Dopamine Modulates Delta-Gamma Phase-Amplitude Coupling in the Prefrontal Cortex of Behaving Rats.
Dopamine release and phase-amplitude cross-frequency coupling (CFC) have independently been implicated in prefrontal cortex (PFC) functioning. To causally investigate whether dopamine release affects phase-amplitude comodulation between different frequencies in local field potentials (LFP) recorded from the medial PFC (mPFC) of behaving rats, we used RuBiDopa, a light-sensitive caged compound that releases the neurotransmitter dopamine when irradiated with visible light. LFP power did not change in any frequency band after the application of light-uncaged dopamine, but significantly strengthened phase-amplitude comodulation between delta and gamma oscillations. Saline did not exert significant changes, while injections of dopamine and RuBiDopa produced a slow increase in comodulation for several minutes after the injection. The results show that dopamine release in the medial PFC shifts phase-amplitude comodulation from theta-gamma to delta-gamma. Although being preliminary results due to the limitation of the low number of animals present in this study, our findings suggest that dopamine-mediated modification of the frequencies involved in comodulation could be a mechanism by which this neurotransmitter regulates functioning in mPFC.


Multi-Talker Speech Promotes Greater Knowledge-Based Spoken Mandarin Word Recognition in First and Second Language Listeners.
Spoken word recognition involves a perceptual tradeoff between the reliance on the incoming acoustic signal and knowledge about likely sound categories and their co-occurrences as words. This study examined how adult second language (L2) learners navigate between acoustic-based and knowledge-based spoken word recognition when listening to highly variable, multi-talker truncated speech, and whether this perceptual tradeoff changes as L2 listeners gradually become more proficient in their L2 after multiple months of structured classroom learning. First language (L1) Mandarin Chinese listeners and L1 English-L2 Mandarin adult listeners took part in a gating experiment. The L2 listeners were tested twice - once at the start of their intermediate/advanced L2 language class and again 2 months later. L1 listeners were only tested once. Participants were asked to identify syllable-tone words that varied in syllable token frequency (high/low according to a spoken word corpus) and syllable-conditioned tonal probability (most probable/least probable in speech given the syllable). The stimuli were recorded by 16 different talkers and presented at eight gates ranging from onset-only (gate 1) through onset +40 ms increments (gates 2 through 7) to the full word (gate 8). Mixed-effects regression modeling was used to compare performance to our previous study which used single-talker stimuli (Wiener et al., 2019). The results indicated that multi-talker speech caused both L1 and L2 listeners to rely greater on knowledge-based processing of tone. L1 listeners were able to draw on distributional knowledge of syllable-tone probabilities in early gates and switch to predominantly acoustic-based processing when more of the signal was available. In contrast, L2 listeners, with their limited experience with talker range normalization, were less able to effectively transition from probability-based to acoustic-based processing. Moreover, for the L2 listeners, the reliance on such distributional information for spoken word recognition appeared to be conditioned by the nature of the acoustic signal. Single-talker speech did not result in the same pattern of probability-based tone processing, suggesting that knowledge-based processing of L2 speech may only occur under certain acoustic conditions, such as multi-talker speech.


Nurses' experiences of guideline implementation: a focus group study.
The aim of the study was to address the following questions: What kind of experiences do primary care nurses have of guideline implementation? What do nurses think are the most important factors affecting the adoption of guidelines? The implementation of clinical guidelines seems to be dependent on multiple context-specific factors. This study sets out to explore the experiences of primary care nurses concerning guideline implementation. Qualitative interview. Data were generated by four focus group interviews involving nurses working in out-patient services in primary health centres in Finland. Purposive sampling was used to select health centres. Inductive content analysis was used to identify themes emerging from the data. Four main groups of factors were identified from the analysis of data: (i) factors related to the organisation, (ii) factors related to nurses, (iii) factors related to the anticipated consequences and (iv) factors related to the patient group. Nurses' awareness and acceptance of guidelines and the anticipated positive consequences facilitate the implementation of guidelines. Organisational support, especially the adapting of guidelines to local circumstances, seems to be crucial for successful implementation. Clinical guidelines can be promising tools in enhancing evidence-based nursing practice, as nurses see them as practical work tools in patient care and so are willing to adopt them. However, support from management and physicians is needed to ensure the successful implementation of guidelines into nursing practices. Based on the findings of this study and previous knowledge of guideline implementation some practical recommendations are suggested. Select the most relevant guidelines to clinical practice, organise the adaptation of guidelines to local circumstances, inform all practitioners involved in treatment and give clear instructions for the adoption of the guidelines.


Effects of GH and/or sex steroid administration on abdominal subcutaneous and visceral fat in healthy aged women and men.
Aging is associated with reduced GH, IGF-I, and sex steroid axis activity and with increased abdominal fat. We employed a randomized, double-masked, placebo-controlled, noncross-over design to study the effects of 6 months of administration of GH alone (20 microg/kg BW), sex hormone alone (hormone replacement therapy in women, testosterone enanthate in men), or GH + sex hormone on total abdominal area, abdominal sc fat, and visceral fat in 110 healthy women (n = 46) and men (n = 64), 65-88 yr old (mean, 72 yr). GH administration increased IGF-I levels in women (P = 0.05) and men (P = 0.0001), with the increment in IGF-I levels being higher in men (P = 0.05). Sex steroid administration increased levels of estrogen and testosterone in women and men, respectively (P = 0.05). In women, neither GH, hormone replacement therapy, nor GH + hormone replacement therapy altered total abdominal area, sc fat, or visceral fat significantly. In contrast, in men, administration of GH and GH + testosterone enanthate decreased total abdominal area by 3.9% and 3.8%, respectively, within group and vs. placebo (P = 0.05). Within-group comparisons revealed that sc fat decreased by 10% (P = 0.01) after GH, and by 14% (P = 0.0005) after GH + testosterone enanthate. Compared with placebo, sc fat decreased by 14% (P = 0.05) after GH, by 7% (P = 0.05) after testosterone enanthate, and by 16% (P = 0.0005) after GH + testosterone enanthate. Compared with placebo, visceral fat did not decrease significantly after administration of GH, testosterone enanthate, or GH + testosterone enanthate. These data suggest that in healthy older individuals, GH and/or sex hormone administration elicits a sexually dimorphic response on sc abdominal fat. The generally proportionate reductions we observed in sc and visceral fat, after 6 months of GH administration in healthy aged men, contrast with the disproportionate reduction of visceral fat reported after a similar period of GH treatment of nonelderly GH deficient men and women. Whether longer term administration of GH or testosterone enanthate, alone or in combination, will reduce abdominal fat distribution-related cardiovascular risk in healthy older men remains to be elucidated.


Automated structure elucidation of organic molecules from (13)c NMR spectra using genetic algorithms and neural networks.
The automated structure elucidation of organic molecules from experimentally obtained properties is extended by an entirely new approach. A genetic algorithm is implemented that uses molecular constitution structures as individuals. With this approach, the structure of organic molecules can be optimized to meet experimental criteria, if in addition a fast and accurate method for the prediction of the used physical or chemical features is available. This is demonstrated using (13)C NMR spectrum as readily obtainable information. (13)C NMR chemical shift, intensity, and multiplicity information is available from (13)C NMR DEPT spectra. By means of artificial neural networks a fast and accurate method for calculating the (13)C NMR spectrum of the generated structures exists. The approach is limited by the size of the constitutional space that has to be searched and by the accuracy of the shift prediction for the unknown substance. The method is implemented and tested successfully for organic molecules with up to 20 non-hydrogen atoms.


Multiscale and morphological analysis of microvascular patterns depicted in contrast-enhanced ultrasound images.
Purpose: Impaired insulin-induced microvascular recruitment in skeletal muscle contributes to insulin resistance in type 2 diabetic disease. Previously, quantification of microvascular recruitment at the capillary level has been performed with either the full image or manually selected region-of-interests. These subjective approaches are imprecise, time-consuming, and unsuitable for automated processes. Here, an automated multiscale image processing approach was performed by defining a vessel diameter threshold for an objective and reproducible analysis at the microvascular level. Approach: A population of C57BL/6J male mice fed standard chow and studied at age 13 to 16 weeks comprised the lean group and 24- to 31-week-old mice who received a high-fat diet were designated the obese group. A clinical ultrasound scanner (Acuson Sequoia 512) equipped with an 15L8-S linear array transducer was used in a nonlinear imaging mode for sensitive detection of an intravascular microbubble contrast agent. Results: By eliminating large vessels from the dynamic contrast-enhanced ultrasound (DCE-US) images (above 300 μ m in diameter), obesity-related changes in perfusion and morphology parameters were readily detected in the smaller vessels, which are known to have a greater impact on skeletal muscle glucose disposal. The results from the DCE-US images including all of the vessels were compared for three different-sized vessel groups, namely, vessels smaller than 300, 200, and 150 μ m in diameter. Conclusions: Our automated image processing provides objective and reproducible results by focusing on a particular size of vessel, thereby allowing for a selective evaluation of longitudinal changes in microvascular recruitment for a specific-sized vessel group between diseased and healthy microvascular networks.


Birthweight and the risk of childhood-onset type 1 diabetes: a meta-analysis of observational studies using individual patient data.
We investigated whether children who are heavier at birth have an increased risk of type 1 diabetes. Relevant studies published before February 2009 were identified from literature searches using MEDLINE, Web of Science and EMBASE. Authors of all studies containing relevant data were contacted and asked to provide individual patient data or conduct pre-specified analyses. Risk estimates of type 1 diabetes by category of birthweight were calculated for each study, before and after adjustment for potential confounders.Meta-analysis techniques were then used to derive combined ORs and investigate heterogeneity between studies. Data were available for 29 predominantly European studies (five cohort, 24 case-control studies), including 12,807 cases of type 1 diabetes. Overall, studies consistently demonstrated that children with birthweight from 3.5 to 4 kg had an increased risk of diabetes of 6% (OR 1.06 [95% CI 1.01-1.11]; p=0.02) and children with birthweight over 4 kg had an increased risk of 10% (OR 1.10 [95% CI 1.04-1.19]; p=0.003), compared with children weighing 3.0 to 3.5 kg at birth. This corresponded to a linear increase in diabetes risk of 3% per 500 g increase in birthweight (OR 1.03 [95% CI 1.00-1.06]; p=0.03). Adjustments for potential confounders such as gestational age, maternal age, birth order, Caesarean section, breastfeeding and maternal diabetes had little effect on these findings. Children who are heavier at birth have a significant and consistent, but relatively small increase in risk of type 1 diabetes.


