as sleep deprivation have been shown to up regulate these inflammatory cytokines. Alterations in these cytokine levels have been demonstrated in certain gastrointestinal diseases such as inflammatory bowel disease, gastro-esophageal reflux, liver disorders and colorectal cancer. In turn, abnormal sleep brought on by these diseases is shown to contribute to the severity of these same gastrointestinal diseases. Knowledge of these relationships will allow gastroenterologists a great opportunity to enhance the care of their patients.


Interventions for reducing unplanned paediatric admissions: an observational study in one hospital.
Evidence on how best to intervene to improve paediatric acute care and therefore reduce unplanned hospital admissions is weak. We describe service evaluation work at one hospital to assess interventions at critical clinical and service decision points. We conducted an observational study using routine daily-collected data (April 2009-December 2015) from a medium-sized district general hospital in south-west UK, using before-and-after comparisons of admissions-related data to evaluate two interventions implemented in April and November 2014, respectively: (1) an advice and guidance (A&G) phone line, where a senior paediatrician is available for general practitioners (GPs) and emergency department (ED) and (2) a Short Stay Paediatric Assessment Unit (SSPAU). We analysed data on all admitted children (<18 years) in the catchment area (population estimate 27 740 in 2015). Outcomes were GP-referred attendances, ward admissions, less than 1 day admissions and length of stay. A&G phone line was associated with a reduction in the mean number of less than 1 day admissions per month (difference in means before and after intervention -16.6 (95% CI -0.2 to -32.9)) and an increase in overall monthly bed-days (difference 72.5 (95% CI 21.0 to 124.0)), but there was little evidence of a change in GP-referred attendances or ward admissions. SSPAU was associated with a reduction in the mean number of monthly ward admissions (difference -34.6 (95% CI -21.3 to -48.0)) and less than 1 day admissions (difference in means -21.7 (95% CI -8.4 to -35.1)) and a reduction in the mean number of overall bed-days per month (difference -50.2 (95% CI -12.1 to -88.3)). Interventions for reducing time taken to senior clinician review may be effective in better managing paediatric acute care. Further work should explore results by age, condition and injury/illness status.


Intraventricular hemorrhage and neurodevelopmental outcomes in extreme preterm infants.
Not many large studies have reported the true impact of lower-grade intraventricular hemorrhages in preterm infants. We studied the neurodevelopmental outcomes of extremely preterm infants in relation to the severity of intraventricular hemorrhage. A regional cohort study of infants born at 23 to 28 weeks' gestation and admitted to a NICU between 1998 and 2004. Primary outcome measure was moderate to severe neurosensory impairment at 2 to 3 years' corrected age defined as developmental delay (developmental quotient >2 SD below the mean), cerebral palsy, bilateral deafness, or bilateral blindness. Of the 1472 survivors assessed, infants with grade III-IV intraventricular hemorrhage (IVH; n = 93) had higher rates of developmental delay (17.5%), cerebral palsy (30%), deafness (8.6%), and blindness (2.2%). Grade I-II IVH infants (n = 336) also had increased rates of neurosensory impairment (22% vs 12.1%), developmental delay (7.8% vs 3.4%), cerebral palsy (10.4% vs 6.5%), and deafness (6.0% vs 2.3%) compared with the no IVH group (n = 1043). After exclusion of 40 infants with late ultrasound findings (periventricular leukomalacia, porencephaly, ventricular enlargement), isolated grade I-II IVH (n = 296) had increased rates of moderate-severe neurosensory impairment (18.6% vs 12.1%). Isolated grade I-II IVH was also independently associated with a higher risk of neurosensory impairment (adjusted odds ratio 1.73, 95% confidence interval 1.22-2.46). Grade I-II IVH, even with no documented white matter injury or other late ultrasound abnormalities, is associated with adverse neurodevelopmental outcomes in extremely preterm infants.


Temporal changes in cell marker expression and cellular infiltration in a controlled cortical impact model in adult male C57BL/6 mice.
Traumatic injury to the central nervous system (CNS) triggers a robust inflammatory response that leads to axonal damage and secondary degeneration of spared tissue. In contrast, some immune responses have neuroprotective effects. However, detailed information regarding the dynamics of immune responses after traumatic CNS injury is still unavailable. In the present study, changes in the immune cells present in the injured brain, spleen, and cervical lymph nodes (CLNs), which are draining lymphatic organs from the CNS, were analyzed after controlled cortical impact (CCI) by flow cytometry and immunohistochemistry. The number of neutrophils and macrophages that infiltrated the injured brain immediately increased 1 d post-injury and declined rapidly thereafter. In the injured brain, resident microglia showed a bimodal increase during the first week and in the chronic phase (≥3 weeks) after injury. Increase in the Iba-1(+) microglia/macrophages was observed around the injured site. Morphologic analysis showed that Iba-1(+) cells were round at 1 week, whereas those at 3 weeks were more ramified. Furthermore, CD86(+)/CD11b(+) M1-like microglia increased at 4 weeks after CCI, whereas CD206(+)/CD11b(+) M2-like microglia increased at 1 week. These results suggest that different subsets of microglia increased in the acute and chronic phases after CCI. Dendritic cells and T cells increased transiently within 1 week in the injured brain. In the CLNs and the spleen, T cells showed dynamic changes after CCI. In particular, the alteration in the number of T cells in the CLNs showed a similar pattern, with a 1-week delay, to that of microglia in the injured brain. The data from this study provide useful information on the dynamics of immune cells in CNS injuries.


Intentionality and meta-awareness of mind wandering: Are they one and the same, or distinct dimensions?
Researchers have recently demonstrated that mind-wandering episodes can vary on numerous dimensions, and it has been suggested that assessing these dimensions will play an important role in our understanding of mind wandering. One dimension that has received considerable attention in recent work is the intentionality of mind wandering. Although it has been claimed that indexing the intentionality of mind wandering will be necessary if researchers are to obtain a coherent understanding of the wandering mind, one concern is that this dimension might be redundant with another, longstanding, dimension: namely, meta-awareness. Thus, the utility of the argument for assessing intentionality rests upon a demonstration that this dimension is distinct from the meta-awareness dimension. To shed light on this issue, across two studies we compared and contrasted these dimensions to determine whether they are redundant or distinct. In both studies, we found support for the view that these dimensions are distinct.


The regenerative effects of CCN2 independent modules on chondrocytes in vitro and osteoarthritis models in vivo.
The role of CCN family proteins has been proven to be of extreme importance in the process of cartilage development and endochondral ossification. The second member, CCN2, consists of 4 conserved modules that interact with a number of cofactors to display multiple functions. Although the potentially therapeutic effect of intact CCN2 on cartilage regeneration has been indicated by a number of studies, the regenerative effect of independent modules comprising CCN2 has never been evaluated before. This study aims to discover a more robust and effective CCN2 derivative to induce regeneration through assessing the effect of CCN2 independent modules on regeneration in vitro and in vivo, in comparison to the full length CCN2. In vitro evaluation using human chondrocytic cells showed a remarkable enhancing effect of several single modules on the gene expression of cartilaginous extracellular matrix components; whereas combinations of 2 or 3 modules rather diminished such effects. Interestingly, combination of all 4 modules redeemed the effect of intact CCN2 in vitro. Suspecting the re-assembly of the 4 modules, interaction among the modules was examined by surface plasmon resonance analysis. However, the results did not support the possible formation of a tetramodular complex. Next, the thrombospondin 1 type 1 repeat module (TSP1), which was found most promising in the experiments in vitro, and the combination of 4 modules were forwarded further to in vivo confirmation using 2 rat osteoarthritis (OA) models. As a result, TSP1 displayed more prominent regenerative effects than intact CCN2 on damaged cartilage. Unexpectedly, the combination of 4 modules showed limited effects in vivo. These results indicate the utility of TSP1 in the regenerative therapeutics of OA. Possible molecular mechanism that enables conditional reconstruction of CCN2 by 4 modules is discussed as well.


