Totally thoracoscopic surgical closure of atrial septal defect in small children.
Totally thoracoscopic cardiac surgery is an alternative to traditional cardiac surgery in adults, and in few cases, in small children. This study assesses totally thoracoscopic cardiac surgery and its advantages for application to small children with low body weight. From March 2009 to October 2010, 28 patients, with a mean age of 5.8±2.1 years and mean weight of 15.0±4.65 kg (range, 13.5 to 22 kg), underwent totally thoracoscopic atrial septal defect closure. Three incisions 1.0 cm to 2.5 cm in length were made on the chest wall. Direct sutures were made in 20 patients, whereas Dacron patches were used in 8 patients. Mean follow-up was 6 months (range, 0 to 24 months). Cardiopulmonary bypass time was 56 to 126 minutes, and the aortic cross-clamp time was 36 to 65 minutes. A total of 28 cases were classified as New York Heart Association functional class I. No patient required further operation. Totally thoracoscopic surgical atrial septal defect closure in small children is feasible, minimally invasive, safe, and has good cosmesis.


Inhalation of Hydrogen Gas Is Beneficial for Preventing Contrast-Induced Acute Kidney Injury in Rats.
Background: The present study aimed at investigating the effect of a novel antioxidant, hydrogen (H2) gas, on the severity of contrast-induced acute kidney injury (CIAKI) in a rat model. Methods: CIAKI was induced in rats by intravenous injection of a contrast medium, Ioversol, in addition to reagents inhibiting prostaglandin and nitric oxide synthesis. During the injection of these reagents, the rats inhaled H2 gas or control gas. Results: One day after the injection, serum levels of urea nitrogen were significantly lower in H2 gas-inhaling CIAKI rats (17.6 ± 2.3 mg/dl) than those in control gas-treated CIAKI rats (36.0 ± 7.3 mg/dl), although they both were elevated as compared to untreated rats (14.9 ± 0.9 mg/dl). Consistently, creatinine clearance in H2 gas-treated CIAKI rats was higher than that in control gas-treated counterparts. Renal histological analysis revealed that the formation of proteinaceous casts and tubular necrosis was improved by H2 gas inhalation. Mechanistic analyses showed that inhalation of H2 gas significantly reduced renal cell apoptosis, expression of cleaved caspase 3, and expression of an oxidative stress marker, 8-hydroxydeoxyguanosine, in injured kidneys. Conclusion: Results suggest that H2 gas inhalation is effective in ameliorating the severity of CIAKI in rats by reducing renal cell apoptosis and oxidative stress. © 2015 S. Karger AG, Basel.


Effects of Dry Needling of Latent Trigger Points on Viscoelastic and Muscular Contractile Properties: Preliminary Results of a Randomized Within-Participant Clinical Trial.
This study aimed to evaluate changes in neuromuscular function and pain perception in latent trigger points (TrPs) in the gastrocnemius muscle after a single session of dry needling. A randomized within-participant clinical trial was conducted. Fifty volunteers with latent TrPs in the gastrocnemius muscles were explored. Each extremity was randomly assigned to a control or experimental (dry needling) group. Viscoelastic parameters and contractile properties were analyzed by tensiomyography. Ankle dorsiflexion range of motion was assessed with the lunge test. Pressure pain thresholds (PPT) and pain perceived were also analyzed. The results observed that three viscoelastic proprieties (myotonometry) showed significant differences in favor of the experimental extremity in the lateral gastrocnemius: stiffness (p = 0.02), relaxation (p = 0.045), and creep (p = 0.03), but not in the medial gastrocnemius. No changes in tensiomyography outcomes were found. The control extremity showed a higher increase in PPTs (i.e., decrease in pressure pain sensitivity) than the experimental extremity (p = 0.03). No significant effects for range of motion or strength were observed. In general, gender did not influence the effects of dry needling over latent TrPs in the gastrocnemius muscle. In conclusion, a single session of dry needling was able to change some parameters of neuromuscular function, such as muscle tone, relaxation, pressure pain sensitivity, and creep in the lateral (but not medial) gastrocnemius but did not improve strength or range of motion.


Co-ordinating interneurones of the locust which convey two patterns of motor commands: their connexions with flight motoneurones.
1. Some flight motoneurones receive two superimposed rhythms of depolarizing synaptic potentials when the locust is not flying; a slow rhythm which is invariably linked to the expiratory phase of ventilation, and a fast rhythm with a period of about 50 ms which is similar to the wingbeat period in flight. 2. By recording simultaneously from groups of motoneurones, the synaptic potentials which underly these rhythms have been revealed in 30 flight motoneurones in the three thoracic ganglia. The inputs occur in elevator motoneurones and some depressors but are of lower amplitude in the latter. The inputs have not been found in leg motoneurones. 3. The rhythmic depolarizations are usually subthreshold but sum with sensory inputs to evoke spikes in flight motoneurones at intervals equal to or multiples of the wingbeat period in flight. 4. Both rhythms originate in the metathoracic ganglion and are mediated by the same interneurones. They can be adequately explained by supposing that there are two symmetrical interneurones which each make widespread connexions with left and right flight motoneurones in the three ganglia. 5. The slow rhythm is coded in the overall burst of interneurone spikes during expiration and the fast rhythm in the interval between the spikes of a burst.