How do foundation year and internship experience shape doctors' career intentions and decisions? A meta-ethnography.
Foundation years or internships are an important period for junior doctors to apply their knowledge and gain clinical competency. Experiences gained during the foundation years or internships are likely to inform newly qualified doctors' opinions about how they want to continue their career. We aimed to understand how medical doctors' internship experiences influence their career intention/decision. We conducted qualitative evidence synthesis using meta-ethnography. We searched six electronic bibliographic databases for papers published between 2000-2020 and included papers exploring how foundation years or internship experiences shape doctors' career intention/decisions, including in relation to migration, public/private/dual practice preference, rural/urban preference, and specialty choice. We used the GRADE-CERQual framework to rate confidence in review findings. We examined 23 papers out of 6085 citations screened. We abstracted three high-level inter-related themes across 14 conceptual categories: (1) Deciding the personal best fit both clinically and in general (which option is 'more me'?) through hands-on and real-life experiences (2) Exploring, experiencing and witnessing workplace norms; and (3) Worrying about the future in terms of job market policies, future training and professional development opportunities. Confidence in findings varied but was rated high in 8 conceptual categories. Our meta-ethnographic review revealed a range of ways in which internship experience shapes medical doctors' career intentions/decisions allowing us to produce a broad conceptual model of this phenomenon. The results highlight the importance of ensuring sufficient, positive and inspiring clinical exposure, improving workplace environment, relationship and culture, refraining from undermining specific specialities and communicating contractual and job market policies early on to young doctors, in order to attract doctors to less popular specialties or work locations where they are most needed. We propose our conceptual model should be further tested in new research across a range of contexts.


Quality of Patient Decisions About Breast Reconstruction After Mastectomy.
Breast reconstruction has the potential to improve a person's body image and quality of life but has important risks. Variations in who undergoes breast reconstruction have led to questions about the quality of patient decisions. To assess the quality of patient decisions about breast reconstruction. A prospective, cross-sectional survey study was conducted from June 27, 2012, to February 28, 2014, at a single, academic, multidisciplinary oncology clinic among women planning to undergo mastectomy for stage I to III invasive ductal or lobular breast cancer, ductal carcinoma in situ, or prophylaxis. Mastectomy only and mastectomy with reconstruction. Knowledge, as ascertained using the Decision Quality Instrument; preference concordance, based on rating and ranking of key attributes; and decision quality, defined as having knowledge of 50% or more and preference concordance. During the 20-month period, 214 patients were eligible, 182 were approached, and 32 missed. We enrolled 145 patients (79.7% enrollment rate), and received surveys from 131 patients (72.0% participation rate). Five participants became ineligible. The final study population was 126 patients. Among the 126 women in the study (mean [SD] age, 53.2 [12.1] years), the mean (SD) knowledge score was 58.5% (16.2%) and did not differ by treatment group (mastectomy only, 55.2% [15.0%]; mastectomy with reconstruction, 60.5% [16.5%]). A total of 82 of 123 participants (66.7%) had a calculated treatment preference of mastectomy only; 39 of these women (47.6%) underwent mastectomy only. A total of 41 participants (32.5%) had a calculated treatment preference of mastectomy with reconstruction; 36 of these women (87.8%) underwent mastectomy with reconstruction. Overall, 52 of 120 participants (43.3%) made a high-quality decision. In multivariable analysis, white race/ethnicity (odds ratio [OR], 2.72; 95% CI, 1.00-7.38; P = .05), having private insurance (OR, 1.61; 95% CI, 1.35-1.93; P < .001), having a high school education or less (vs some college) (OR, 4.84; 95% CI, 1.22-19.21; P = .02), having a college degree (vs some college) (OR, 1.95; 95% CI, 1.53-2.49; P < .001), and not having a malignant neoplasm (eg, BRCA carriers) (OR, 3.13; 95% CI, 1.25-7.85; P = .01) were independently associated with making a high-quality decision. A minority of patients undergoing mastectomy in a single academic center made a high-quality decision about reconstruction. Shared decision making is needed to support decisions about breast reconstruction.


Effect of Radiation Emitted by Wireless Devices on Male Reproductive Hormones: A Systematic Review.
Exposure to radiofrequency electromagnetic radiation (RF-EMR) from various wireless devices has increased dramatically with the advancement of technology. One of the most vulnerable organs to the RF-EMR is the testes. This is due to the fact that testicular tissues are more susceptible to oxidative stress due to a high rate of cell division and mitochondrial oxygen consumption. As a result of extensive cell proliferation, replication errors occur, resulting in DNA fragmentation in the sperm. While high oxygen consumption increases the level of oxidative phosphorylation by-products (free radicals) in the mitochondria. Furthermore, due to its inability to effectively dissipate excess heat, testes are also susceptible to thermal effects from RF-EMR exposure. As a result, people are concerned about its impact on male reproductive function. The aim of this article was to conduct a review of literature on the effects of RF-EMR emitted by wireless devices on male reproductive hormones in experimental animals and humans. According to the findings of the studies, RF-EMR emitted by mobile phones and Wi-Fi devices can cause testosterone reduction. However, the effect on gonadotrophic hormones (follicle-stimulating hormone and luteinizing hormone) is inconclusive. These findings were influenced by several factors, which can influence energy absorption and the biological effect of RF-EMR. The effect of RF-EMR in the majority of animal and human studies appeared to be related to the duration of mobile phone use. Thus, limiting the use of wireless devices is recommended.


Efficacy of bupropion for relapse prevention in smokers with and without a past history of major depression.
This study evaluated the efficacy of bupropion for relapse prevention in smokers with and without a past history of major depressive disorder. Changes in depressive symptoms were also examined. Data were gathered prospectively from a randomized, double-blind relapse prevention trial of bupropion conducted at five study sites. A total of 784 smokers (54% female, 97% white) were enrolled. Using the Structured Clinical Interview for Depression, 17% of the subjects reported a past history of major depressive disorder at baseline. All subjects received open-label bupropion SR (300 mg/d) for 7 weeks. Subjects abstinent from smoking at the end of 7 weeks (N = 429) were randomized to bupropion SR (300 mg/d) or placebo for the remainder of the year and followed for 1 year off medication. The primary outcome measures were median time to relapse to smoking and the 7-day point-prevalence smoking abstinence rate. Self-reported abstinence from smoking was verified by expired air carbon monoxide. The Beck Depression Inventory was used to assess depressive symptoms at baseline and at weeks 8 and 12. Median time to relapse did not differ by past history of major depressive disorder. Bupropion was associated with higher point-prevalence smoking abstinence at the end of medication compared to placebo (P = .007), independent of a past history of major depressive disorder. Moreover, change in depressive symptoms during the double-blind phase did not differ for those with and without a past history of major depressive disorder. Extended use of bupropion for relapse prevention is effective for smokers with and without a history of major depression.


Neuroscience. Feeling the pain of social loss.
Poets have long waxed lyrical about the pain of a broken heart. Now, as Panksepp explains in his Perspective, this metaphor may reflect real events in the mammalian brain. A new brain neuroimaging study (Eisenberger et al.) reveals that the brain areas that are activated during the distress caused by social exclusion are also those activated during physical pain. Thus, we now have an explanation for the feeling of physical pain that accompanies emotional loss-whether that be the loss of a loved one, rejection by one's social group, or the distress of separation experienced by young animals.


A systematic review of genes involved in the inverse resistance relationship between cisplatin and paclitaxel chemotherapy: role of BRCA1.
A systematic review of cell models of acquired drug resistance not involving genetic manipulation showed that 80% of cell models had an inverse resistance relationship between cisplatin and paclitaxel. Here we systematically review genetically modified cell lines in which the inverse cisplatin/paclitaxel resistance phenotype has resulted. This will form a short list of genes which may play a role in the mechanism of the inverse resistance relationship as well as act as potential markers for monitoring the development of resistance in the clinical treatment of cancer. The literature search revealed 91 genetically modified cell lines which report toxicity or viability/apoptosis data for cisplatin and paclitaxel relative to their parental cell lines. This resulted in 26 genes being associated with the inverse cisplatin/paclitaxel phenotype. The gene with the highest number of genetically modified cell lines associated with the inverse resistance relationship was BRCA1 and this gene is discussed in detail with reference to chemotherapy response in cell lines and in the clinical treatment of breast, ovarian and lung cancer. Other genes associated with the inverse resistance phenotype included dihydrodiol dehydrogenase (DDH) and P-glycoprotein. Genes which caused cross resistance or cross sensitivity between cisplatin and paclitaxel were also examined, the majority of these genes were apoptosis associated genes which may be useful for predicting cross resistance. We propose that BRCA1 should be the first of a panel of cellular markers to predict the inverse cisplatin/paclitaxel resistance phenotype.


CRISPR/Cas9-Mediated Scanning for Regulatory Elements Required for HPRT1 Expression via Thousands of Large, Programmed Genomic Deletions.
The extent to which non-coding mutations contribute to Mendelian disease is a major unknown in human genetics. Relatedly, the vast majority of candidate regulatory elements have yet to be functionally validated. Here, we describe a CRISPR-based system that uses pairs of guide RNAs (gRNAs) to program thousands of kilobase-scale deletions that deeply scan across a targeted region in a tiling fashion ("ScanDel"). We applied ScanDel to HPRT1, the housekeeping gene underlying Lesch-Nyhan syndrome, an X-linked recessive disorder. Altogether, we programmed 4,342 overlapping 1 and 2 kb deletions that tiled 206 kb centered on HPRT1 (including 87 kb upstream and 79 kb downstream) with median 27-fold redundancy per base. We functionally assayed programmed deletions in parallel by selecting for loss of HPRT function with 6-thioguanine. As expected, sequencing gRNA pairs before and after selection confirmed that all HPRT1 exons are needed. However, HPRT1 function was robust to deletion of any intergenic or deeply intronic non-coding region, indicating that proximal regulatory sequences are sufficient for HPRT1 expression. Although our screen did identify the disruption of exon-proximal non-coding sequences (e.g., the promoter) as functionally consequential, long-read sequencing revealed that this signal was driven by rare, imprecise deletions that extended into exons. Our results suggest that no singular distal regulatory element is required for HPRT1 expression and that distal mutations are unlikely to contribute substantially to Lesch-Nyhan syndrome burden. Further application of ScanDel could shed light on the role of regulatory mutations in disease at other loci while also facilitating a deeper understanding of endogenous gene regulation.


Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1.
The effects of human immunodeficiency virus (HIV) protease inhibitors (PI) on the accumulation of the fluorescent bile salt analogue cholyl-glycylamido-fluorescein (CGamF) were determined in organic anion transporting polypeptide (OATP)-1B1 and -1B3-expressing Chinese hamster ovary (CHO) cells. In addition, interaction studies in Caco-2 monolayers, known only to express the OATP2B1 isoform, were conducted using the established OATP substrate estrone 3-sulfate (E3S), since no CGamF accumulation was observed in Caco-2 monolayers. CGamF appeared an excellent substrate for the OATP1B subfamily, with net accumulation clearance values of 7.8 and 142 microl min(-1) mg(-1) protein in OATP1B1 and OATP1B3-transfected cells, respectively. K(i)-values reflecting inhibition of CGamF accumulation by HIV PI correlated well between OATP1B1 and OATP1B3-expressing cells. Lopinavir was the most potent inhibitor (K(i) = 0.5-1.4 microM) of OATP1B-mediated CGamF accumulation compared with atazanavir, darunavir, ritonavir, and saquinavir (K(i) between 1.4 and 3.3 microM). Inhibitory profiles towards OATP2B1-mediated E3S accumulation were different with only indinavir, saquinavir, and ritonavir showing substantial effects. In conclusion, OATP1B3 appears to be a major transport mechanism mediating sodium-independent CGamF accumulation in human liver, and CGamF could be used as a probe substrate for in vitro drug interaction studies. The remarkably potent inhibition of OATP1B1 by lopinavir may explain some clinically relevant drug interactions between lopinavir and OATP1B substrates such as fexofenadine.


The Effect of Photoluminescence of Bioceramic Irradiation on Middle Cerebral Arterial Occlusion in Rats.
The purpose of this study is to determine the possible effect of photoluminescence of bioceramic (PLB) on ischemic cerebral infarction (stroke), by using an animal model of transient middle cerebral artery occlusion (MCAO). Sprague-Dawley rats were used to induce MCAO to block the origin of the left MCAO; three months later, the positive chronic stroke rats were selected by running tunnel maze; the MCAO rats with significant chronic stroke and neurological defects were used for treadmill experiments with varying speed settings to test their capability for restoration after muscular fatigue under conditions of with and without PLB irradiation. As a result, PLB irradiation could improve exercise completion rate and average running speed during slow and fast treadmill settings. After PLB irradiation, the selected MCAO rats successfully completed all the second-round treadmill exercises at the maximum speed setting, and they had better restoration from muscular fatigue. An in vitro cell study on astrocytes of rats by bioceramic irradiation further demonstrated increased intracellular nitric oxide. To explain these results, we suggest that cortical brain stimulation of microcirculation and enhancement of peripheral muscular activity are the main causes of the improved exercise performance in MCAO rats by PLB.


INPP4B overexpression is associated with poor clinical outcome and therapy resistance in acute myeloid leukemia.
In this study, we investigated the role of inositol polyphosphate-4-phosphatase, type-II (INPP4B) in acute myeloid leukemia (AML). We observed that AML patients with high levels of INPP4B (INPP4B(high)) had poor response to induction therapy, shorter event-free survival and shorter overall survival. Multivariate analyses demonstrated that INPP4B(high) was an independent predictor of poor prognosis, significantly improving current predictive models, where it outperformed conventional biomarkers including FLT3-ITD and NPM1. Furthermore, INPP4B(high) effectively segregated relative risk in AML patients with normal cytogenetics. The role of INPP4B on the biology of leukemic cells was assessed in vitro. Overexpression of INPP4B in AML cell lines enhanced colony formation potential, recapitulated the chemotherapy resistance observed in AML patients and promoted proliferation in a phosphatase-dependent, and Akt-independent manner. These findings reveal that INPP4B(high) has an unexpected role consistent with oncogenesis in AML, in contrast to its previously reported tumor-suppressive role in epithelial cancers. Overall, we propose that INPP4B is a novel prognostic biomarker in AML that has potential to be translated into clinical practice both as a disease marker and therapeutic target.


Hormone Use, Reproductive History, and Risk of Lung Cancer: The Women's Health Initiative Studies.
Results from the Women's Health Initiative clinical trials demonstrated no increase in the risk of lung cancer in postmenopausal women treated with hormone therapy (HT). We conducted a joint analysis of the Women's Health Initiative observational study data and clinical trials data to further explore the association between estrogen and estrogen-related reproductive factors and lung cancer risk. Reproductive history, oral contraceptive use, and postmenopausal HT were evaluated in 160,855 women with known HT exposures. Follow-up for lung cancer was through September 17, 2012; 2467 incident lung cancer cases were ascertained, with median follow-up of 14 years. For all lung cancers, women with previous use of estrogen plus progestin of less than 5 years (hazard ratio = 0.84; 95% confidence interval = 0.71-0.99) were at reduced risk. A limited number of reproductive factors demonstrated associations with risk. There was a trend toward decreased risk with increasing age at menopause (ptrend = 0.04) and a trend toward increased risk with increasing number of live births (ptrend = 0.03). Reduced risk of non-small-cell lung cancer was associated with age 20-29 years at first live birth. Risk estimates varied with smoking history, years of HT use and previous bilateral oophorectomy. Indirect measures of estrogen exposure to lung tissue, as used in this study, provide only weak evidence for an association between reproductive history or HT use and risk of lung cancer. More detailed mechanistic studies and evaluation of risk factors in conjunction with estrogen receptor expression in the lung should continue as a role for estrogen cannot be ruled out and may hold potential for prevention and treatment strategies.


Pulmonary collectins selectively permeabilize model bacterial membranes containing rough lipopolysaccharide.
We have reported that Gram-negative organisms decorated with rough lipopolysaccharide (LPS) are particularly susceptible to the direct antimicrobial actions of the pulmonary collectins, surfactant proteins A (SP-A) and D (SP-D). In this study, we examined the lipid and LPS components required for the permeabilizing effects of the collectins on model bacterial membranes. Liposomes composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), with or without rough Escherichia coli LPS (J5), smooth E. coli LPS (B5), or cholesterol, were loaded with self-quenching probes and exposed to native or oxidatively modified SP-A. Fluorescence that resulted from permeabilization of liposomes and diffusion of dyes was assessed by microscopy or fluorimetry. Human SP-A and melittin increased the permeability of J5 LPS/POPE liposomes, but not B5 LPS/POPE liposomes or control (POPE only) liposomes. At a human SP-A concentration of 100 microg/mL, the permeability of the J5 LPS/POPE membranes increased 4.4-fold (p < 0.02) compared to the control with no added SP-A. Rat SP-A and SP-D also permeabilized the J5-containing liposomes. Incorporation of cholesterol into J5 LPS/POPE liposomes at a POPE:cholesterol molar ratio of 1:0.15 blocked human SP-A or melittin-induced permeability (p < 0.05) compared to cholesterol-free liposomes. Exposure of human SP-A to surfactant lipid peroxidation blocked the permeabilizing activity of the protein. We conclude that SP-A permeabilizes phospholipid membranes in an LPS-dependent and rough LPS-specific manner, that the effect is neither SP-A- nor species-specific, and that oxidative damage to SP-A abolishes its membrane destabilizing properties. Incorporation of cholesterol into the membrane enhances resistance to permeabilization by SP-A, most likely by increasing the packing density and membrane rigidity.


Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression.
Depression is associated with alterations in corticostriatal reward circuitry. One pathophysiological pathway that may drive these changes is inflammation. Biomarkers of inflammation (for example, cytokines and C-reactive protein (CRP)) are reliably elevated in depressed patients. Moreover, administration of inflammatory stimuli reduces neural activity and dopamine release in reward-related brain regions in association with reduced motivation and anhedonia. Accordingly, we examined whether increased inflammation in depression affects corticostriatal reward circuitry to lead to deficits in motivation and goal-directed motor behavior. Resting-state functional magnetic resonance imaging was conducted on 48 medically stable, unmedicated outpatients with major depression. Whole-brain, voxel-wise functional connectivity was examined as a function of CRP using seeds for subdivisions of the ventral and dorsal striatum associated with motivation and motor control. Increased CRP was associated with decreased connectivity between ventral striatum and ventromedial prefrontal cortex (vmPFC) (corrected P<0.05), which in turn correlated with increased anhedonia (R=-0.47, P=0.001). Increased CRP similarly predicted decreased dorsal striatal to vmPFC and presupplementary motor area connectivity, which correlated with decreased motor speed (R=0.31 to 0.45, P<0.05) and increased psychomotor slowing (R=-0.35, P=0.015). Of note, mediation analyses revealed that these effects of CRP on connectivity mediated significant relationships between CRP and anhedonia and motor slowing. Finally, connectivity between striatum and vmPFC was associated with increased plasma interleukin (IL)-6, IL-1beta and IL-1 receptor antagonist (R=-0.33 to -0.36, P<0.05). These findings suggest that decreased corticostriatal connectivity may serve as a target for anti-inflammatory or pro-dopaminergic treatment strategies to improve motivational and motor deficits in patients with increased inflammation, including depression.