Dysregulation of Signaling Pathways Due to Differentially Expressed Genes From the B-Cell Transcriptomes of Systemic Lupus Erythematosus Patients - A Bioinformatics Approach.
Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disorder that is clinically complex and has increased production of autoantibodies. Via emerging technologies, researchers have identified genetic variants, expression profiling of genes, animal models, and epigenetic findings that have paved the way for a better understanding of the molecular and genetic mechanisms of SLE. Our current study aimed to illustrate the essential genes and molecular pathways that are potentially involved in the pathogenesis of SLE. This study incorporates the gene expression profiling data of the microarray dataset GSE30153 from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) between the B-cell transcriptomes of SLE patients and healthy controls were screened using the GEO2R web tool. The identified DEGs were subjected to STRING analysis and Cytoscape to explore the protein-protein interaction (PPI) networks between them. The MCODE (Molecular Complex Detection) plugin of Cytoscape was used to screen the cluster subnetworks that are highly interlinked between the DEGs. Subsequently, the clustered DEGs were subjected to functional annotation with ClueGO/CluePedia to identify the significant pathways that were enriched. For integrative analysis, we used GeneGo MetacoreTM, a Cortellis Solution software, to exhibit the Gene Ontology (GO) and enriched pathways between the datasets. Our study identified 4 upregulated and 13 downregulated genes. Analysis of GO and functional enrichment using ClueGO revealed the pathways that were statistically significant, including pathways involving T-cell costimulation, lymphocyte costimulation, negative regulation of vascular permeability, and B-cell receptor signaling. The DEGs were mainly enriched in metabolic networks such as the phosphatidylinositol-3,4,5-triphosphate pathway and the carnitine pathway. Additionally, potentially enriched pathways, such as the signaling pathways induced by oxidative stress and reactive oxygen species (ROS), chemotaxis and lysophosphatidic acid signaling induced via G protein-coupled receptors (GPCRs), and the androgen receptor activation pathway, were identified from the DEGs that were mainly associated with the immune system. Four genes (EGR1, CD38, CAV1, and AKT1) were identified to be strongly associated with SLE. Our integrative analysis using a multitude of bioinformatics tools might promote an understanding of the dysregulated pathways that are associated with SLE development and progression. The four DEGs in SLE patients might shed light on the pathogenesis of SLE and might serve as potential biomarkers in early diagnosis and as therapeutic targets for SLE.


Role of rivaroxaban in the management of atrial fibrillation: insights from clinical practice.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and it leads to significant morbidity and mortality, predominantly from ischemic stroke. Vitamin K antagonists, mainly warfarin, have been used for decades to prevent ischemic stroke in AF, but their use is limited due to interactions with food and other drugs, as well as the requirement for regular monitoring of the international normalized ratio. Rivaroxaban, a direct factor Xa inhibitor and the most commonly used non-vitamin K oral anticoagulant, avoids many of these challenges and is being prescribed with increasing frequency for stroke prevention in non-valvular AF. Randomized controlled trial (RCT) data from the ROCKET-AF(Rivaroxaban once daily oral direct Factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation) trial have shown rivaroxaban to be non-inferior to warfarin in preventing ischemic stroke and systemic embolism and to have comparable overall bleeding rates. Applicability of the RCT data to real-world practice can sometimes be limited by complex clinical scenarios or multiple comorbidities not adequately represented in the trials. Available real-world evidence in non-valvular AF patients with comorbidities - including renal impairment, acute coronary syndrome, diabetes mellitus, malignancy, or old age - supports the use of rivaroxaban as safe and effective in preventing ischemic stroke in these subgroups, though with some important considerations required to reduce bleeding risk. Patient perspectives on rivaroxaban use are also considered. Real-world evidence indicates superior rates of drug adherence with rivaroxaban when compared with vitamin K antagonists and with alternative non-vitamin K oral anticoagulants - perhaps, in part, due to its once-daily dosing regimen. Furthermore, self-reported quality of life scores are highest among patients compliant with rivaroxaban therapy. The generally high levels of patient satisfaction with rivaroxaban therapy contribute to overall favorable clinical outcomes.


Uncovering Cryptic Parasitoid Diversity in Horismenus (Chalcidoidea, Eulophidae).
Horismenus parasitoids are an abundant and understudied group of eulophid wasps found mainly in the New World. Recent surveys based on morphological analyses in Costa Rica have quadrupled the number of named taxa, with more than 400 species described so far. This recent revision suggests that there is still a vast number of unknown species to be identified. As Horismenus wasps have been widely described as parasitoids of insect pests associated with crop plants, it is of high importance to properly establish the extant diversity of the genus, in order to provide biological control practitioners with an exhaustive catalog of putative control agents. In this study, we first collected Horismenus wasps from wild Phaseolus bean seeds in Central Mexico and Arizona to assess the genetic relatedness of three morphologically distinct species with overlapping host and geographical ranges. Sequence data from two nuclear and two mitochondrial gene regions uncovered three cryptic species within each of the three focal species (i.e., H. missouriensis, H. depressus and H. butcheri). The monophyly of each cryptic group is statistically supported (except in two of them represented by one single tip in which monophyly cannot be tested). The phylogenetic reconstruction is discussed with respect to differences between gene regions as well as likely reasons for the differences in variability between species.


Impact of Gamification of Vision Tests on the User Experience.
Gamification has been incorporated into vision tests and vision therapies in the expectation that it may increase the user experience and engagement with the task. The current study aimed to understand how gamification affects the user experience, specifically during the undertaking of psychophysical tasks designed to estimate vision thresholds (chromatic and achromatic contrast sensitivity). Three tablet computer-based games were developed with three levels of gaming elements. Game 1 was designed to be a simple clinical test (no gaming elements), game 2 was similar to game 1 but with added gaming elements (i.e., feedback, scores, and sounds), and game 3 was a complete game. Participants (N = 144, age: 9.9-42 years) played three games in random order. The user experience for each game was assessed using a Short Feedback Questionnaire. The median (interquartile range) fun level for the three games was 2.5 (1.6), 3.9 (1.7), and 2.5 (2.8), respectively. Overall, participants reported greater fun level and higher preparedness to play the game again for game 2 than games 1 and 3 (P < 0.05). There were significant positive correlations observed between fun level and preparedness to play the game again for all the games (p < 0.05). Engagement (assessed as completion rates) did not differ between the games. Gamified version (game 2) was preferred to the other two versions. Over the short term, the careful application of gaming elements to vision tests was found to increase the fun level of users, without affecting engagement with the vision test.


Electrosorption at functional interfaces: from molecular-level interactions to electrochemical cell design.
Adsorption at charged interfaces plays an important role across all aspects of physical chemistry, from biological interactions within living organisms to chemical processes such as catalysis and separations. With recent advances in materials chemistry, there are a host of modified electrodes being investigated for electrosorption, especially in separations science. In this perspective, we provide an overview of functional interfaces being used for electrosorption, ranging from electrochemical separations such as deionization and selective product recovery to biological applications. We cover the various molecular mechanisms which can be used to enhance ion capacity, and in some cases, provide selectivity; as well as discuss the parasitic Faradaic reactions which often impair electrosorption performance. Finally, we point to the importance of electrochemical configurations, in particular the advantages of asymmetric cell design, and highlight the opportunities for selective electrosorption brought about by redox-mediated systems.