Yeast CBP1 mRNA 3' end formation is regulated during the induction of mitochondrial function.
Alternative mRNA processing is one mechanism for generating two or more polypeptides from a single gene. While many mammalian genes contain multiple mRNA 3' cleavage and polyadenylation signals that change the coding sequence of the mature mRNA when used at different developmental stages or in different tissues, only one yeast gene has been identified with this capacity. The Saccharomyces cerevisiae nuclear gene CPB1 encodes a mitochondrial protein that is required for cytochrome b mRNA stability. This 66-kDa protein is encoded by a 2.2-kb mRNA transcribed from CPB1. Previously we showed that a second 1.2-kb transcript is initiated at the CBP1 promoter but has a 3' end near the middle of the coding sequence. Furthermore, it was shown that the ratio of the steady-state level of 2.2-kb CBP1 message to 1.2-kb message decreases 10-fold during the induction of mitochondrial function, while the combined levels of both messages remain constant. Having proposed that regulation of 3' end formation dictates the amount of each CBP1 transcript, we now show that a 146-bp fragment from the middle of CBP1 is sufficient to direct carbon source-regulated production of two transcripts when inserted into the yeast URA3 gene. This fragment contains seven polyadenylation sites for the wild-type 1.2-kb mRNA, as mapped by sequence analysis of CBP1 cDNA clones. Deletion mutations upstream of the polyadenylation sites abolished formation of the 1.2-kb transcript, whereas deletion of three of the sites only led to a reduction in abundance of the 1.2-kb mRNA. Our results indicate that regulation of the abundance of both CBP1 transcripts is controlled by elements in a short segment of the gene that directs 3' end formation of the 1.2-kb transcript, a unique case in yeast cells.


Spinal glomus-type arteriovenous malformations: microsurgical treatment in 20 cases.
Glomus-type spinal arteriovenous malformations (AVMs) are rare. In the literature only small series and anecdotal reports can be found, and there are no prospective series elucidating the natural course or the superiority of 1 treatment regimen over another (such as surgery versus embolization versus conservative treatment). Microsurgical treatment of spinal AVMs often seems difficult because many lesions are not anatomically suitable for primary microsurgical occlusion and are therefore treated with first-line neuroradiological interventions or not at all. Between 1989 and 2005, 20 patients with glomus-type AVMs underwent microsurgical treatment at 2 major neurosurgical centers in Germany. The history of symptoms in these patients ranged from 2 days to 11 years. Four patients presented with subarachnoid hemorrhage, 2 with intramedullary hematoma, 4 with paresthesia or pain, and 10 with clinical signs of myelopathy. Seven patients underwent partial embolization prior to microsurgery. The authors only operated on AVMs accessible from a dorsal or dorsolateral approach. Neurological status was assessed with the McCormick classification scheme. Follow-up data were obtained from outpatient records. Three patients were interviewed over the telephone and 4 patients were not available for follow-up evaluation. Surgery was performed via a laminectomy in 14 and hemilaminectomy in 6 patients. The microsurgical technique used consisted of retrograde dissection of the AVM from the venous side in most cases. Four (20%) of 20 patients showed worsening of neurological symptoms to a worse McCormick grade, probably caused by suspected venous stasis directly after surgery, however only 1 patient (5%) suffered permanent deterioration after surgery. In 14 patients postoperative angiography proved complete occlusion in 11 patients, including the presence of a remnant requiring a second operation with complete occlusion thereafter in 1 patient. In 3 patients occlusion was incomplete: a small residual AVM remained in 1 patient, and a discrete feeding vessel without a vein was evident in 2 patients. Spinal cord AVMs are rare. If embolization is not possible, surgery may be indicated in selected cases. Spinal AVMs behave differently after incomplete occlusion either surgically or with embolization. A postoperative reduction in symptoms is frequent despite the presence of small remnants, and the risk of neurological deficits seems relatively low even in residual AVMs. Therefore, treatment need not necessarily aim at complete occlusion if that would be associated with an unacceptably high risk of neurological deficits.