The role of working memory capacity in analytic and multiply-constrained problem-solving in demanding situations.
Working memory processes are important for analytic problem-solving; however, their role in multiply-constrained problem-solving is currently debated. This study explored individual differences in working memory and successful completion of analytic and multiply-constrained problem-solving by having participants solve algebra and compound remote associate (CRAT) problems of varying difficulty under low and high memory demand conditions. Working memory was predictive of both algebra and multiply-constrained problem-solving. Specifically, participants with high working memory solved more problems than those with low working. Memory load did not differentially affect performance for low and high working memory participants. However, for multiply-constrained problem-solving the effect of item difficulty was more detrimental for high-span participants than low-span participants. Together, these findings suggest that working memory processes are important for both types of problem-solving and that participants with low working memory capacity may need to offload internal memory demands onto the environment to efficiently solve problems.


N-methyl-D-aspartate receptors activate transcription of c-fos and NGFI-A by distinct phospholipase A2-requiring intracellular signaling pathways.
Activation of N-methyl-D-aspartate (NMDA) receptors is required for induction of some lasting changes in nervous system structure and function. The cellular mechanisms involved in transducing receptor stimulation into long-lasting changes in cellular activity are unknown. Immediate-early genes (IEGs) have been implicated in the conversion of short term stimuli to long term changes in cellular phenotype, by regulation of gene expression. Activation of NMDA receptors on dentate gyrus neurons triggers the transcriptional activation of several IEGs. To determine whether the same intracellular pathways transduce the signal from this ligand-gated ion channel to the nucleus, we compared NMDA induction of two IEGs. NMDA was sufficient to produce a striking increase in both c-fos and NGFI-A mRNAs in dentate granule neurons, in a calcium-dependent manner. The induction of both IEGs was blocked by structurally distinct inhibitors of phospholipase A2, an enzyme that catalyzes phospholipid degradation and formation of arachidonic acid. Arachidonic acid itself is catalyzed to biologically active metabolites by multiple enzymes, including cyclooxygenase and lipoxygenase. Selective inhibitors of cyclooxygenase attenuated NMDA induction of c-fos but not NGFI-A. Conversely, structurally distinct inhibitors of lipoxygenase blocked NMDA induction of NGFI-A but not c-fos. The signaling pathways linking NMDA receptors to the transcriptional activation of c-fos and NGFI-A are related but distinct. We suggest that phospholipase A2 and the arachidonic acid cascade play a pivotal role in NMDA receptor regulation of gene expression.


Bowtie nano-aperture as interface between near-fields and a single-mode fiber.
We present the development and study of a single bowtie nano-aperture (BNA) at the end of a monomode optical fiber as an interface between near-fields/nano-optical objects and the fiber mode. To optimize energy conversion between BNA and the single fiber mode, the BNA is opened at the apex of a specially designed polymer fiber tip which acts as an efficient mediator (like a horn optical antenna) between the two systems. As a first application, we propose to use our device as polarizing electric-field nanocollector for scanning near-field optical microscopy (SNOM). However, this BNA-on-fiber probe may also find applications in nanolithography, addressing and telecommunications as well as in situ biological and chemical probing and trapping.


Experimental demonstration of ultrasharp unpolarized filtering by resonant gratings at oblique incidence.
The peaks in the reflectivity spectrum of waveguide gratings observed when the incident beam couples to a mode of the structure are promising features for many applications. However their weak angular tolerance and their strong polarization sensitivity, especially under oblique incidence, limit their interest in practice. These problems can be overcome by forming slow degenerate modes outside the usual high symmetry points of the Brillouin zone with a complex periodic pattern [Fehrembach, Appl. Phys. Lett. 86, 121105 (2005)]. We show experimentally that spectrally sharp, lambda/Deltalambda approximately 4000, polarization-independent, angularly tolerant optical resonances can be obtained by exciting these modes under oblique incidence.


Vitamin D and the anti-viral state.
Vitamin D has long been recognized as essential to the skeletal system. Newer evidence suggests that it also plays a major role regulating the immune system, perhaps including immune responses to viral infection. Interventional and observational epidemiological studies provide evidence that vitamin D deficiency may confer increased risk of influenza and respiratory tract infection. Vitamin D deficiency is also prevalent among patients with HIV infection. Cell culture experiments support the thesis that vitamin D has direct anti-viral effects particularly against enveloped viruses. Though vitamin D's anti-viral mechanism has not been fully established, it may be linked to vitamin D's ability to up-regulate the anti-microbial peptides LL-37 and human beta defensin 2. Additional studies are necessary to fully elucidate the efficacy and mechanism of vitamin D as an anti-viral agent.


Hybrid planar microresonators with organic and InGaAs active media.
The authors report on the fabrication of hybrid planar micro-resonators based on InGaAs microdisks with an evaporated organic material. Samples of InGaAs grown on InP(100) substrates are obtained by Chemical Beam Epitaxy, and microdisks of InGaAs with different diameters are fabricated by focused ion beam. The hybrid disks are obtained by the subsequent evaporation of 8-hydroxyquinoline aluminium doped with 4-Dicyanomethylene-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran on the InGaAs microdisks. The devices, characterized by micro- and confocal photoluminescence imaging and spectroscopy, exhibit emission around 650 nm, from the organic material for disks with different radius. Finally, simultaneous emission in the visible and at whispering gallery resonant modes in the 1350-1450 nm range are observed due to excitation transfer to InGaAs. These devices open the possibility to combine the flexibility of organics with the high gain of III-V compounds for wavelength down conversion and telecom applications.


Selected reaction monitoring (SRM) mass spectrometry without isotope labeling can be used for rapid protein quantification.
The validation of putative biomarker candidates has become the major bottle-neck in protein biomarker development. Conventional immunoaffinity methods are limited by the availability of antibodies and kits. Here we demonstrate the feasibility of using selected reaction monitoring (SRM) without isotope labeling to achieve fast and reproducible quantification of serum proteins. The SRM/MRM assays for three standard serum proteins, including ceruloplasmin (CP), serum aymloid A (SAA) and sex hormone binding globulin (SHBG), have good linear ranges, generally 10(3) to 10(4) . There are almost perfect correlations between SRM intensities and the loaded peptide amounts (R(2) is usually ~0.99). Our data suggest that SRM/MRM is able to quantify proteins within the range of 0.2-2 fmol, which is comparable to the commercial ELISA/LUMINEX kits for these proteins. Excellent correlations between SRM/MRM and ELISA/LUMINEX assays were observed for SAA and SHBG (R(2)=0.928 and 0.851, respectively). However, the correlation between SRM/MRM and ELISA for CP is less desirable (R(2)=0.565). The reproducibility for SRM/MRM assays is generally very good but may depend on the proteins/peptides being analyzed (R(2)=0.931 and 0.882 for SAA and SHBG, and 0.723 for CP). The SRM/MRM assay without isotope labeling is a rapid and useful method for protein biomarker validation in a modest number of samples and is especially useful when other assays such as ELISA or LUMINEX are not available.


Information assimilation and distribution challenges and goals for real and virtual journals.
The distribution of biomedical information was transfigured over three centuries ago with the introduction of scientific journals. This enabled the widespread dissemination of data to global audiences and greatly facilitated not only the advance of science but amplified the interaction between investigators despite their different locations. This process continued to expand in a linear fashion prior to the emergence of the Internet. The latter system has prompted a phenomenal augmentation of information accessibility, and its ever-expanding use has resulted in an exponential increase in the demand for digital technology and online resources. This technology has achieved unprecedented acceptance in the scientific domain and enabled publishers to expeditiously produce and distribute journal contents online. Such unparalleled access to information has sparked incendiary debate within the scientific community and among journal publishers in regard to numerous issues. It is thus much debated as to who has the right to "own" or control intellectual property, whether information should be made freely available to the online global community, how to gauge the legitimacy and authenticity of published research, and the need to reexamine the feasibility and profitability of paper journals in consideration of the digital, online formats that continue to gain popularity. To assess the current status of the situation, a meeting of journal editors, research scientists, and publishing executives was held in Constance, Germany, on June 26, 2004, to discuss these issues and formulate strategies and recommendations for the future of biomedical publishing. Herewith we provide a summation (manifesto) of the meeting's proceedings and provide a consensus opinion with the aim of illuminating the subject and also proposing some putative solutions for the major challenges that currently confront the scientific and publishing community.


Admixture and recombination among Toxoplasma gondii lineages explain global genome diversity.
Toxoplasma gondii is a highly successful protozoan parasite that infects all warm-blooded animals and causes severe disease in immunocompromised and immune-naïve humans. It has an unusual global population structure: In North America and Europe, isolated strains fall predominantly into four largely clonal lineages, but in South America there is great genetic diversity and the North American clonal lineages are rarely found. Genetic variation between Toxoplasma strains determines differences in virulence, modulation of host-signaling pathways, growth, dissemination, and disease severity in mice and likely in humans. Most studies on Toxoplasma genetic variation have focused on either a few loci in many strains or low-resolution genome analysis of three clonal lineages. We use whole-genome sequencing to identify a large number of SNPs between 10 Toxoplasma strains from Europe and North and South America. These were used to identify haplotype blocks (genomic regions) shared between strains and construct a Toxoplasma haplotype map. Additional SNP analysis of RNA-sequencing data of 26 Toxoplasma strains, representing global diversity, allowed us to construct a comprehensive genealogy for Toxoplasma gondii that incorporates sexual recombination. These data show that most current isolates are recent recombinants and cannot be easily grouped into a limited number of haplogroups. A complex picture emerges in which some genomic regions have not been recently exchanged between any strains, and others recently spread from one strain to many others.


Does seed size mediate sex-specific reproduction costs in the Callosobruchus maculatus bean beetle?
There is a trade-off between reproductive effort and adult longevity, and when resource allocation is taken into account, it is especially pronounced in species that have aphagous adult forms. This trade-off may be further complicated by environmental factors such as nutrient availability during larval development and by the other sex, which influences the costs of reproduction due to the presentation of nuptial gifts. Here, we examined the influence of larval nutrient quantity on the sex-specific longevity costs of reproduction in the gift-giving seed beetle Callosobruchus maculatus. We found no indication that differences in the nutrient quality of larger and smaller host seeds influence survival in virgin and reproducing individuals or nuptial gift size in reproducing individuals. However, in the case of reproducing individuals, the effect of seed size on survival was statistically marginal. Therefore, we advise taking this into account when investigating reproductive efforts in this species. We have also observed interesting interactions between male and female reproductive costs. While females had generally higher mortality than males, nuptial gifts resulted in lowered female mortality and increased male mortality. Additionally, we found a possibly non-linear relationship between nuptial gift size and the offspring production rate of female recipients.