Correlation of stellar scintillation in different photometric bands.
Theoretical relations were obtained to calculate the correlation of stellar scintillation, when a star is measured simultaneously in two different photometric bands (channels). Differential color scintillation and the respective indices are proposed for practical evaluation of the correlation. Asymptotic dependence for the case of an infinitely small receiving aperture is derived and analyzed. The effect of atmospheric dispersion, which transforms the color differences into spatial differences, is examined. Additionally, the effect of the deviation of real optical turbulence from Kolmogorov turbulence is estimated. The obtained relations were compared with simultaneous measurements in three photometric bands and different receiving apertures in the range of 1 to 15 cm. It is shown that the measurements and calculated estimations of the color scintillation agree well.


Hermansky-Pudlak syndrome type 4 in a patient from Sri Lanka with pulmonary fibrosis.
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and a platelet storage pool deficiency. Some patients also develop fatal pulmonary fibrosis and some have granulomatous colitis. Six human genes HPS1, ADB3A, HPS3, HPS4, HPS5, and HPS6 have been identified as cause of the six known subtypes of HPS. While there exist nearly 500 Puerto Rican and non-Puerto Rican HPS-1 patients, very few HPS-4 patients have been reported, and most of these have not been described in detail. We now delineate the clinical characteristics of an HPS-4 patient homozygous for a novel HPS-4 mutation, P685delC. The patient, the first individual with HPS reported from Sri Lanka, had severe pulmonary fibrosis, typical of HPS-1 disease, without granulomatous colitis. We conclude that pulmonary fibrosis occurs as part of HPS-4 and that HPS should be considered in all ethnic groups.


Numerical chromosomal instability mediates susceptibility to radiation treatment.
The exquisite sensitivity of mitotic cancer cells to ionizing radiation (IR) underlies an important rationale for the widely used fractionated radiation therapy. However, the mechanism for this cell cycle-dependent vulnerability is unknown. Here we show that treatment with IR leads to mitotic chromosome segregation errors in vivo and long-lasting aneuploidy in tumour-derived cell lines. These mitotic errors generate an abundance of micronuclei that predispose chromosomes to subsequent catastrophic pulverization thereby independently amplifying radiation-induced genome damage. Experimentally suppressing whole-chromosome missegregation reduces downstream chromosomal defects and significantly increases the viability of irradiated mitotic cells. Further, orthotopically transplanted human glioblastoma tumours in which chromosome missegregation rates have been reduced are rendered markedly more resistant to IR, exhibiting diminished markers of cell death in response to treatment. This work identifies a novel mitotic pathway for radiation-induced genome damage, which occurs outside of the primary nucleus and augments chromosomal breaks. This relationship between radiation treatment and whole-chromosome missegregation can be exploited to modulate therapeutic response in a clinically relevant manner.


Cardiac catheter complications related to left main stem disease.
To examine the incidence and outcome of cardiac catheter complications related to left main coronary artery disease or damage using the CECCC (Confidential Enquiry into Cardiac Catheter Complications) database. Coordinating centre for national database. Retrospective analysis of reports to a national multicentre database for cardiac catheter complications. Complications involving the left main coronary artery were flagged at entry. Where necessary additional information was sought from participating centres. 112,921 procedures were registered, 12,849 of which were coronary angioplasties and the remainder diagnostic studies. The total number of cases for which complications were recorded was 993 (0.88%). In 61 (6.14%) of the 993 cases complications were associated with left main coronary disease or damage. In 57 (93%) of these 61 cases complications were major, necessitating resuscitation or immediate coronary bypass grafting. Ten patients (16%) died in the catheter laboratory, a further 9 (15%) within 24 hours, and a total of 23 patients (38%) died within one month of the procedure. Left main stem related complications account for 17% of total mortality in the CECCC database. Urgent coronary bypass grafting was attempted in 42 patients, of whom 31 were alive at one month. In all of the six reported PTCA-related complications the cause was traumatic damage to the left main coronary artery. Operators of all grades of seniority experienced complications in similar proportions. The risk of a complication relating to the left main stem is relatively low, but when such complications occur they tend to be life-threatening and contribute a fifth of total catheter-related mortality. In the absence of a widely available non-invasive investigation with good predictive value for left main stem disease, the best safeguard is careful technique. Patients who do develop complications should have emergency coronary bypass grafting.


Interrater agreement and reliability of clinical tests for assessment of patients with shoulder pain in primary care.
Background: There is limited information about the agreement and reliability of clinical shoulder tests. Objectives: To assess the interrater agreement and reliability of clinical shoulder tests in patients with shoulder pain treated in primary care. Methods: Patients with a primary report of shoulder pain underwent a set of 21 clinical shoulder tests twice on the same day, by pairs of independent physical therapists. The outcome parameters were observed and specific interrater agreement for positive and negative scores, and interrater reliability (Cohen's kappa (κ)). Positive and negative interrater agreement values of ≥0.75 were regarded as sufficient for clinical use. For Cohen's κ, the following classification was used: <0.20 poor, 0.21-0.40 fair, 0.41-0.60 moderate, 0.61-0.80 good, 0.81-1.00 very good reliability. Participating clinics were randomized in two groups; with or without a brief practical session on how to conduct the tests. Results: A total of 113 patients were assessed in 12 physical therapy practices by 36 physical therapists. Positive and negative interrater agreement values were both sufficient for 1 test (the Full Can Test), neither sufficient for 5 tests, and only sufficient for either positive or negative agreement for 15 tests. Interrater reliability was fair for 11 tests, moderate for 9 tests, and good for 1 test (the Full Can Test). An additional brief practical session did not result in better agreement or reliability. Conclusion: Clinicians should be aware that interrater agreement and reliability for most shoulder tests is questionable and their value in clinical practice limited.


Formation of nanowires via single particle-triggered linear polymerization of solid-state aromatic molecules.
Nanowires occupy a prestigious place in nanoelectronics, nanomechanics, and biomimetics. Although there are notable methods to grow nanowires via self-assembly, there is a key drawback in the need to find out the specific conditions appropriate for each system. In this sense, universal techniques to fabricate such nanowires from various organic materials have been sought for the continued progress of the related research field. Here we report one of the promising and facile methodologies to quantitatively produce nanowires with controlled geometrical parameters. In this method, referred to as "Single Particle-Triggered Linear Polymerization (STLiP)", organic thin films on a supporting substrate were irradiated with high-energy charged particles, accelerated by particle accelerators. Each particle penetrates from the top of the films to the substrate while gradually releasing kinetic energy along its trajectory (ion track), generating reactive intermediates such as radical species that eventually induce propagation reactions. The resulting polymerized products were integrated into nanowires with uniform diameter and length that can be isolated via development with appropriate organic solvents. Considering the widely applicable nature of STLiP to organic materials, the present technique opens a new door for access to a number of functional nanowires and their assembly.


Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU.
Prophylaxis for gastrointestinal stress ulceration is frequently given to patients in the intensive care unit (ICU), but its risks and benefits are unclear. In this European, multicenter, parallel-group, blinded trial, we randomly assigned adults who had been admitted to the ICU for an acute condition (i.e., an unplanned admission) and who were at risk for gastrointestinal bleeding to receive 40 mg of intravenous pantoprazole (a proton-pump inhibitor) or placebo daily during the ICU stay. The primary outcome was death by 90 days after randomization. A total of 3298 patients were enrolled; 1645 were randomly assigned to the pantoprazole group and 1653 to the placebo group. Data on the primary outcome were available for 3282 patients (99.5%). At 90 days, 510 patients (31.1%) in the pantoprazole group and 499 (30.4%) in the placebo group had died (relative risk, 1.02; 95% confidence interval [CI], 0.91 to 1.13; P=0.76). During the ICU stay, at least one clinically important event (a composite of clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection, or myocardial ischemia) had occurred in 21.9% of patients assigned to pantoprazole and 22.6% of those assigned to placebo (relative risk, 0.96; 95% CI, 0.83 to 1.11). In the pantoprazole group, 2.5% of patients had clinically important gastrointestinal bleeding, as compared with 4.2% in the placebo group. The number of patients with infections or serious adverse reactions and the percentage of days alive without life support within 90 days were similar in the two groups. Among adult patients in the ICU who were at risk for gastrointestinal bleeding, mortality at 90 days and the number of clinically important events were similar in those assigned to pantoprazole and those assigned to placebo. (Funded by Innovation Fund Denmark and others; SUP-ICU ClinicalTrials.gov number, NCT02467621 .).