Initial evaluation of subcutaneous daclizumab treatments for noninfectious uveitis: a multicenter noncomparative interventional case series.
To assess the feasibility of a study design that may determine whether subcutaneous administration of the interleukin-2 receptor antibody daclizumab can safely reduce the dependence on standard systemic corticosteroids or other immunosuppressive regimens in patients with sight-threatening, noninfectious intermediate uveitis, posterior uveitis, or panuveitis. Prospective, multicenter, nonrandomized, noncomparative, open-label interventional trial. Fifteen patients, 5 each at 3 clinical centers, with noninfectious intermediate, posterior, or panuveitis, who require a currently stable immunosuppression regimen of systemic corticosteroids and/or other systemic treatments to control noninfectious intraocular inflammation. After enrollment and baseline ophthalmic evaluations, 2 induction treatments were given 2 weeks apart using subcutaneous (SC) daclizumab at 2 mg/kg. Subcutaneous daclizumab maintenance treatments were then continued every 2 weeks at 1 mg/kg for 6 months. The initial immunosuppression load was tapered over 8 to 12 weeks in a staggered fashion beginning with the first induction treatment. Safety evaluations were performed at each treatment visit, with a primary efficacy evaluation at 12 weeks and a repeat efficacy evaluation at 26 weeks. Best-corrected visual acuity (Early Treatment of Diabetic Retinopathy Study [ETDRS] method) with a concurrent taper of concomitant systemic immunosuppression medication load (tabulated by use of a weighted scoring system) was assessed; target for success was defined as a 50% or greater reduction in concomitant immunosuppression load by 12 weeks while maintaining visual acuity within 5 ETDRS letters of baseline. Ocular inflammation was assessed at each visit with standardized grading scales. Ten of 15 patients (67%) receiving SC daclizumab treatments every other week successfully achieved the primary efficacy end point of reducing their concomitant immunosuppression load by at least 50% while maintaining their baseline visual acuity at 12 and 26 weeks. Subcutaneous daclizumab injections were well tolerated with no serious adverse events observed during the 6 months of treatments, although 3 patients experienced possibly related, nonserious adverse events. Subcutaneous daclizumab induction treatments at 2 mg/kg followed by 1 mg/kg maintenance treatments every other week seems safe and, in most cases, may reduce the concomitant immunosuppressive load required to treat noninfectious uveitis for 12 to 26 weeks.


Systematic Review of Pain Medicine Content, Teaching, and Assessment in Medical School Curricula Internationally.
Pain management is a major health care challenge in terms of the significant prevalence of pain and the negative consequences of poor management. Consequently, there have been international calls to improve pain medicine education for medical students. This systematic review examines the literature on pain medicine education at medical schools internationally, with a particular interest in studies that make reference to: a defined pain medicine curriculum, specific pain medicine learning objectives, dedicated pain education modules, core pain topics, medical specialties that teach pain medicine, elective study opportunities, hours allocated to teaching pain medicine during the curriculum, the status of pain medicine in the curriculum (compulsory or optional), as well as teaching, learning, and assessment methods. A systematic review was undertaken of relevant studies on pain medicine education for medical students published between January 1987 and May 2018 using PubMed, Medline, Excerpta Medica database (EMBASE), Education Resources Information Center (ERIC), and Google Scholar, and Best Evidence Medical Education (BEME) data bases. Fourteen studies met the inclusion criteria. Evaluation of pain medicine curricula has been undertaken at 383 medical schools in Australia, New Zealand, the United States of America (USA), Canada, the United Kingdom (UK), and Europe. Pain medicine was mostly incorporated into medical courses such as anaesthesia or pharmacology, rather than presented as a dedicated pain medicine module. Ninety-six percent of medical schools in the UK and USA, and nearly 80% of medical schools in Europe had no compulsory dedicated teaching in pain medicine. On average, the median number of hours of pain content in the entire curriculum was 20 in Canada (2009), 20 in Australia and New Zealand (2018), 13 in the UK (2011), 12 in Europe (2012/2013), and 11 in the USA (2009). Neurophysiology and pharmacology pain topics were given priority by medical schools in all countries. Lectures, seminars, and case-based instruction were the teaching methods most commonly employed. When it was undertaken, medical schools mostly assessed student competency in pain medicine using written examinations rather than clinical assessments. This systematic review has revealed that pain medicine education at medical schools internationally does not adequately respond to societal needs in terms of the prevalence and public health impact of inadequately managed pain.