Parallel incidences of sudden infant death syndrome and infantile hypertrophic pyloric stenosis: a common cause?
To determine whether there was a correlation between the incidence of infantile hypertrophic pyloric stenosis (IHPS) and the incidence of sudden infant death syndrome (SIDS) during the period 1970 to 1997 and to discuss different causative factors that could be influencing the changing trend in incidence. We compared the incidence of IHPS in the Stockholm Health Care Region with the incidence of SIDS in Sweden each year between 1970 and 1997. First, the relation was assessed by calculation of a correlation coefficient; second, the relative linear decrease was estimated for the time period 1990 to 1997. The incidence of IHPS increased steadily during the 1970s, from 0.5 per 1000 live births in 1970 to 2.7 in 1979. During the 1980s, the average incidence was 2.8. During the 1990s, there was a significant decrease in the number of IHPS cases in Stockholm. The incidence rate of IHPS parallels the incidence of SIDS during the study period (r = 0.58). The incidence of SIDS dropped after the risk-reduction campaign in the beginning of the 1990s, which recommended that infants sleep on their back. We could not identify any other changes of behavioral risk factors in early exposures that could explain the temporal trends. The statistical findings suggest that IHPS and SIDS have causative factors in common. We suggest that prone sleeping is one of those factors.


Key characteristics of knowledge transfer and exchange in healthcare: integrative literature review.
This paper presents the results of a review of literature relating to knowledge transfer and exchange in healthcare. Treatment, planning and policy decisions in contemporary nursing and healthcare should be based on sound evidence wherever possible, but research knowledge remains generally underused. Knowledge transfer and exchange initiatives aim to facilitate the accessibility, application and production of evidence and may provide solutions to this challenge. This review was conducted to help inform the design and implementation of knowledge transfer and exchange activities for a large healthcare organization. Databases: ASSIA, Business Source Premier, CINAHL, PsychInfo, Medline and the Cochrane Database of Systematic Reviews. An integrative literature review was carried out including an extensive literature search. English language systematic reviews, literature reviews, primary quantitative and qualitative papers and grey literature of high relevance evaluating, describing or discussing knowledge transfer or exchange activities in healthcare were included for review (January 1990-September 2009). Thirty-three papers were reviewed (four systematic reviews, nine literature reviews, one environmental scan, nine empirical studies and ten case studies). Robust research into knowledge transfer and exchange in healthcare is limited. Analysis of a wide range of evidence indicates a number of commonly featured characteristics but further evaluation of these activities would benefit their application in facilitating evidence-based practice in nursing.


The influence of rosuvastatin on liver microsomal CYP2C6 in hereditary hypertriglyceridemic rat.
The aim of this study was to investigate whether rosuvastatin affects expression and activity of rat CYP2C6. This cytochrome P450 is considered to be a counterpart of human CYP2C9, which metabolizes many drugs, including diclofenac, ibuprofen or warfarin. Male hereditary hypertriglyceridemic (HHTg) rats were fed standard laboratory diet (STD) or high cholesterol diet (HCD: STD + 1% of cholesterol w/w + 10% of lard fat w/w) for 21 days. A third group of rats were fed high a cholesterol diet with rosuvastatin added (0.03% w/w). Expression of CYP2C6 was measured in liver samples using real-time PCR (mRNA level) and Western blotting (protein level). Formation of diclofenac metabolites (typical enzyme activity of CYP2C6) was analyzed using HPLC with UV detection. Administration of rosuvastatin to HHTg rats resulted in significantly increased mRNA expression and enzyme activity in HCD-fed animals; changes of CYP2C6 protein were non-significant. These results suggest that CYP2C6 expression and activity are positively affected by rosuvastatin in hereditary hypertriglyceridemic rats after intake of HCD. The results presented open the possibility that in humans, rosuvastatin may affect the metabolism of many drugs by influencing expression and activity of CYP2C6 (counterpart of human CYP2C9). Further studies are needed to elucidate the effects of this statin on CYP2C9 in humans.


Babesia spp. and other pathogens in ticks recovered from domestic dogs in Denmark.
Newly recognized endemic foci for human babesiosis include Europe, where Ixodes ricinus, a vector for several species of Babesia, is the most commonly identified tick. Vector-based surveillance provides an early warning system for the emergence of human babesiosis, which is likely to be under-reported at emerging sites. In the present study, we set out to screen I. ricinus collected from Danish domestic dogs for Babesia, in order to identify whether humans in Denmark are exposed to the parasite. A total of 661 ticks (Ixodes spp.) were collected from 345 Danish domestic dogs during April-September 2011 and pooled, one sample per dog. DNA was extracted from each sample and examined by PCR and sequencing for Rickettsia spp., Borrelia burgdorferi sensu lato, Bartonella spp., Francisella tularensis, Candidatus Neoehrlichia mikurensis, and Babesia spp. In total, 34% of the samples were positive for tick-borne microorganisms potentially pathogenic to humans: Rickettsia spp. were detected in 16% of the pools, with 79% being R. helvetica. Borrelia burgdorferi sensu lato was found in 15%, with the main species identified as Borrelia afzelii (39%). Likewise, 8% of the samples were positive for Babesia spp. (Babesia microti, 82%; Babesia venatorum ('EU1'), 18%). Lastly, 1% of the samples tested positive for Candidatus Neoehrlichia mikurensis, and 0.6% for Bartonella spp. No ticks were found to be infected with Francisella tularensis. Our data are in support of endemic occurrence of potentially zoonotic Babesia in Denmark and confirms I. ricinus as a vector of multiple pathogens of public health concern.


Detection of epidermal growth factor receptor in the serum of patients with cervical carcinoma.
Epidermal growth factor receptor (EGFR) is overexpressed in a variety of malignancies, including breast, lung, gastric, and cervical carcinoma. Its overexpression has been associated with disease progression or poor prognosis in patients with cervical carcinoma. In the present study, the levels of EGFR were determined in serum from 38 patients with cervical carcinoma [invasive or recurrent carcinoma (n = 26) and carcinoma in situ (CIS; n = 12)] and 38 healthy female controls using ELISA. The mean serum level for EGFR in patients with invasive or recurrent carcinoma (165 +/- 60 fmol/ml) was significantly elevated (P < 0.0001) compared with that of healthy controls (66 +/- 17 fmol/ml) and also higher (P = 0.015) than that of patients with CIS (126 +/- 25 fmol/ml). In addition, there was a significant difference in the mean serum levels of EGFR between patients with CIS and healthy controls (P < 0.0001). Thirty-five patients (92%) with cervical carcinoma [invasive or recurrent (n = 24) and CIS (n = 11)] had elevated serum, EGFR levels above the cutoff value of 100 fmol/ml (defined as 2 SD above the mean of the controls). In conclusion, the serum EGFR level was elevated in a significant proportion of patients with cervical carcinoma, and it demonstrated an increasing tendency according to disease progression from normal tissue through CIS to invasive cervical carcinoma. Therefore, it may have a potential usefulness as a biological marker of cervical carcinoma.


Ontogenetic variation of heritability and maternal effects in yellow-bellied marmot alarm calls.
Individuals of many species produce distinctive vocalizations that may relay potential information about the signaller. The alarm calls of some species have been reported to be individually specific, and this distinctiveness may allow individuals to access the reliability or kinship of callers. While not much is known generally about the heritability of mammalian vocalizations, if alarm calls were individually distinctive to permit kinship assessment, then call structure should be heritable. Here, we show conclusively for the first time that alarm call structure is heritable. We studied yellow-bellied marmots (Marmota flaviventris) and made nine quantitative measurements of their alarm calls. With a known genealogy, we used the animal model (a statistical technique) to estimate alarm call heritability. In juveniles, only one of the measured variables had heritability significantly different from zero; however, most variables had significant maternal environmental effects. By contrast, yearlings and adults had no significant maternal environmental effects, but the heritability of nearly all measured variables was significantly different from zero. Some, but not all of these heritable effects were significantly different across age classes. The presence of significantly non-zero maternal environmental effects in juveniles could reflect the impact of maternal environmental stresses on call structure. Regardless of this mechanism, maternal environmental effects could permit kinship recognition in juveniles. In older animals, the substantial genetic basis of alarm call structure suggests that calls could be used to assess kinship and, paradoxically, might also suggest a role of learning in call structure.


SU-D-BRA-06: Investigation of Prostate Intrafractional Motion during External Beam Radiotherapy for a Large Patient Population.
To analyze and report prostate intrafractional motion recorded online during external beam radiotherapy and to provide guidance for advanced prostate IMRT. Prostate intrafractional motion during IMRT and RapidARC treatments was tracked and recorded using a Calypso 4D-localization system. Data for 8600 treatment fractions of 230 prostate patients was analyzed. The percentage of treatment fractions, the fractional treatment time, and the fractional time of any individual minute were analyzed separately for prostate movements greater than the thresholds (2, 3, 5 and 7mm). The percentages of fractions in which prostate shifted more than the thresholds for a duration >10 seconds are 66.2%, 34.9%, 8.9% and 2.6% (57.9%, 27.9%, 5.2% and 0.8% for >30 seconds duration), respectively. For 10 patients who exhibited the largest motion, the percentages are 95.2%, 76.0%, 43.2% and 14.7% (91.3%, 72.4%, 36.3% and 6.0% for >30 seconds duration). The fractional time for motion larger than the thresholds is 27.8%, 10.7%, 1.6% and 0.3% (56.2%, 33.7%, 11.2% and 2.1% for these patients). The posterior-direction motion is significantly higher than those in other directions. The fractional time of an individual minute with shift >3mm is higher at the 10th minute than at the 5th minute (20% vs. 10%) after the initial setup. For treatments completed within 5 minutes, the average fractional time with motion >3mm was lower than those within 10 minutes (4% vs. 12%). Irregular movements were observed most likely in the first minute after patient's setup, which were 12% and 7% among all fractions with movements >2mm and >3mm, respectively. The prostate intrafractional motion was within 3mm for most treatment fractions. However, larger movements were observed for some patients, who require real-time corrections or larger treatment margins. The results indicate that it is beneficial if the treatment can be completed within 5 minutes.