Plasma amyloid beta, apolipoprotein E, lacunar infarcts, and white matter lesions.
Lacunar brain infarcts and cerebral white matter lesions are frequently observed on magnetic resonance imaging scans in elderly subjects. These lesions are also frequent in patient with cerebral amyloid angiopathy. We examined whether plasma amyloid beta peptide (Abeta) levels are associated with lacunar infarcts and white matter lesions in the general population, and whether the apolipoprotein E (APOE) genotype modifies these associations. We studied 1,077 participants within the population-based Rotterdam Scan Study, who were 60 to 90 years of age and free of dementia. Cross-sectional associations were analyzed by regression models with adjustments for age, sex, creatinine levels, and hypertension. In APOE epsilon4 carriers, plasma Abeta levels were positively associated with lacunar infarcts and white matter lesions, whereas in noncarriers no associations were observed. Per standard deviation increase in Abeta(1-40) and Abeta(1-42) levels the odds ratios for lacunar infarcts were 1.72 (95% confidence interval [CI] = 1.22-2.43) and 1.93 (95% CI = 1.31-2.85), the periventricular white matter lesion grade increased by 0.32 (95% CI = 0.08-0.57) and 0.29 (95% CI = 0.00-0.57), and the subcortical white matter lesion volume increased by 0.48 ml (95% CI = 0.04-0.91) and 0.24 ml (95% CI = -0.27-0.75). Higher Abeta levels are associated with more lacunar infarcts and white matter lesions in elderly subjects who carry an APOE epsilon4 allele.


Sensory gaze stabilization in echolocating bats.
Sensing from a moving platform is challenging for both man-made machines and animals. Animals' heads jitter during movement, so if the sensors they carry are not stabilized, any spatial estimation might be biased. Flying animals, like bats, seriously suffer from this problem because flapping flight induces rapid changes in acceleration which moves the body up and down. For echolocating bats, the problem is crucial. Because they emit a sound to sense the world, an unstable head means sound energy pointed in the wrong direction. It is unknown how bats mitigate this problem. By tracking the head and body of flying fruit bats, we show that they stabilize their heads, accurately maintaining a fixed acoustic-gaze relative to a target. Bats can solve the stabilization task even in complete darkness using only echo-based information. Moreover, the bats point their echolocation beam below the target and not towards it, a strategy that should result in better estimations of target elevation.


Differences in planning performance, a neurocognitive endophenotype, are associated with a functional variant in PER3 gene.
Performance alterations in executive function have been studied as potential endophenotypes for several neuropsychiatric diseases. Planning is an important component of executive function and has been shown to be affected in diseases such as attention deficit hyperactivity disorder, schizophrenia, obsessive-compulsive disorder and Parkinson's disease. Several genes related to dopaminergic systems, such as COMT, have been explored as candidates for influencing planning performance. The circadian clock gene PERIOD3 (PER3) has been shown to be associated with several complex behaviors in humans and could be involved in different signaling mechanisms. In this study, we evaluated the possible association between a functional polymorphism in the PER3 gene (PER3-VNTR, rs57875989) and performance in a commonly used test of planning (Tower of London, TOL) in 229 healthy subjects from Bogotá, Colombia. PER3-VNTR genotyping was carried out with conventional PCR and all participants completed the TOL test using the computerized Psychology Experiment Building Language (PEBL) battery. A linear regression model was used for the analysis of association with the SNPStats program. We found that 4/4 genotype carriers showed a better performance and made fewer moves, in comparison to 4/5 and 5/5 genotype carriers (p = 0.003). These results appear to be independent from effects of this polymorphism on self-reported average hours of sleep during work days in our sample. This is the first evidence of an association between PER3-VNTR and planning performance in a sample of healthy subjects and our results are consistent from previous findings for alterations in other cognitive domains. Future studies examining additional genes could lead to the identification of novel molecular underpinnings of planning in healthy subjects and in patients with neuropsychiatric disorders.


Screening Cranial Imaging at Multiple Time Points Improves Cystic Periventricular Leukomalacia Detection.
The aim of this study is to determine whether the cystic periventricular leukomalacia (cPVL) detection rate differs between imaging studies performed at different time points. We retrospectively reviewed the prospectively collected data of 31,708 infants from the NICHD Neonatal Research Network. Inclusion criteria were infants < 1,000 g birth weight or < 29 weeks' gestational age who had cranial imaging performed using both early criterion (cranial ultrasound [CUS] < 28 days chronological age) and late criterion (CUS, magnetic resonance imaging, or computed tomography closest to 36 weeks postmenstrual age [PMA]). We compared the frequency of cPVL diagnosed by early and late criteria. About 664 (5.2%) of the 12,739 infants who met inclusion criteria had cPVL using either early or late criteria; 569 using the late criterion, 250 using the early criterion, and 155 patients at both times. About 95 (14.3%) of 664 cPVL cases seen on early imaging were no longer visible on repeat screening closest to 36 weeks PMA. Such disappearance of cPVL was more common in infants < 26 weeks' gestation versus infants of 26 to 28 weeks' gestation (18.5 vs. 11.5%; p = 0.013). Cranial imaging at both < 28 days chronological age and closest to 36 weeks PMA improves cPVL detection, especially for more premature infants.


Innovation in Indigenous Health and Medical Education: The Leaders in Indigenous Medical Education (LIME) Network as a Community of Practice.
The Leaders in Indigenous Medical Education (LIME) Network aims to improve the quality and effectiveness of Indigenous health in medical education as well as best practice in the recruitment, retention, and graduation of Indigenous medical students. In this article we explore the utility of Etienne Wenger's "communities of practice" (CoP) concept in providing a theoretical framework to better understand the LIME Network as a form of social infrastructure to further knowledge and innovation in this important area of health care education reform. The Network operates across all medical schools in Australia and New Zealand. Utilizing a model of evaluation of communities of practice developed by Fung-Kee-Fung et al., we seek to analyze the outcomes of the LIME Network as a CoP and assess its approach and contribution to improving the implementation of Indigenous health in the medical curriculum and the graduation of Indigenous medical students. By reflecting on the Network through a community of practice lens, this article highlights the synthesis between the LIME Network and Wenger's theory and provides a framework with which to measure Network outputs. It also posits an opportunity to better capture the impact of Network activities into the future to ensure that it remains a relevant and sustainable entity.


Frequency and severity of harm of medication errors related to the parenteral nutrition process in a large university teaching hospital.
To determine the frequency of medication errors, as well as the severity of harm resulting from these errors, related to the prescription, transcription, preparation, and administration of parenteral nutrition formulations. Prospective, observational study. 471-bed, academic teaching hospital. All adult and pediatric inpatients receiving parenteral nutrition between November 1, 2002 and May 31, 2004. The occurrence of incorrect prescribing practices, wrong formulation preparation, operational system errors, order entry errors related to automated technology, and incorrect administration practices were documented. In addition, the specific step in the drug process--prescription, transcription, preparation, and administration--at the time that the error occurred was noted. Harm scores, to assess the severity of the error in relation to the safety of the patient, were assigned based on the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP). The rate of errors with parenteral nutrition was then compared with the rate of errors with other high-alert drugs, both at our institution and at a health care consortium. A total of 4730 prescriptions for parenteral nutrition were written during the study period; 74 (1.6%) were associated with a medication error. Of these errors, 1 (1%) occurred during the prescription process (and was detected before preparation), 29 (39%) occurred during the transcription process, 18 (24%) during preparation, and 26 (35%) during the administration process. Sixty-seven (91%) of the 74 errors were considered nonharmful, as defined by NCC MERP, whereas 6 (8%) contributed to or resulted in temporary harm to a patient. The rate of errors was similar between our institution and the consortium, both for parenteral nutrition formulations and for other high-alert drugs. The overall incidence of medication errors during the study was 15.6 errors/1000 parenteral nutrition prescriptions compounded. Our results demonstrate that medication errors related to the prescription, transcription, preparation, and administration of parenteral nutrition formulations occur and occasionally result in harm. Health care institutions should develop quality assurance programs to document compliance with published safe practice guidelines for parenteral nutrition.