Patient Reactions to Surgeon Recommendations About Contralateral Prophylactic Mastectomy for Treatment of Breast Cancer.
Guidelines assert that contralateral prophylactic mastectomy (CPM) should be discouraged in patients without an elevated risk for a second primary breast cancer. However, little is known about the impact of surgeons discouraging CPM on patient care satisfaction or decisions to seek treatment from another clinician. To examine the association between patient report of first-surgeon recommendation against CPM and the extent of discussion about it with 3 outcomes: patient satisfaction with surgery decisions, receipt of a second opinion, and receipt of surgery by a second surgeon. This population-based survey study was conducted in Georgia and California. We identified 3880 women with stages 0 to II breast cancer treated in 2013-2014 through the Surveillance, Epidemiology, and End Results registries of Georgia and Los Angeles County. Surveys were sent approximately 2 months after surgery (71% response rate, n = 2578). In this analysis conducted from February to May 2016, we included patients with unilateral breast cancer who considered CPM (n = 1140). Patients were selected between July 2013 and September 2014. We examined report of surgeon recommendations, level of discussion about CPM, satisfaction with surgical decision making, receipt of second surgical opinion, and surgery from a second surgeon. The mean (SD) age of patients included in this study was 56 (10.6) years. About one-quarter of patients (26.7%; n = 304) reported that their first surgeon recommended against CPM and 30.1% (n = 343) reported no substantial discussion about CPM. Dissatisfaction with surgery decision was uncommon (7.6%; n = 130), controlling for clinical and demographic characteristics. One-fifth of patients (20.6%; n = 304) had a second opinion about surgical options and 9.8% (n = 158) had surgery performed by a second surgeon. Dissatisfaction was very low (3.9%; n = 42) among patients who reported that their surgeon did not recommend against CPM but discussed it. Dissatisfaction was substantively higher for those whose surgeon recommended against CPM with no substantive discussion (14.5%; n = 37). Women who received a recommendation against CPM were not more likely to seek a second opinion (17.1% among patients with recommendation against CPM vs 15.1% of others; P = .52) nor to receive surgery by a second surgeon (7.9% among patients with recommendation against CPM vs 8.3% of others; P = .88). Most patients are satisfied with surgical decision making. First-surgeon recommendation against CPM does not appear to substantively increase patient dissatisfaction, use of second opinions, or loss of the patient to a second surgeon.


Alcohol-attributable morbidity and resulting health care costs in Canada in 2002: recommendations for policy and prevention.
Alcohol is one of the most important risk factors for burden of disease, particularly in high-income countries such as Canada. The purpose of this article was to estimate the number of hospitalizations, hospital days, and the resulting costs attributable to alcohol for Canada in 2002. Exposure distribution was taken from the Canadian Addiction Survey and corrected for per capita consumption from production and sales. For chronic disease, risk relations were taken from the published literature and combined with exposure to calculate age- and gender-specific alcohol-attributable fractions. For injury, alcohol-attributable fractions were taken directly from available statistics. Data on the most responsible diagnosis, length of stay for hospitalizations, and costs were obtained from the national Canadian databases. For Canada in 2002, there were 195,970 alcohol-related diagnoses among acute care hospitalizations, 2,058 alcohol-attributable psychiatric hospitalizations, and 183,589 alcohol-attributable admissions to specialized treatment centers. These accounted for 1,246,945 hospital days in acute care facilities, 54,114 hospital days in psychiatric hospitals, and 3,018,688 hospital days in specialized treatment centers (inpatient and outpatient). The main causes of alcohol-attributable morbidity were neuropsychiatric conditions, cardiovascular disease, and unintentional injuries. In total, Can. $2.29 billion were spent on alcohol-related health care. Alcohol poses a heavy burden of disease as well as a financial strain on Canadian society. However, there are evidence-based effective and cost-effective policy and legislative interventions as well as measures to better enforce these laws.


Laser ranging and mapping with a photon-counting detector.
We propose a new technique for remote sensing: photon-counting laser mapping. MicroChannel plate detectors with a crossed delay-line (MCP/CDL) readout combine high position accuracy and subnanosecond photon timing, at event rates of 10(6) detected photons per second and more. A mapping system would combine an MCP/CDL detector with a fast-pulse, high-repetition-rate laser illuminator. The system would map solid targets with exceptional in-range and cross-range resolution. The resulting images would be intrinsically three dimensional, without resorting to multiple viewing angles, so that objects of identical albedo could be discriminated. For a detector time resolution and pulse width of the order of 10(-10) s, the in-range resolution would be a few centimeters, permitting the discrimination of surfaces by their textures. Images could be taken at night, at illumination levels up to full moonlight, from ground, airborne, or space platforms. We discuss signal to noise as a function of laser flux and background level and present simulated images.