Cost Utility of Intermittent Inhaled Corticosteroids in Preschoolers with Viral-Triggered Wheeze.
Background: Evidence has demonstrated that adding intermittent inhaled corticosteroids (ICS) to treatment with short-acting b2-agonists (SABAs) in children 5 years of age and younger who experience intermittent viral-induced wheezing (VIW) reduces the risk of severe exacerbations. However, there is concern about whether the extra benefit offered by this drug outweighs the additional cost. This study aimed to evaluate the cost-effectiveness of intermittent ICS in children 5 years of age and younger who experience intermittent VIW. Methods: We constructed a probabilistic Markov model to estimate the cost and quality-adjusted life-years (QALYs) of intermittent ICS compared with SABA reliever therapy in preschoolers with viral-triggered wheezing in Colombia. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at a willingness-to-pay value of $5,180. Results: In an analysis of the Markov cohort model, we estimated a gain of 0.2 QALYs per patient per year on intermittent ICS compared with SABA and a reduction of cost per patient of USD $37 per year. This position of dominance negated the need to calculate an incremental cost-effectiveness ratio. Deterministic and probabilistic sensitivity analyses, our base case results were robust to variations of all assumptions and parameters. Conclusion: Adding intermittent ICS to treatment with SABAs in children 5 years of age and younger who experience intermittent VIW was found to be cost effective. These results could improve the use of health care resources, especially in settings with limited economic resources.


Inhibition of interleukin 1 beta-converting enzyme-mediated apoptosis of mammalian cells by baculovirus IAP.
Apoptosis can be a potent weapon against viral infection and consequently has selected for viruses carrying antiapoptosis genes. Two baculovirus proteins, IAP and p35, can prevent insect cells from dying in response to infection. p35, which interferes with members of the Ced-3 family of cysteine proteases, can also function in mammalian cells. We investigated the ability of IAP from Orgyia pseudotsugata nuclear polyhedrosis virus to prevent death of mammalian cells. IAP was transiently expressed in mammalian cells and its ability to block cell death caused by expression of interleukin-1 beta converting enzyme (ICE), FADD, or the ICE homologues ICH-1 and ICE-Lap3, was investigated. IAP strongly inhibited ICE- and ICH-1-induced cell death but protected only partially against death by overexpression of FADD and not at all against death due to enforced ICE-Lap3 expression. These results demonstrate that a baculoviral IAP protein can functionally interact with conserved components of the apoptosis machinery in mammalian cells.


C-ON bond homolysis of alkoxyamines: when too high polarity is detrimental.
Throughout the last decade, the effect of electron withdrawing groups (EWGs) has been known to play a role - minor or moderate depending on the nitroxyl fragment R1R2NO - in the change in the homolysis rate constant (kd) for C-ON bond homolysis in alkoxyamines (R1R2NOR). It has been shown that the effect of EWGs on kd is described by a linear relationship with the electrical Hammett constant σI. Since then, linear multi-parameter relationships f(σRS,ν,σI) have been developed to account for the effects involved in the changes in kd, which are the stabilization of the released radical (σRS) and the bulkiness (ν) and polarity (σI) of the alkyl fragment. Since a decade ago, new results have been published highlighting the limits of such correlations. In this article, previous multi-parameter linear relationships are amended using a parabolic model, i.e. (σI,nitroxide - σI,alkyl)2, to describe the effect of EWGs in the alkyl fragment on kd. In contrast to previous studies, these improved linear multi-parameter relationships f(σRS,ν,ΔσI2) are able to account for the presence of several EWGs on the alkyl fragment, R. An unexpectedly strong solvent effect - a ca. 1500-fold increase in kd - from tert-butylbenzene to the water/methanol mixture is also observed for 3-((2,2,6,6-tetramethylpiperidin-1-yl)oxyl)pentane-2,4-dione 1b in comparison to a ca. 5-fold increase in kd that is generally observed.


The Components of Nursing Competence in Caring for Older People in Iranian Hospitals: A Qualitative Study.
There is limited research on gerontological nursing competence in hospitals. However, there is no comprehensive and integrated description of the gerontological nursing competence requirements in hospitals. The purpose of this study was to explain the components of nursing competence in caring for older people in Iranian hospitals. This is a qualitative descriptive-exploratory study. The data were collected through a semi-structured interview with nurses, nurse managers, and clinical educators in teaching hospitals and nursing schools affiliated to Arak, Isfahan, and Tehran Universities of Medical Sciences in Iran from September 2015 to July 2016. Participants included 25 people who were selected by purposive and snowball sampling method. Sampling continued until data saturation. Data were analyzed using conventional content analysis method. Data analysis generated three main categories including (1) Patient and family centered care; (2) Process-oriented care; and (3) Self-care and continuing professional development. Nurses should have competencies such as participation and empowerment of the patient and family; ease of comfort in the elderly; comprehensive geriatric assessment; development, implementation and evaluation of care plan; development of knowledge and clinical proficiency; and coaching so that they can work effectively during the care of the elderly. The results of this study can be used by nursing educators, nursing students, and nurses to develop their individual and professional skills in the field of gerontological nursing.


A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse.
The mouse autosomal dominant mutation Mody develops hyperglycemia with notable pancreatic beta-cell dysfunction. This study demonstrates that one of the alleles of the gene for insulin 2 in Mody mice encodes a protein product that substitutes tyrosine for cysteine at the seventh amino acid of the A chain in its mature form. This mutation disrupts a disulfide bond between the A and B chains and can induce a drastic conformational change of this molecule. Although there was no gross defect in the transcription from the wild-type insulin 2 allele or two alleles of insulin 1, levels of proinsulin and insulin were profoundly diminished in the beta cells of Mody mice, suggesting that the number of wild-type (pro)insulin molecules was also decreased. Electron microscopy revealed a dramatic reduction of secretory granules and a remarkably enlarged lumen of the endoplasmic reticulum. Little proinsulin was processed to insulin, but high molecular weight forms of proinsulin existed with concomitant overexpression of BiP, a molecular chaperone in the endoplasmic reticulum. Furthermore, mutant proinsulin expressed in Chinese hamster ovary cells was inefficiently secreted, and its intracellular fraction formed complexes with BiP and was eventually degraded. These findings indicate that mutant proinsulin was trapped and accumulated in the endoplasmic reticulum, which could induce beta-cell dysfunction and account for the dominant phenotype of this mutation.


Identification of molecular and physiological responses to chronic environmental challenge in an invasive species: the Pacific oyster, Crassostrea gigas.
Understanding the environmental responses of an invasive species is critical in predicting how ecosystem composition may be transformed in the future, especially under climate change. In this study, Crassostrea gigas, a species well adapted to the highly variable intertidal environment, was exposed to the chronic environmental challenges of temperature (19 and 24°C) and pH (ambient seawater and a reduction of 0.4 pH units) in an extended 3-month laboratory-based study. Physiological parameters were measured (condition index, shell growth, respiration, excretion rates, O:N ratios, and ability to repair shell damage) alongside molecular analyses. Temperature was by far the most important stressor, as demonstrated by reduced condition indexes and shell growth at 24°C, with relatively little effect detected for pH. Transcriptional profiling using candidate genes and SOLiD sequencing of mantle tissue revealed that classical "stress" genes, previously reported to be upregulated under acute temperature challenges, were not significantly expressed in any of the treatments, emphasizing the different response between acute and longer term chronic stress. The transcriptional profiling also elaborated on the cellular responses underpinning the physiological results, including the identification of the PI3K/AKT/mTOR pathway as a potentially novel marker for chronic environmental challenge. This study represents a first attempt to understand the energetic consequences of cumulative thermal stress on the intertidal C. gigas which could significantly impact on coastal ecosystem biodiversity and function in the future.


Development of a gas phase source for perfluoroalkyl acids to examine atmospheric sampling methods.
An inability to produce environmentally relevant gaseous mixing ratios of perfluoroalkyl acids (PFAAs), ubiquitous global contaminants, limits the analytical reliability of atmospheric chemists to make accurate gas and particulate measurements that are demonstrably free of interferences due to sampling artefacts. A gas phase source for PFAAs based on the acid displacement mechanism using perfluoropropionate (PFPrA), perfluorobutanoate (PFBA), perfluorohexanoate (PFHxA), and perfluorooctanoate (PFOA) has been constructed. The displacement efficiency of gas phase perfluorocarboxylic acids (PFCAs) is inversely related to chain length. Decreasing displacement efficiencies for PFPrA, PFBA, PFHxA, and PFOA were 90% ± 20%, 40% ± 10%, 40% ± 10%, 9% ± 4%, respectively. Generating detectable amounts of gas phase perfluorosulfonic acids (PFSAs) was not possible. It is likely that lower vapour pressure and much higher acidity play a role in this lack of emission. PFCA emission rates were not elevated by increasing relative humidity (25%-75%), nor flow rate of carrier gas from 33-111 sccm. Overall, reproducible gaseous production of PFCAs was within the error of the production of hydrochloric acid (HCl) as a displacing acid (±20%) and was accomplished using a dry nitrogen flow of 33 ± 2 sccm. A reproducible mass emission rate of 0.97 ± 0.10 ng min(-1) (n = 8) was observed for PFBA. This is equivalent to an atmospheric mixing ratio of 12 ppmv, which is easily diluted to environmentally relevant mixing ratios of PFBA. Conversely, generating gas phase perfluorononanoic acid (PFNA) by sublimating the solid acid under the same conditions produced a mass emission rate of 2800 ng min(-1), which is equivalent to a mixing ratio of 18 ppthv and over a million times higher than suspected atmospheric levels. Thus, for analytical certification of atmospheric sampling methods, generating gas phase standards for PFCAs is best accomplished using acid displacement under dry conditions. This yields quickly stabilized, reproducible emissions and mixing ratios that are easily diluted to environmentally relevant levels. Gas phase PFBA from this source has also been shown to be quantitatively collected using an annular denuder coated with sodium carbonate (Na2CO3) according to Environmental Protection Agency (EPA) method Compendium I.O-4.2. Overall, producing gas phase PFAAs at constant atmospherically-relevant levels will enable the development of standard approaches in certifying gas and particle collection efficiencies for instruments interrogating the gas-particle partitioning and long-range transport of PFCAs in the atmosphere.