Effects of air pollution on ecosystems and biological diversity in the eastern United States.
Conservation organizations have most often focused on land-use change, climate change, and invasive species as prime threats to biodiversity conservation. Although air pollution is an acknowledged widespread problem, it is rarely considered in conservation planning or management. In this synthesis, the state of scientific knowledge on the effects of air pollution on plants and animals in the Northeastern and Mid-Atlantic regions of the United States is summarized. Four air pollutants (sulfur, nitrogen, ozone, and mercury) and eight ecosystem types ranging from estuaries to alpine tundra are considered. Effects of air pollution were identified, with varying levels of certainty, in all the ecosystem types examined. None of these ecosystem types is free of the impacts of air pollution, and most are affected by multiple pollutants. In aquatic ecosystems, effects of acidity, nitrogen, and mercury on organisms and biogeochemical processes are well documented. Air pollution causes or contributes to acidification of lakes, eutrophication of estuaries and coastal waters, and mercury bioaccumulation in aquatic food webs. In terrestrial ecosystems, the effects of air pollution on biogeochemical cycling are also very well documented, but the effects on most organisms and the interaction of air pollution with other stressors are less well understood. Nevertheless, there is strong evidence for effects of nitrogen deposition on plants in grasslands, alpine areas, and bogs, and for nitrogen effects on forest mycorrhizae. Soil acidification is widespread in forest ecosystems across the eastern United States and is likely to affect the composition and function of forests in acid-sensitive areas over the long term. Ozone is known to cause reductions in photosynthesis in many terrestrial plant species. For the most part, the effects of these pollutants are chronic, not acute, at the exposure levels common in the eastern United States. Mortality is often observed only at experimentally elevated exposure levels or in combination with other stresses such as drought, freezing, or pathogens. The notable exceptions are the acid/aluminum effects on aquatic organisms, which can be lethal at levels of acidity observed in many surface waters in the region. Although the effects are often subtle, they are important to biological conservation. Changes in species composition caused by terrestrial or aquatic acidification or eutrophication can propagate throughout the food webs to affect many organisms beyond those that are directly sensitive to the pollution. Likewise, sublethal doses of toxic pollutants may reduce the reproductive success of the affected organisms or make them more susceptible to potentially lethal pathogens. Many serious gaps in knowledge that warrant further research were identified. Among those gaps are the effects of acidification, ozone, and mercury on alpine systems, effects of nitrogen on species composition of forests, effects of mercury in terrestrial food webs, interactive effects of multiple pollutants, and interactions among air pollution and other environmental changes such as climate change and invasive species. These gaps in knowledge, coupled with the strong likelihood of impacts on ecosystems that have not been studied in the region, suggests that current knowledge underestimates the actual impact of air pollutants on biodiversity. Nonetheless, because known or likely impacts of air pollution on the biodiversity and function of natural ecosystems are widespread in the Northeast and Mid-Atlantic regions, the effects of air pollution should be considered in any long-term conservation strategy. It is recommended that ecologically relevant standards, such as "critical loads," be adopted for air pollutants and the importance of long-term monitoring of air pollution and its effects is emphasized.


Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial.
Purpose Most crizotinib-treated patients with anaplastic lymphoma kinase gene ( ALK)-rearranged non-small-cell lung cancer (ALK-positive NSCLC) eventually experience disease progression. We evaluated two regimens of brigatinib, an investigational next-generation ALK inhibitor, in crizotinib-refractory ALK-positive NSCLC. Patients and Methods Patients were stratified by brain metastases and best response to crizotinib. They were randomly assigned (1:1) to oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (180 mg once daily [with lead-in]; arm B). Investigator-assessed confirmed objective response rate (ORR) was the primary end point. Results Of 222 patients enrolled (arm A: n = 112, 109 treated; arm B: n = 110, 110 treated), 154 (69%) had baseline brain metastases and 164 of 222 (74%) had received prior chemotherapy. With 8.0-month median follow-up, investigator-assessed confirmed ORR was 45% (97.5% CI, 34% to 56%) in arm A and 54% (97.5% CI, 43% to 65%) in arm B. Investigator-assessed median progression-free survival was 9.2 months (95% CI, 7.4 to 15.6) and 12.9 months (95% CI, 11.1 to not reached) in arms A and B, respectively. Independent review committee-assessed intracranial ORR in patients with measurable brain metastases at baseline was 42% (11 of 26 patients) in arm A and 67% (12 of 18 patients) in arm B. Common treatment-emergent adverse events were nausea (arm A/B, 33%/40%), diarrhea (arm A/B, 19%/38%), headache (arm A/B, 28%/27%), and cough (arm A/B, 18%/34%), and were mainly grades 1 to 2. A subset of pulmonary adverse events with early onset (median onset: day 2) occurred in 14 of 219 treated patients (all grades, 6%; grade ≥ 3, 3%); none occurred after escalation to 180 mg in arm B. Seven of 14 patients were successfully retreated with brigatinib. Conclusion Brigatinib yielded substantial whole-body and intracranial responses as well as robust progression-free survival; 180 mg (with lead-in) showed consistently better efficacy than 90 mg, with acceptable safety.


Pre- and postsynaptic beta-adrenergic activation enhances excitatory synaptic transmission in layer V/VI pyramidal neurons of the medial prefrontal cortex of rats.
Norepinephrine exerts an important influence on prefrontal cortical functions. The physiological effects of beta-adrenoceptors (beta-ARs) have been examined in other brain regions. However, little is known about beta-AR regulation of synaptic transmission in the prefrontal cortex (PFC). The present study investigated beta-AR modulation of glutamate synaptic transmission in layer V/VI pyramidal cells of the medial PFC (mPFC) of rats. Our results show that 1) isoproterenol (ISO), a selective beta-AR agonist, increased the frequency of spontaneous and miniature excitatory postsynaptic currents (EPSC's); 2) ISO enhancement of miniature EPSC's (mEPSC's) frequency no longer appeared in the presence of the voltage-gated Ca(2+) channel blocker cadmium; 3) ISO enhanced the evoked excitatory postsynaptic currents (eEPSC's) mediated by non-N-methyl-D-aspartic acid receptors (non-NMDA-Rs) and NMDA-Rs. The ISO facilitation of non-NMDA-R eEPSC was blocked by the membrane-permeable cyclic adenosine monophosphate (cAMP) inhibitor Rp-adenosine 3',5'-cyclic monophosphorothioate triethylammonium salt (Rp-cAMPS); 4) ISO enhanced NMDA-induced current, with no effect on glutamate-induced non-NMDA-R current; 5) ISO enhancement of NMDA-R eEPSC and NMDA-induced current was blocked by intracellular application of Rp-cAMPS or the cAMP-dependent protein kinase (PKA) inhibitor PKI(5-24); and 6) ISO suppressed the paired-pulse facilitation of non-NMDA-R and NMDA-R eEPSC's. Taken together, these results provide the first electrophysiological demonstration that beta-AR activation facilitates excitatory synaptic transmission in mPFC pyramidal cells through pre- and postsynaptic mechanisms, probably via cAMP or cAMP/PKA signaling.