Development of pulmonary fibrosis after heart failure induced by elevated left atrial pressure.
Chronic heart failure (CHF) is a common and serious complication of patients with ischemic heart disease that may eventually lead to the development of pulmonary fibrosis. While other forms of pulmonary fibrosis have been studied extensively, little is known about the mechanisms that lead to heart failure associated with pulmonary fibrosis. The purpose of our study was to develop a rat pulmonary edema/fibrosis model induced by chronically elevated left atrial pressure (LAP), simulating CHF pathophysiology. In adult rats, LAP was elevated by 15-20 mmHg through mechanical restriction of left ventricular diastolic filling with a maximum effect occurring at 7 days. Sham rats were surgically operated without LAP elevation. Lung tissues were analyzed for wet-to-dry ratio, hydroxyproline content, cellular invasion, and tissue integrity. Lung compliance and airway resistance served as pulmonary mechanical parameters. Hemodynamic parameters, including arterial pressure, heart rate, and cardiac output, were recorded in Sham and LAP elevated rats for 7 days. With increased LAP, pulmonary water content was significantly elevated accompanied by a decrease in lung compliance. Hydroxyproline markedly increased with chronic left atrial pressure elevation, suggesting fibrosis development. Simultaneously, heart failure induced a decrease in cardiac function. LAP elevation resulted in chronic pulmonary edema and tissue fibrosis formation associated with pulmonary dysfunction as measured by decreased dynamic lung compliance.


Optimization of wavelet coherence analysis as a measure of neural synchrony during hyperscanning using functional near-infrared spectroscopy.
Significance: The expanding field of human social interaction is enabled by functional near-infrared spectroscopy (fNIRS) that acquires hemodynamic signals during live two-person interactions. These advances call for development of methods to quantify interactive processes. Aim: Wavelet coherence analysis has been applied to cross-brain neural coupling. However, fNIRS-specific computations have not been explored. This investigation determines the effects of global mean removal, wavelet equation, and choice of oxyhemoglobin versus deoxyhemoglobin signals. Approach: We compare signals with a known coherence with acquired signals to determine optimal computational approaches. The known coherence was calculated using three visual stimulation sequences of a contrast-reversing checkerboard convolved with the canonical hemodynamic response function. This standard was compared with acquired human fNIRS responses within visual cortex using the same sequences. Results: Observed coherence was consistent with known coherence with highest correlations within the wavelength range between 10 and 20 s. Removal of the global mean improved the correlation irrespective of the specific equation for wavelet coherence, and the oxyhemoglobin signal was associated with a marginal correlation advantage. Conclusions: These findings provide both methodological and computational guidance that enhances the validity and interpretability of wavelet coherence analysis for fNIRS signals acquired during live social interactions.


Control of energy homeostasis and insulin action by adipocyte hormones: leptin, acylation stimulating protein, and adiponectin.
Adipose tissue performs complex metabolic and endocrine functions. This review will focus on the recent literature on the biology and actions of three adipocyte hormones involved in the control of energy homeostasis and insulin action, leptin, acylation-stimulating protein, and adiponectin, and mechanisms regulating their production. Results from studies of individuals with absolute leptin deficiency (or receptor defects), and more recently partial leptin deficiency, reveal leptin's critical role in the normal regulation of appetite and body adiposity in humans. The primary biological role of leptin appears to be adaptation to low energy intake rather than a brake on overconsumption and obesity. Leptin production is mainly regulated by insulin-induced changes of adipocyte metabolism. Consumption of fat and fructose, which do not initiate insulin secretion, results in lower circulating leptin levels, a consequence which may lead to overeating and weight gain in individuals or populations consuming diets high in energy derived from these macronutrients. Acylation-stimulating protein acts as a paracrine signal to increase the efficiency of triacylglycerol synthesis in adipocytes, an action that results in more rapid postprandial lipid clearance. Genetic knockout of acylation-stimulating protein leads to reduced body fat, obesity resistance and improved insulin sensitivity in mice. The primary regulator of acylation-stimulating protein production appears to be circulating dietary lipid packaged as chylomicrons. Adiponectin increases insulin sensitivity, perhaps by increasing tissue fat oxidation resulting in reduced circulating fatty acid levels and reduced intramyocellular or liver triglyceride content. Adiponectin and leptin together normalize insulin action in severely insulin-resistant animals that have very low levels of adiponectin and leptin due to lipoatrophy. Leptin also improves insulin resistance and reduces hyperlipidemia in lipoatrophic humans. Adiponectin production is stimulated by agonists of peroxisome proliferator-activated receptor-gamma; an action may contribute to the insulin-sensitizing effects of this class of compounds. The production of all three hormones is influenced by nutritional status. These adipocyte hormones, the pathways controlling their production, and their receptors represent promising targets for managing obesity, hyperlipidemia, and insulin resistance.