Lipothioureas as Lipids for Gene Transfection: A Review.
Non-viral gene therapy requires innovative strategies to achieve higher transfection efficacy. A few years ago, our group proposed bioinspired lipids whoseinteraction with DNA was not based on ionic interactions, but on hydrogen bonds. We thusdeveloped lipids bearing a thiourea head which allowed an interaction with DNAphosphates through hydrogen bonds. After a proof of concept with a lipid bearing threethiourea functions, a molecular and cellular screening was performed by varying all partsof the lipids: the hydrophobic anchor, the spacer, the linker, and the thiourea head. Twolipothiourea-based structures were identified as highly efficient in vitro transfecting agents.The lipothioureas were shown to reduce non specific interactions with cell membranes anddeliver their DNA content intracellularly more efficiently, as compared to cationiclipoplexes. These lipids could deliver siRNA efficiently and allowed specific cell targetingin vitro. In vivo, thiourea lipoplexes presented a longer retention time in the blood and lessaccumulation in the lungs after an intravenous injection in mice. They also inducedluciferase gene expression in muscle and tumor after local administration in mice.Therefore, these novel lipoplexes represent an excellent alternative to cationic lipoplexes astransfecting agents. In this review we will focus on the structure activity studies thatpermitted the identification of the two most efficient thiourea lipids.


[Obtain best usage of meropenem dose in severe infections. Results of an observational multicenter study].
To describe the effectiveness and tolerability of the dose adjustment of meropenem in empirical treatment of nosocomial infections in critically-ill patients admitted to intensive care medicine services. Prospective, observational and multicenter study in patients admitted to 17 intensive care medicine services with nosocomial infection, who were initially treated with meropenem, 1 g every 8 h, were eligible. The initial dose was adjusted to 0.5 g every 8 h if there were: a) a favorable clinical course, and b) microbiological isolation of meropenem-susceptible pathogens or absence of pathogens in cultures. Ninety-two patients in whom meropenem doses were adjusted to 0.5 g every 8 h were included. Ventilator-associated pneumonia followed by bacteremia was the most frequently treated infections. Microbiological studies were positive in 53 patients, with a predominance of gram-positive bacteria (53.7%), especially methicillin-susceptible Staphylococcus aureus, followed by gram-negative bacteria (42.7 %). A total of 18 patients were not evaluable at the end of treatment. Sixty-seven (90.5 %) of the 74 evaluable patients had a favorable clinical course (54 patients cured and 13 improved). In 50 out of 53 microbiologically evaluable cases, eradication or apparent eradication of initial microorganisms was achieved. In 3 cases, the initial pathogen persisted: Acinetobacter baumannii (2 cases) and Pseudomonas aeruginosa (1 case). On three occasions, new pathogens developed during treatment: A. baumannii (2 cases) and methicillin-resistant S. aureus (1 case). Adverse events occurred in 3 patients (4%), none of which was considered severe, and withdrawal of meropenem was not necessary. A total of 25 (27.2 %) patients died, three of them in relation to the infectious process. Dose adjustment of meropenem to 0.5 g every 8 h is a useful tool in the treatment of severe nosocomial infections in patients admitted to services of intensive care medicine except in cases in which causative pathogens are non-fermenting Gram-negative bacteria.


Culture-specific care for indigenous people: a primary health care perspective.
This article argues that a primary health care approach is an appropriate conceptual framework for addressing the health needs of Indigenous people. Primary health care is strategic, focusing on equity, access, empowerment and intersectoral partnerships as essential elements for maintaining health. Stereotypical notions of Indigenous ill health as being embedded in a general view of 'culture' can mitigate against achieving equity, access to health care and ultimately self-determinism. Because health is embedded in the social conditions of people's lives, the emphasis in Indigenous health care should first address Indigenous social disadvantage and ways of working in partnership with various groups of Indigenous people to achieve their health goals. A critical multicultural approach situates cultural differences within the wider nexus of power relations, and helps overcome the negative stereotyping that often prevents inclusive, self-determined care. Recommendations are suggested for change at the societal, professional and individual level.


Impact of EU risk assessment process and administrative regulations for manufacturers of combined hormonal contraceptive prescribing. An analysis of developments in Germany and the implications.
Combined hormonal contraceptives (CHC) exhibit differing risks for cardiovascular and thrombotic events (VTE). A European referral process confirmed higher VTE risks for 3rd generation gestagens and drospirenone. CHC are now grouped in risk classes (RC) I, II, and III, with RC III having a higher risk than RC I and X (risk not yet known). Marketing authorization holders were obliged to implement pharmacovigilance measures and risk minimization measures including changes of prescribing information. The study assessed whether these activities induced changes in prescription patterns. German prescription data for 1.1 million women below 20 years of age were used to analyze the effects of interventions and potential influence factors using logistic regression. Descriptive statistics were calculated for prescriptions for 3.3 million women from January 2011 to March 2016. Shares of RC I and RC X recipients rose substantially over the observation period, while RC III recipient share showed a steady decrease. The referral induced a slightly faster decrease in RC III and increase in RC X. The implementation of pharmacovigilance measures manifested no additional effect. The decrease in RC III share already observed before the referral process can be explained with pre-existing discussions around CHC. The effect attributable to the referral was statistically significant, although very small. While evidence for a connection between interventions and prescription change is only indirect, the study shows that routine data are suitable for impact analyses, and monitoring prescribing patterns can be recommended as feedback after regulatory or political interventions. This is being followed up.


Nonparaxial diffraction-limited propagation of light in a graded-index planar medium with a hyperbolic secant refractive-index profile.
Nonparaxial diffraction-limited propagation of light with amplitude distribution in hyperbolic functions through an inhomogeneous planar medium with a hyperbolic secant refractive-index profile is studied by means of the stationary phase method. The irradiance distribution at geometrical shadow, edge of shadow, and a geometrically illuminated region is analyzed for a particular case.


Biochemical properties of human dehydrogenase/reductase (SDR family) member 7.
Dehydrogenase/reductase (SDR family) member 7 (DHRS7, retSDR4, SDR34C1) is a previously uncharacterized member of the short-chain dehydrogenase/reductase (SDR) superfamily. While human SDR members are known to play an important role in various (patho)biochemical pathways including intermediary metabolism and biotransformation of xenobiotics, only 20% of them are considered to be well characterized. Based on phylogenetic tree and SDR sequence clusters analysis DHRS7 is a close relative to well-known SDR member 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) that participates in metabolism of endogenous and xenobiotic substances with carbonyl group. The aim of present study is to determine the basic biochemical properties of DHRS7 and its possible involvement in metabolism of substrates with carbonyl group. For the first time the computational predictions of this membrane protein and membrane topology were experimentally confirmed. DHRS7 has been demonstrated to be an integral protein facing the lumen of the endoplasmic reticulum with lack of posttranscriptional glycosylation modification. Subsequently, NADP(H) cofactor preference and enzymatic reducing activity of DHRS7 was determined towards endogenous substrates with a steroid structure (cortisone, 4-androstene-3,17-dion) and also toward relevant exogenous substances bearing a carbonyl group harmful to human health (1,2-naphtoquinone, 9,10-phenantrenequinone). In addition to 11β-HSD1, DHRS7 is another enzyme from SDR superfamily that have been proved, at least in vitro, to contribute to the metabolism of xenobiotics with carbonyl group.


Large Gastric Teratoma: A Rare Intra-abdominal Mass of Infancy.
Amongst the varied, diverse causes of intraabdominal masses in infancy and early childhood, gastric teratomas (GTs) account for a very small proportion. A worldwide literature search reveals only around one hundred cases of GT and also supports the fact that its preoperative diagnosis remains elusive. Here we report the case of a two-month-old male who presented to the pediatric surgery outpatient department of Kasturba Medical College and Hospital, Karnataka, India, with progressive distension of abdomen since birth. Clinically, a large firm, non-mobile and non-tender mass involving all four quadrants of the abdomen was seen. Ultrasound revealed a large solid-cystic mass with internal septations extending from the epigastrium up to the pelvis. Computed tomography revealed a large intraperitoneal fat containing solid-cystic mass lesion showing curvilinear and chunky areas of calcification, with the mass focally indenting the posterior gastric wall and showing focal polypoidal intragastric extension. Exploratory laparotomy revealed a large cystic tumor with a solid component, arising from lesser curvature of the stomach, showing focal intraluminal extension across the posterior gastric wall, and occupying the whole lesser sac and abdominal cavity. The tumor was excised in toto along with the body of the stomach. Histopathological examination showed mature tissue derived from all three germ cell layers and confirmed the diagnosis of mature gastric teratoma. The patient was disease free at one-year follow-up.


Seamless warping of diffusion tensor fields.
To warp diffusion tensor fields accurately, tensors must be reoriented in the space to which the tensors are warped based on both the local deformation field and the orientation of the underlying fibers in the original image. Existing algorithms for warping tensors typically use forward mapping deformations in an attempt to ensure that the local deformations in the warped image remains true to the orientation of the underlying fibers; forward mapping, however, can also create "seams" or gaps and consequently artifacts in the warped image by failing to define accurately the voxels in the template space where the magnitude of the deformation is large (e.g., |Jacobian| > 1). Backward mapping, in contrast, defines voxels in the template space by mapping them back to locations in the original imaging space. Backward mapping allows every voxel in the template space to be defined without the creation of seams, including voxels in which the deformation is extensive. Backward mapping, however, cannot reorient tensors in the template space because information about the directional orientation of fiber tracts is contained in the original, unwarped imaging space only, and backward mapping alone cannot transfer that information to the template space. To combine the advantages of forward and backward mapping, we propose a novel method for the spatial normalization of diffusion tensor (DT) fields that uses a bijection (a bidirectional mapping with one-to-one correspondences between image spaces) to warp DT datasets seamlessly from one imaging space to another. Once the bijection has been achieved and tensors have been correctly relocated to the template space, we can appropriately reorient tensors in the template space using a warping method based on Procrustean estimation.