China has faster pace than Japan in population aging in next 25 years.
The aging of a population structure is an inevitable path of demographic transition, as an inescapable result of decline in fertility rate and extension in life expectancy. Although demographic transition occurred earlier in Japan than in China, the two countries had similar patterns, both of which took a much shorter period of time than Western countries to complete demographic transition, as well as have been aging at a rapid speed that has rarely been seen in the world. Japan has the highest level of population aging in the world, and China has been experiencing a very fast pace of the population aging process and has the largest older population. Drawing upon data from World Population Prospects (2019), this paper compares changes in population aging in both China and Japan. Findings show that Japan's aging process is 30 years ahead of China, but China has been changing in a similar way as Japan. To be specific, both countries experienced four phases of the population aging process: accelerated development period, rapid development period, slow down period and high-level maintained period. In addition, both countries had a quick growing rate of population aging. It will take China 23 years and 10 years respectively for the aging rate increasing from 7% to 14% and then to 20%, while Japan took 24 and 11 years respectively, which is much shorter than developed countries in the West. Furthermore, China has a faster pace than Japan in population aging in the next 25 years. We found that from 2019-2044, China's aging rate, elderly dependency ratio, oldest-old coefficient and median age of population will increase 13.24 percent points, 24.21 percent points, 8.33 percent points, and 8.47 years, while the four indicators of Japan will increase 8.38 percent points, 22.52 percent points, 8.29 percent points, and 6.20 years, respectively.


Central serotonergic lesions increase voluntary alcohol consumption in Sprague Dawley rats: moderation by long-term ethanol administration.
The relationship between central serotonergic activities and voluntary alcohol consumption was studied in Sprague-Dawley rats, which normally have low alcohol preference. After initial screening for an evenly matched baseline alcohol preference, selective central serotonergic lesioning was induced by intracisternal injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). Control rats received injections of vehicle only. Both 5,7-DHT and vehicle-treated rats were further divided into two subgroups, which either had continued free access to ethanol (alcohol-drinking) or were deprived of it (alcohol-free). All rats were then tested again for alcohol preference. All rats were then killed, and the levels of monoamines in the brains were determined by high performance liquid chromatography with electrochemical detection. Behavioral results indicated that all 5,7-DHT-treated rats had significantly higher alcohol preference and consumption than the corresponding sham controls. Except in the cerebellum, the 5,7-DHT-treated rats had significantly lower levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in most brain regions compared with those in the corresponding sham controls. Treatment with 5,7-DHT also resulted in a decrease in serotonin turnover in all brain regions in the alcohol-free rats, except in the cerebellum. In alcohol-drinking rats, however, 5,7-DHT treatment only reduced serotonin turnover in the pons. The levels of norepinephrine and dopamine in several brain regions were not significantly different. Thus, it appeared that in the Sprague Dawley rats, 5,7-DHT treatment depleted 5-HT and 5-HIAA levels in most brain regions while increasing alcohol consumption. Chronic alcohol-drinking attenuated the increase in alcohol consumption associated with serotonergic lesions. Voluntary alcohol consumption seemed more associated with 5-HT turnover than with tissue 5-HT levels. Our data also suggested that tolerance to alcohol-induced hypothermia was primarily attributable to long-term alcohol drinking rather than serotonergic lesioning.


Honey and cardiovascular risk factors, in normal individuals and in patients with diabetes mellitus or dyslipidemia.
Diabetes mellitus, hypercholesteremia, hypertension (HTN), and obesity are well-known risk factors for cardiovascular diseases (CVD). Various medications are currently in use for management of these comorbidities. Undesirable side effects are unavoidable and the ultimate and ideal goal is hardly achieved. Honey and other bee products are widely used in traditional medicine for management of many diseases. Others and the authors have found potent biological activities of these products. Honey is now reintroduced in modern medicine as part of wound and burn management. Honey has antioxidant, anti-inflammatory, and antimicrobial activities. More studies are exploring other aspects of honey activity such as its effect on blood sugar, body weight, lipid profile, C-reactive protein, nitric oxide, proinflammatory prostaglandins, and homocysteine. Growing evidence and scientific data support the use of honey in patients with diabetes, HTN, dyslipidemia, obesity, and CVD. This review discusses clinical and preclinical studies on potential influence of honey on diabetes mellitus and cardiovascular risk factors, and emphasizes the importance of conducting more clinical and controlled studies.


Licochalcone A attenuates abdominal aortic aneurysm induced by angiotensin II via regulating the miR-181b/SIRT1/HO-1 signaling.
Licochalcone A (LA), a chalcone derived from liquorice, exhibits multiple biological activities, including anti-oxidation and anti-inflammation. This study aimed to investigate the role and underlying mechanism of LA in the abdominal aortic aneurysm (AAA). AAA model was established by continuous infusion of 1000 ng/kg/min of angiotensin II (AngII) in ApoE -/- mice for 4 weeks. At 7 days before AngII administration, 5 mg/kg/day or 10 mg/kg/day of LA was intraperitoneally administered to mice and continued for 4 weeks. The characteristics and quantification of AAAs were determined in situ. Real-time PCR or western blot was used to measure mRNA or protein levels of matrix metalloproteinase 2 and matrix metalloproteinase 9; pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6; apoptosis-related proteins Bax, Bcl-2, and active caspase-3; miR-181b; Sirtuin 1 (SIRT1); and heme oxygenase-1 (HO-1). Mouse-aorta-origin vascular smooth muscle (MOVAS) cells were used to confirm the involved pathways in vitro. We found LA administration dose-dependently reduced the incidence of AngII-induced AAA, aneurysm diameter enlargement, elastin degradation, matrix metalloproteinase production, pro-inflammatory cytokines and miR-181b expression, and vascular smooth muscle cell apoptosis. It elevated SIRT1 and HO-1 expression that was suppressed by AngII. AngII enhanced miR-181b but reduced SIRT1 and HO-1 expression in MOVAS cells. In AngII-stimulated MOVAS cells, downregulation of miR-181b significantly upregulated the expression of SIRT1 and HO-1, the effect of which was abrogated by SIRT1 siRNA. Collectively, LA could attenuate AngII-induced AAA by modulating the miR-181b/SIRT1/HO-1 signaling. LA might be a potential medical therapy for small AAA.


Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: treating cancer like an infectious disease.
Here, we propose a new strategy for the treatment of early cancerous lesions and advanced metastatic disease, via the selective targeting of cancer stem cells (CSCs), a.k.a., tumor-initiating cells (TICs). We searched for a global phenotypic characteristic that was highly conserved among cancer stem cells, across multiple tumor types, to provide a mutation-independent approach to cancer therapy. This would allow us to target cancer stem cells, effectively treating cancer as a single disease of "stemness", independently of the tumor tissue type. Using this approach, we identified a conserved phenotypic weak point - a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells. Interestingly, several classes of FDA-approved antibiotics inhibit mitochondrial biogenesis as a known "side-effect", which could be harnessed instead as a "therapeutic effect". Based on this analysis, we now show that 4-to-5 different classes of FDA-approved drugs can be used to eradicate cancer stem cells, in 12 different cancer cell lines, across 8 different tumor types (breast, DCIS, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma (brain)). These five classes of mitochondrially-targeted antibiotics include: the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug, and chloramphenicol. Functional data are presented for one antibiotic in each drug class: azithromycin, doxycycline, tigecycline, pyrvinium pamoate, as well as chloramphenicol, as proof-of-concept. Importantly, many of these drugs are non-toxic for normal cells, likely reducing the side effects of anti-cancer therapy. Thus, we now propose to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types. These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent clinical trials with doxycycline and azithromycin (intended to target cancer-associated infections, but not cancer cells) have already shown positive therapeutic effects in cancer patients, although their ability to eradicate cancer stem cells was not yet appreciated.