Cochlear Implantation in a Patient with Kabuki Syndrome.
Criteria for cochlear implants are expanding and now include children with disabilities in addition to hearing loss, such as those with Kabuki syndrome (KS). This case report describes language outcomes and changes in the quality of life of a female child with KS after cochlear implantation. The subject had a profound progressive sensorineural hearing loss, cognitive impairments, and other disabilities and communicated using vocalized sounds and the Dutch Sign Language. After cochlear implantation at an age of nine years and three months, the patient displayed no progress in speech production and minimal progress in receptive language development, but she had an increased awareness of the world and an increase in the quality of life.


Cancer diagnoses after living kidney donation: linking U.S. Registry data and administrative claims.
Mortality records identify cancer as the leading cause of death among living kidney donors, but information on the burden of cancer outside death records is limited in this population. We examined a database wherein U.S. Organ Procurement and Transplantation Network identifiers for 4,650 living kidney donors in 1987 to 2007 were linked to administrative data of a U.S. private health insurer (2000-2007 claims) to identify postdonation cancer diagnoses. Skin cancer and non-skin cancer diagnoses were ascertained from International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes on billing claims. Donors were also matched one-to-one with general insurance beneficiaries by sex and age when benefits began. Diagnosis rates within observation windows were compared as rate ratios. The median time from donation to the end of plan insurance enrollment was 7.7 years, with a median observation period of 2.1 years. Skin cancer rates were similar among prior living donors in the observation period and nondonor controls (rate ratio, 0.91; 95% confidence interval [CI], 0.59-1.40). In contrast, the rate of total non-skin cancers was significantly less common among donors than among controls (rate ratio, 0.74; 95% CI, 0.55-0.99), although reduced relative risk was limited to donors captured earlier in relation to donation. Several cases of cancer diagnosis (uterine, melanoma, "other") were identified within the first year after donation. Prostate cancer diagnosis was significantly more common among living donors compared with controls (rate ratio, 3.80; 95% CI, 1.42-10.2). Continued study of cancer after kidney donation is warranted to ensure that evaluation, selection, and long-term follow-up support overall good health of the donor.


Two-dimensional NiO nanosheets with enhanced room temperature NO2 sensing performance via Al doping.
High-performance gas sensors based on metal oxides operated at room temperature are of great interest due to their energy saving and cost effective characteristics. How to improve the sensitivity of metal oxide gas sensors and enable their room-temperature operation are challenging for their realistic applications. In this work, we have designed and fabricated Al-doped NiO nanosheets for greatly enhanced NO2 detection at room temperature. Different amounts of Al were doped into two-dimensional (2D) NiO nanosheets via a fast and facile microwave assisted solvent-thermal technique. Sensing tests of the as-fabricated devices indicated that Al doping could significantly affect the gas-sensing properties of the NiO nanosheets due to increased oxygen vacancies as well as the formation of Lewis acid and base sites. When 12 at% of Al was added to the raw materials, the response value of the device to 10 ppm NO2 was enhanced more than 35 times compared with those of pure NiO nanosheets. In addition, when the amount of Al reached 20 at%, it took only 200 s for the gas sensor to achieve full recovery, which was a breakthrough for room temperature gas sensors based on metal oxides. Above all, the excellent performances of the as-fabricated devices make Al-doped NiO nanosheets a potential candidate for NO2 sensing applications. This design strategy can also give guidance for designing high-performance gas sensors based on other similar 2D sensing materials.


Cure of inguinal hernias with large preperitoneal prosthesis: Experience of 2,312 cases.
It is clear that the recurrence rates after nonprosthetic methods for the repair of inguinal hernias, like McVay, Bassini or Shouldice techniques, are high (6-10%). Since 20 years, we are convinced, in the GREPA-EHS group, about the advantages of the use of a prosthetic mesh in majority of patients for repairs of primary or recurrent inguinal hernias and incisional hernias. We describe our typical technique for the cure of all inguinal hernias. We place a large supple mesh, by open inguinal route, posterior to the transversalis fascia and anterior to the peritoneum. We have made a double modification in the initial technique of Rives - the use of a very large unsplit prosthesis (15 × 17 cm) and the parietalization of the spermatic cord helped by a wide opening of the Fruchaud's orifice by diversion of the epigastric vessels. The positioning of the mesh is about the same as in the TEP technique but with the advantages of reduction in the vital laparoscopic risks and reinforcement of the wall by a short tension-free McVay technique.For this prospective study, we repaired 2,312 consecutive hernias in 1,828 patients, 284 of which were recurrent. We present our results in terms of quality of repairs, recurrence rates (0.4%), morbidity rate (8%), and mortality rate (0.8%).This technique involves the placement by an open incisional route of a large preperitoneal sheet of mesh for initial treatment of all inguinal hernias - including scrotal, giant or femoral - to ensure a definitive solid muscular wall, even for recurrent hernias.