The foot function index with verbal rating scales (FFI-5pt): A clinimetric evaluation and comparison with the original FFI.
To assess the clinimetric value of the Dutch version of the Foot Function Index (FFI) in comparison with the original FFI using verbal rating scales (FFI-5pt) rather than visual analog scales (VAS). A prospective study was performed on 206 patients with nontraumatic forefoot complaints. Scoring, internal consistency, and construct validity of the FFI-5pt were compared with those of the original FFI, which rates all items on VAS. We also studied agreement between the scores at baseline and after one and 8 weeks and the scale scores with regard to sex, age, presence of osteoarthritis, limitation of mobility, bodily pain, and poor physical functioning (using SF-36). Some items were not applicable; removal of these items left 2 scales (Pain and Disability) with high internal consistency (alpha = 0.88 to 0.94) and good agreement between both versions (intraclass correlation coefficient 0.64 to 0.79). Principal component analysis with varimax rotation using a forced 2 factor model fitted well (65% explained variance). Test-retest reliability was high (ICC 0.70 to 0.83), while the stability over 8 weeks was lower, but still good (ICC 0.63 to 0.71). Responsiveness to change was low to moderate. However, a small number of patients reported an overall change (19%). Scores of patients with limited mobility and poor physical health (SF-36) were higher than those of patients with fewer physical problems, indicating good concurrent validity. The FFI-5pt is a suitable generic measure. Its clinimetric properties are comparable with those of the original FFI. Its administration and data entry are less time consuming. However, responsiveness has to be more exactly assessed in an intervention study.


Evaluating cumulative risk assessment for environmental justice: a community case study.
A key feature of cumulative risk assessment (CRA) is the ability to estimate differential health risks from environmental exposures within populations. Identifying populations at increased risk from environmental exposures is the first step toward mitigating such risks as required by the fair treatment mandate of environmental justice. CRA methods remain under development except for a limited application in pesticide regulations. The goals of this research were to advance CRA methods and to test their application in a community case study. We compared cumulative risk and health assessments for South and Southwest Philadelphia communities. The analysis found positive correlations between cumulative risk and mortality measurements for total mortality in Whites and non-Whites when we conducted the risk assessment using a multi-end point toxicological database developed for this project. Cumulative risk scores correlated positively with cause-specific mortality in non-Whites. Statistically significant increases in total and respiratory mortality rates were associated with incremental increases in the hazard ratio cumulative risk scores, with ranges of 2-6% for total and 8-23% for respiratory. Regression analyses controlled for percent non-White population and per capita income, indicating that risk scores represent an environmental effect on health independent of race and income. This case study demonstrated the successful application of CRA at the community level. CRA adds a health dimension to pollutant concentrations to produce a more comprehensive understanding of environmental inequities that can inform decision making. CRA is a viable tool to identify high-risk areas and to guide surveillance, research, or interventions.


Vitamin D metabolites and the gut microbiome in older men.
The vitamin D receptor is highly expressed in the gastrointestinal tract where it transacts gene expression. With current limited understanding of the interactions between the gut microbiome and vitamin D, we conduct a cross-sectional analysis of 567 older men quantifying serum vitamin D metabolites using LC-MSMS and defining stool sub-Operational Taxonomic Units from16S ribosomal RNA gene sequencing data. Faith's Phylogenetic Diversity and non-redundant covariate analyses reveal that the serum 1,25(OH)2D level explains 5% of variance in α-diversity. In β-diversity analyses using unweighted UniFrac, 1,25(OH)2D is the strongest factor assessed, explaining 2% of variance. Random forest analyses identify 12 taxa, 11 in the phylum Firmicutes, eight of which are positively associated with either 1,25(OH)2D and/or the hormone-to-prohormone [1,25(OH)2D/25(OH)D] "activation ratio." Men with higher levels of 1,25(OH)2D and higher activation ratios, but not 25(OH)D itself, are more likely to possess butyrate producing bacteria that are associated with better gut microbial health.


Acupuncture has potential in managing axial stiffness in steeplechase racehorses: a blinded prospective randomized preliminary study.
Evaluate the short-term effects of acupuncture on the dynamic manifestations of axial stiffness in steeplechase racehorses. 12 steeplechase racehorses presenting signs of axial stiffness during training. Horses were randomly assigned to either an acupuncture treatment by an experienced certified acupuncturist (n = 6) or no treatment as negative controls (6). The horses' locomotion was evaluated during training before treatment (D0) and 7 (D7) and 14 (D14) days after by their rider and trainer through a questionnaire. Additionally, the improvement of their dorsal flexibility 2 days after treatment was evaluated subjectively at the trot, free jumping at the canter was evaluated by expert clinicians, and free jumping at the trot was evaluated objectively via inertial measurement units. Significantly more horses were improved on D7 and D14 in the acupuncture group (6/6) compared with the control group (1/5; P =.01) according to the scores set by the trainer and riders. Subjective evaluation of the dorsal flexibility also revealed a significant improvement (P = .04) for horses receiving the acupuncture treatment (median improvement score, 0.50 [reference range, 0.5 to 0.9]) compared with control horses (-0.25 [reference range, -0.5 to 0]). Acupuncture may be an interesting nondoping strategy to improve clinical signs of axial stiffness and performance on steeplechase racehorses.


ED presentations of acute renal infarction.
The objective of the study was to investigate initial clinical characteristics that can suggest an early diagnosis of patients with acute renal infarction presenting with flank and/or abdominal pain in the emergency department (ED). From January 1, 1996, through December 31, 2005, 20 adult patients with renal infarction diagnosed by contrast-enhanced computed tomography in the ED were enrolled. Medical records, including demographic data, risk factors for thromboembolism, initial clinical presentations, laboratory data, treatment programs and outcomes, were retrospectively reviewed and analyzed. Mean patient age was 60.3 years (range, 21-80). The estimated incidence of renal infarction was 0.004% (20 of 481,540) among the ED census. The median time of onset of symptoms before the ED visit was 31 hours (range, 1-285). Eighteen patients (90%) had a history of more than 1 risk factor for thromboembolic events. In clinical presentations, all the patients had either abdominal or flank pain and tenderness. Nineteen patients (95%) had an elevated serum lactate dehydrogenase level with a mean +/- SD of 812.1 +/- 569.4 U/L. Sixteen patients (80%) presented with the triad--persisting flank or abdominal pain/tenderness, elevated serum lactate dehydrogenase level, and proteinuria. Among all 20 patients, 10 patients (50%) were diagnosed as having renal infarction at the initial ED visit. No specific clinical characteristics could be identified to distinguish those patients diagnosed early and those with delayed diagnosis. All 20 patients received medical treatment with coumadin, which was given in combination with heparin treatment in 11, peripheral intravenous and/or local intra-arterial thrombolytics with urokinase in 5, and mitral valve replacement in 1. No patient died. Although 4 patients had a mildly elevated serum creatinine level (>1.5 mg/dL) during hospitalization, none of them needs dialysis after more than 1 year of follow-up. In this study, we delineated specifically clinical features for emergency physicians to raise their suspicion index for an early diagnosis of patients with renal infarction, a disease which is uncommon and is usually delayed or missed at initial ED presentation.


Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis.
All domains of life feature diverse molecular clock machineries that synchronize physiological processes to diurnal environmental fluctuations. However, no mechanisms are known to cross-regulate prokaryotic and eukaryotic circadian rhythms in multikingdom ecosystems. Here, we show that the intestinal microbiota, in both mice and humans, exhibits diurnal oscillations that are influenced by feeding rhythms, leading to time-specific compositional and functional profiles over the course of a day. Ablation of host molecular clock components or induction of jet lag leads to aberrant microbiota diurnal fluctuations and dysbiosis, driven by impaired feeding rhythmicity. Consequently, jet-lag-induced dysbiosis in both mice and humans promotes glucose intolerance and obesity that are transferrable to germ-free mice upon fecal transplantation. Together, these findings provide evidence of coordinated metaorganism diurnal rhythmicity and offer a microbiome-dependent mechanism for common metabolic disturbances in humans with aberrant circadian rhythms, such as those documented in shift workers and frequent flyers.


Hedgehog signaling regulates segment formation in the annelid Platynereis.
Annelids and arthropods share a similar segmented organization of the body whose evolutionary origin remains unclear. The Hedgehog signaling pathway, prominent in arthropod embryonic segment patterning, has not been shown to have a similar function outside arthropods. We show that the ligand Hedgehog, the receptor Patched, and the transcription factor Gli are all expressed in striped patterns before the morphological appearance of segments in the annelid Platynereis dumerilii. Treatments with small molecules antagonistic to Hedgehog signaling disrupt segment formation. Platynereis Hedgehog is not necessary to establish early segment patterns but is required to maintain them. The molecular similarity of segment patterning functions of the Hedgehog pathway in an annelid and in arthropods supports a common origin of segmentation in protostomes.


Population genetic analysis of the recently rediscovered Hula painted frog (Latonia nigriventer) reveals high genetic diversity and low inbreeding.
After its recent rediscovery, the Hula painted frog (Latonia nigriventer) has remained one of the world's rarest and least understood amphibian species. Together with its apparently low dispersal capability and highly disturbed niche, the low abundance of this living fossil calls for urgent conservation measures. We used 18 newly developed microsatellite loci and four different models to calculate the effective population size (Ne) of a total of 125 Hula painted frog individuals sampled at a single location. We compare the Ne estimates to the estimates of potentially reproducing adults in this population (Nad) determined through a capture-recapture study on 118 adult Hula painted frogs captured at the same site. Surprisingly, our data suggests that, despite Nad estimates of only ~234-244 and Ne estimates of ~16.6-35.8, the species appears to maintain a very high genetic diversity (HO = 0.771) and low inbreeding coefficient (FIS = -0.018). This puzzling outcome could perhaps be explained by the hypotheses of either genetic rescue from one or more unknown Hula painted frog populations nearby or by recent admixture of genetically divergent subpopulations. Independent of which scenario is correct, the original locations of these populations still remain to be determined.