Patients as subjects for research: ethical dilemmas for the primary care clinician-investigator.
Past studies suggested an association between human papillomavirus (HPV) and cervical intraepithelial neoplasia (CIN). In 1987, University of North Carolina (UNC) Hospitals Family Practice Center clinicians were approached for a control population to study this association. One hundred five patients attending the UNC Hospitals Neoplasia Clinic with biopsy-proven CIN 2 or 3 and 268 control patients attending the UNC Family Practice Center for a routine Papanicolaou smear were enrolled in this case-control study. Case and control patients consented to having an additional cervical specimen taken and to being interviewed. The cervical specimens were classified by the Southern blot and polymerase chain reaction techniques for HPV. Early results suggested the control patients who had HPV were at high risk of developing CIN. Interventions were made to inform these patients of this risk and need for closer follow-up, causing a wide range of patient reactions. The final results showed no association of HPV with CIN, indicating the early interventions were premature. Physicians engaged in research need to be prepared to deal with the discovery of health risks in the otherwise "normal" control patient. They bear the ethical responsibility of scrutinizing study design and methods and planning communication with patients from the inception of a study.


Electrophysiological findings and long-term outcomes of percutaneous ablation of atrial arrhythmias after surgical ablation for atrial fibrillation†.
Percutaneous ablation (PA) for relapsing atrial tachyarrhythmias after surgical ablation is an emerging therapy. The aim of this study is to report the electrophysiological findings and the procedural long-term outcomes of reablation, in this particular clinical setting. We retrospectively analysed all patients who were readmitted to our centre for relapsing atrial arrhythmias after surgical ablation for atrial fibrillation (AF). From 2000 to 2011, 36 patients with previous surgical ablation of AF received additional percutaneous management. Seven patients had had biatrial Maze, 18 left atrial ablation lesion set and 11 pulmonary vein isolation. Energy sources involved were unipolar radiofrequency (RF) (n = 13), bipolar RF (n = 19), combined bipolar RF and cryoenergy (n = 2), cryoenergy (n = 1) and high intensity focused ultrasound (n = 1). The median time to reablation was 34 months (interquartile range: 10-66). The relapsing arrhythmias were left atrial tachycardia (n = 17), AF (n = 15), right atrial flutter (n = 2), right atrial tachycardia (n = 1) and biatrial atrial tachycardia (n = 1). Origin of re-entrant circuits was perimitral (n = 27), around pulmonary veins (PV) including posterior left atrium (n = 15) and cavotricuspid isthmus (n = 3). Twenty-seven (75%) patients had left isthmus catheter ablation and 11 (30%) reablation of PV. Eighteen out of the 27 perimitral circuits were in patients with previous left-atrial Maze; in 17 patients the mitral line was performed with bipolar RF only, without the addition of cryoenergy. The importance of an appropriate energy source is also underlined by the prevalence of gaps in PV isolation that occurred for two-thirds of patients treated using unipolar RF only, which has been discontinued since 2001. Ten patients (27%) needed more than 1 PA for relapsing arrhythmia. At the last follow-up of 97 ± 42 months, freedom from arrhythmias was 53% after single PAs and 67% after more than one procedure. No morbidity, mortality or strokes were recorded during the follow-up. Percutaneous treatment of highly symptomatic patients with unsuccessful previous surgical ablation is feasible, and relatively effective at the late follow-up. A multidisciplinary approach significantly improves the outcomes in these challenging patients.


The two pore channel TPC2 is dispensable in pancreatic β-cells for normal Ca²⁺ dynamics and insulin secretion.
Ca(2+) signals are central to the stimulation of insulin secretion from pancreatic β-cells by glucose and other agents, including glucagon-like peptide-1 (GLP-1). Whilst Ca(2+) influx through voltage-gated Ca(2+) channels on the plasma membrane is a key trigger for glucose-stimulated secretion, mobilisation of Ca(2+) from acidic stores has been implicated in the control of more localised Ca(2+) changes and membrane potential. Nicotinic acid adenine dinucleotide phosphate (NAADP), generated in β-cells in response to high glucose, is a potent mobiliser of these stores, and has been proposed to act through two pore channels (TPC1 and TPC2, murine gene names Tpcn1 and Tpcn2). Whilst the role of TPC1 in the control of Ca(2+) mobilisation and insulin secretion was recently confirmed, conflicting data exist for TPC2. Here, we used the selective and efficient deleter strain, Ins1Cre to achieve β-cell selective deletion of the Tpcn2 gene in mice. βTpcn2 KO mice displayed normal intraperitoneal and oral glucose tolerance, and glucose-stimulated Ca(2+) dynamics and insulin secretion from islets were similarly normal. GLP-1-induced Ca(2+) increases involved an increase in oscillation frequency from 4.35 to 4.84 per minute (p=0.04) at 8mM glucose, and this increase was unaffected by the absence of Tpcn2. The current data thus indicate that TPC2 is not absolutely required for normal glucose- or incretin-stimulated insulin secretion from the β-cell. Our findings suggest that TPC1, whose expression tended to increase in Tpcn2 null islets, might be sufficient to support normal Ca(2+) dynamics in response to stimulation by nutrients or incretins.


Human immunodeficiency virus types 1 and 2 and simian immunodeficiency virus Nef use distinct but overlapping target sites for downregulation of cell surface CD4.
Although the Nef proteins encoded by human immunodeficiency virus type 1 (HIV-1) and simian immuno-deficiency virus (SIV) are known to induce the efficient internalization and degradation of cell surface CD4, it remains unclear whether this process involves a direct interaction between Nef and CD4. Here, we report that CD4 downregulation by HIV-1 and SIV Nef requires distinct but overlapping target sites within the CD4 intracytoplasmic domain. In particular, mutation of a glutamic acid residue located at CD4 residue 405 or of arginine and methionine residues located, respectively, at residue 406 and 407 results in a mutant CD4 protein that is efficiently downregulated by HIV-1 Nef but refractory to downregulation by SIV Nef. However, both HIV-1 and SIV Nef require an isoleucine located at residue 410 and the dileucine motif found at CD4 residues 413 and 414. CD4 downregulation induced by the Nef protein encoded by HIV-2 is shown to require a CD4 target sequence that is similar to, but distinct from, that observed with SIV Nef. These data explain the previous finding that the murine CD4 protein, which has an alanine at residue 405, is refractory to downregulation by SIV, but not HIV-1, Nef (J. L. Foster, S.J. Anderson, A. L. B. Frazier, and J. V. Garcia, Virology 201:373-379, 1994). In addition, these observations provide strong genetic support for the hypothesis that the Nef-mediated downregulation of cell surface CD4 requires a direct Nef-CD4 interaction.


Roles of individual prolyl-4-hydroxylase isoforms in the first 24 hours following transient focal cerebral ischaemia: insights from genetically modified mice.
This study investigated the function of each of the hypoxia inducible factor (HIF) prolyl-4-hydroxylase enzymes (PHD1–3) in the first 24 h following transient focal cerebral ischaemia by using mice with each isoform genetically suppressed. Male, 8- to 12-week old PHD1−/−, PHD2+/− and PHD3−/− mice and their wild-type (WT) littermate were subjected to 45 min of middle cerebral artery occlusion (MCAO). During the experiments, regional cerebral blood flow (rCBF) was recorded by laser Doppler flowmetry. Behaviour was assessed at both 2 h and 24 h after reperfusion with a common neuroscore. Infarct volumes, blood–brain barrier (BBB) disruption, cerebral vascular density, apoptosis, reactive oxygen species (ROS), HIF1α, and glycogen levels were then determined using histological and immunohistochemical techniques. When compared to their WT littermates, PHD2+/− mice had significantly increased cerebral microvascular density and more effective restoration of CBF upon reperfusion. PHD2+/− mice showed significantly better functional outcomes and higher activity rates at both 2 h and 24 h after MCAO, associated with significant fewer apoptotic cells in the penumbra and less BBB disruption; PHD3−/− mice had impaired rCBF upon early reperfusion but comparable functional outcomes; PHD1−/− mice did not show any significant changes following the MCAO. Production of ROS, HIF1α staining and glycogen content in the brain were not different in any comparison. Life-long genetic inhibition of PHD enzymes produces different effects on outcome in the first 24 h after transient cerebral ischaemia. These need to be considered in optimizing therapeutic effects of PHD inhibitors, particularly when isoform specific inhibitors become available.