MTHFR polymorphisms and 5-FU-based adjuvant chemotherapy in colorectal cancer.
Methylenetetrahydrofolate reductase is a pivotal enzyme in folate metabolism and 5-fluorouracil (5-FU) cytotoxicity. Two common single-nucleotide polymorphisms (SNPs), MTHFR 677C>T (rs1801133) and 1298A>C (rs1801131), reduce enzyme activity. Initially, these SNPs were claimed to predict clinical efficacy, but further studies have yielded contradictory results. We tested whether these two polymorphisms are determinants of clinical outcome in a large patient group with a long follow-up time. We included 331 patients who had been treated with adjuvant 5-FU/leucovorin chemotherapy after intended curative resection between 1997 and 2003. Clinical data, including relapse rates, overall survival, and tumor stage, were collected. DNA was extracted from formalin-fixed tumor tissue and analyzed for the MTHFR 677C>T and 1298A>C SNPs with real-time PCR. The MTHFR 677C>T and 1298A>C polymorphisms were not associated with survival or relapse-free survival (P > 0.2). The 677 CC genotype was associated to toxicity (odds ratio = 1.83, P = 0.01). The MTHFR 677C>T and 1298A>C polymorphisms probably do not predict efficacy of adjuvant 5-FU treatment in colorectal cancer after complete resection; however, the 677C>T polymorphism may be associated with lower toxicity in 5-FU treatment. Implementation of SNP analysis for these polymorphisms for individualized treatment is premature.


Photochemically Driven Polymeric Network Formation: Synthesis and Applications.
Polymeric networks have been intensely investigated and a large number of applications have been found in areas ranging from biomedicine to materials science. Network fabrication via light-induced reactions is a particularly powerful tool, since light provides ready access to temporal and spatial control, opening an array of synthetic access routes for structuring the network geometry as well as functionality. Herein, the most recent light-induced modular reactions and their use in the formation of precision polymeric networks are collated. The synthetic strategies including photoinduced thiol-based reactions, Diels-Alder systems, and photogenerated reactive dipoles, as well as photodimerizations, are discussed in detail. Importantly, applications of the fabricated networks via the aforementioned reactions are highlighted with selected examples. Concomitantly, we provide future directions for the field, emphasizing the most critically required advances.


Case report: pulmonary calcification after liver transplantation in children.
Pulmonary calcification following liver transplantation is a recognized phenomenon in adults but has not been previously described in children. We describe two children who developed pulmonary calcification after liver transplantation. Pulmonary calcification should be considered after liver transplantation when radiographic changes fail to resolve with appropriate treatment.


A framework to model exposure to per- and polyfluoroalkyl substances in indoor environments.
Per- and polyfluoroalkyl substances (PFAS) include a wide range of halogenated chemicals, which have been used as water- and stain-resistant coatings for consumer products and industrial purposes. PFAS are persistent in the environment and several are bioaccumulative, and thus relevant for human and environmental health. Given their pervasiveness, we need to understand how we are exposed to PFAS, especially in indoor environments where many people spend most of their time. Research on indoor exposure to semivolatile organic compounds (SVOCs) has progressed rapidly in recent years. Because many PFAS can be considered SVOCs, much of what has been learned about SVOCs may be used to guide research on PFAS exposure in indoor environments. Here, we briefly review what has been done to assess indoor exposure to PFAS. Then, we propose a systematic indoor exposure framework for PFAS based on methods to estimate exposure to SVOCs. We illustrate how critical parameters such as partition coefficients for different media (particles, dust, surfaces, and clothing) for different types of PFAS could be measured, how these measurements can be used in exposure models for PFAS, and how fundamental, predictive relationships might be used to estimate necessary parameters for emerging compounds.


Stoichiometry of the T cell antigen receptor (TCR) complex: each TCR/CD3 complex contains one TCR alpha, one TCR beta, and two CD3 epsilon chains.
The stoichiometry of the subunits that comprise the T cell antigen receptor (TCR) complex is not completely known. In particular, it is uncertain whether TCR alpha and TCR beta proteins are present in the TCR complex as one or multiple heterodimeric pairs. In this study we have used mice transgenic for two different TCR alpha and two different TCR beta proteins to determine the number of TCR alpha and TCR beta chains in a single TCR complex. Individual thymocytes and splenic T cells from double TCR transgenic mice simultaneously expressed all four transgenic TCR proteins on their surfaces. Because the individual TCR alpha and individual TCR beta proteins were biochemically distinguishable, we were able to examine association among the transgenic TCR products. We found that each TCR alpha chain paired with each TCR beta chain, but that each TCR complex contained only one TCR alpha and one TCR beta protein. Furthermore, quantitative immunofluorescence revealed that T cells expressed twice as many CD3 epsilon as TCR beta proteins. These findings demonstrate that there are precisely one TCR alpha, one TCR beta, and two CD3 epsilon chains in each TCR/CD3 complex expressed on the surfaces of both thymocytes and mature T cells.