Prediction of breeding values and selection responses with genetic heterogeneity of environmental variance.
There is empirical evidence that genotypes differ not only in mean, but also in environmental variance of the traits they affect. Genetic heterogeneity of environmental variance may indicate genetic differences in environmental sensitivity. The aim of this study was to develop a general framework for prediction of breeding values and selection responses in mean and environmental variance with genetic heterogeneity of environmental variance. Both means and environmental variances were treated as heritable traits. Breeding values and selection responses were predicted with little bias using linear, quadratic, and cubic regression on individual phenotype or using linear regression on the mean and within-family variance of a group of relatives. A measure of heritability was proposed for environmental variance to standardize results in the literature and to facilitate comparisons to "conventional" traits. Genetic heterogeneity of environmental variance can be considered as a trait with a low heritability. Although a large amount of information is necessary to accurately estimate breeding values for environmental variance, response in environmental variance can be substantial, even with mass selection. The methods developed allow use of the well-known selection index framework to evaluate breeding strategies and effects of natural selection that simultaneously change the mean and the variance.


Consultation needs in perinatal HIV care: experience of the National Perinatal HIV Consultation Service.
This study evaluates the consultation needs of clinicians who provide perinatal human immunodeficiency virus (HIV) care in the United States. The Perinatal Hotline (1-888-448-8765) is a telephone consultation service for providers who treat HIV-infected pregnant women and their infants. Hotline calls were analyzed for demographics about callers and their patients and information about consultation topics. There were 430 calls to the hotline from January 1, 2005, through June 30, 2006. Most calls (59.5%) were related to pregnant patients; 5.1% of the calls pertained to women currently in labor. The most common topic was HIV care in pregnancy (49.1%), particularly antiretroviral drug use (42.1%). HIV testing was discussed in 21.9%, and intrapartum treatment was discussed in 24.0%. Callers most often requested help choosing antiretroviral drug regimens; many of the discussions were about drug toxicities and viral resistance. Although the hotline received few calls about women in labor, the need for these consultations is expected to increase with the expanding use of rapid HIV testing. Access to 24-hour consultation can help ensure that state-of-the-art care is provided.


Adherence Determinants in Cystic Fibrosis: Cluster Analysis of Parental Psychosocial, Religious, and/or Spiritual Factors.
Cystic fibrosis is a progressive disease requiring a complex, time-consuming treatment regimen. Nonadherence may contribute to an acceleration of the disease process. Spirituality influences some parental healthcare behaviors and medical decision-making. We hypothesized that parents of children with cystic fibrosis, when classified into groups based on adherence rates, would share certain psychosocial and religious and/or spiritual variables distinguishing them from other adherence groups. We conducted a multisite, prospective, observational study focused on parents of children younger than 13 years old at two cystic fibrosis center sites (Site 1, n= 83; Site 2, n = 59). Religious and/or spiritual constructs, depression, and marital adjustment were measured by using previously validated questionnaires. Determinants of adherence included parental attitude toward treatment, perceived behavioral norms, motivation, and self-efficacy. Adherence patterns were measured with the Daily Phone Diary, a validated instrument used to collect adherence data. Cluster analysis identified discrete adherence patterns, including parents' completion of more treatments than prescribed. For airway clearance therapy, four adherence groups were identified: median adherence rates of 23%, 52%, 77%, and 120%. These four groups differed significantly for parental depression, sanctification of their child's body, and self-efficacy. Three adherence groups were identified for nebulized medications: median adherence rates of 35%, 82%, and 130%. These three groups differed significantly for sanctification of their child's body and self-efficacy. Our results indicated that parents in each group shared psychosocial and religious and/or spiritual factors that differentiated them. Therefore, conversations about adherence likely should be tailored to baseline adherence patterns. Development of efficacious religious and/or spiritual interventions that promote adherence by caregivers of children with cystic fibrosis may be useful.


Characterization and surface-reactivity of nanocrystalline anatase in aqueous solutions.
The chemical and electrostatic interactions at mineral-water interfaces are of fundamental importance in many geochemical, materials science, and technological processes; however, the effects of particle size at the nanoscale on these interactions are poorly known. Therefore, comprehensive experimental and characterization studies were completed, to begin to assess the effects of particle size on the surface reactivity and charging of metal-oxide nanoparticles in aqueous solutions. Commercially available crystalline anatase (TiO2) particles were characterized using neutron and X-ray small-angle scattering, electron microscopy, and laser diffraction techniques. The 4 nm primary nanoparticles were found to exist almost exclusively in a hierarchy of agglomerated structures. Potentiometric and electrophoretic mobility titrations were completed in NaCl media at ionic strengths from (0.005 to 0.3) mol/kg, and 25 degrees C, with these two experimental techniques matched as closely as the different procedures permitted. The pH of zero net proton charge (pHznpc, from potentiometric titration) and isoelectric point pH value (pHiep, from electrophoretic mobility titrations) were both in near perfect agreement (6.85 +/- 0.02). At high ionic strengths the apparent pHznpc value was offset slightly toward lower pH values, which suggests some specific adsorption of the Na+ electrolyte ions. Proton-induced surface charge curves of nanocrystalline anatase were very similar to those of larger rutile crystallites when expressed relative to their respective pHznpc values, indicating that the development of positive and negative surface charge away from the pHznpc for nanocrystalline anatase is similar to that of larger TiO2 crystallites.


Accelerating electrostatic pair methods on graphical processing units to study molecules in supercritical carbon dioxide.
Traditionally, electrostatic interactions are modelled using Ewald techniques, which provide a good approximation, but are poorly suited to GPU architectures. We use the GPU versions of the LAMMPS MD package to implement and assess the Wolf summation method. We compute transport and structural properties of pure carbon dioxide and mixtures of carbon dioxide with either methane or difluoromethane. The diffusion of pure carbon dioxide is indistinguishable when using the Wolf summation method instead of PPPM on GPUs. The optimum value of the potential damping parameter, α, is 0.075. We observe a decrease in accuracy when the system polarity increases, yet the method is robust for mildly polar systems. We anticipate the method can be used for a number of techniques, and applied to a variety of systems. Substitution of PPPM can yield a two-fold decrease in the wall-clock time.


A novel transient structure with phylogenetic implications found in ratite spermatids.
A novel transient structure was observed in the spermatids of three ratite species using transmission electron microscopy. The structure first appeared at the circular manchette stage of sperm development, was most prominent during the longitudinal manchette phase and disappeared abruptly prior to spermiation. It was composed of regularly-spaced finger-like projections which were closely associated with the outer nuclear membrane, giving the nucleus a cogwheel-like appearance. The projections were approximately 30 nm long and 14 nm wide. Although a similar structure has been described in certain lizard and crocodile species, this is the first report of a similar structure in the developing spermatids of birds. The potential value of non-traditional characters, such as spermiogenesis and sperm ultrastructure, as phylogenetic markers has recently been advocated. The morphologically unique structure found in ratite spermatids provides additional evidence of a possible phylogenetic link between the reptiles and birds. It also endorses the basal positioning of the ratites as a monophyletic group within the avian phylogenetic tree.