HMG CoA reductase inhibitor-induced myotoxicity: pravastatin and lovastatin inhibit the geranylgeranylation of low-molecular-weight proteins in neonatal rat muscle cell culture.
In previous studies, inhibition of cholesterol synthesis by HMG CoA reductase inhibitors (HMGRI) was associated with myotoxicity in cultures of neonatal rat skeletal myotubes, and rhabdomyolysis in rats, rabbits, and humans in vivo. In vitro myotoxicity was directly related to HMGRI-induced depletion of mevalonate, farnesol, and geranylgeraniol, since supplementation with these intermediate metabolites abrogated the toxicity. Both farnesol and geranylgeraniol are required for the posttranslational modification, or isoprenylation, of essential regulatory proteins in mammalian cells. The objective of the present study was to measure changes in protein isoprenylation in cultured neonatal rat skeletal muscle cells exposed for 24 hr to increasing concentrations of pravastatin or lovastatin. Proteins were labeled with [3H]mevalonate, [3H]farnesyl pyrophosphate (FPP), or [3H]geranylgeranyl pyrophosphate (GGPP), and then separated by SDS-PAGE and quantitated by scintillation counting and densitometry of autoradiographs. Mevalonate and FPP labeling of the majority of proteins increased in a concentration-dependent manner, even at concentrations greater than 2 microM lovastatin and 25 microM pravastatin that completely inhibited cholesterol synthesis. In contrast, mevalonate and FPP labeling of three protein bands with molecular weights of 26.6, 27.7, and 28.9 kDa was markedly inhibited at concentrations higher than 1 microM lovastatin and 400 microM pravastatin, which inhibited protein synthesis and disrupted myotube morphology after longer exposures in a previous study. In contrast, these proteins were equally well labeled by GGPP at all HMGRI concentrations tested, suggesting that isoprenylation of the 26.9-, 27.8-, and 28.9-kDa proteins requires geranylgeraniol. The results of this study indicate that HMGRI-induced myotoxicity is most likely related to reduced posttranslational modification of specific regulatory proteins by geranylgeraniol.


Modulation of the osteosarcoma expression phenotype by microRNAs.
Osteosarcomas are the most common primary malignant tumors of bone and show multiple and complex genomic aberrations. miRNAs are non-coding RNAs capable of regulating gene expression at the post transcriptional level, and miRNAs and their target genes may represent novel therapeutic targets or biomarkers for osteosarcoma. In order to investigate the involvement of miRNAs in osteosarcoma development, global microarray analyses of a panel of 19 human osteosarcoma cell lines was performed. We identified 177 miRNAs that were differentially expressed in osteosarcoma cell lines relative to normal bone. Among these, miR-126/miR-126*, miR-142-3p, miR-150, miR-223, miR-486-5p and members of the miR-1/miR-133a, miR-144/miR-451, miR-195/miR-497 and miR-206/miR-133b clusters were found to be downregulated in osteosarcoma cell lines. All miRNAs in the paralogous clusters miR-17-92, miR-106b-25 and miR-106a-92 were overexpressed. Furthermore, the upregulated miRNAs included miR-9/miR-9*, miR-21*, miR-31/miR-31*, miR-196a/miR-196b, miR-374a and members of the miR-29 and miR-130/301 families. The most interesting inversely correlated miRNA/mRNA pairs in osteosarcoma cell lines included miR-9/TGFBR2 and miR-29/p85α regulatory subunit of PI3K. PTEN mRNA correlated inversely with miR-92a and members of the miR-17 and miR-130/301 families. Expression profiles of selected miRNAs were confirmed in clinical samples. A set of miRNAs, miR-1, miR-18a, miR-18b, miR-19b, miR-31, miR-126, miR-142-3p, miR-133b, miR-144, miR-195, miR-223, miR-451 and miR-497 was identified with an intermediate expression level in osteosarcoma clinical samples compared to osteoblasts and bone, which may reflect the differentiation level of osteosarcoma relative to the undifferentiated osteoblast and fully differentiated normal bone. This study provides an integrated analysis of miRNA and mRNA in osteosarcoma, and gives new insight into the complex genetic mechanisms of osteosarcoma development and progression.


A survey on beliefs and attitudes of trainee surgeons towards placebo.
The aim of this study was to investigate the beliefs and attitudes of trainee surgeons regarding placebo interventions, in surgical practice and in research, and to compare them to those of senior orthopaedic surgeons. An invitation to participate in an online survey was sent to all the email addresses in the members' database of the British Orthopaedic Trainees Association (BOTA). All 987 members of BOTA were invited to participate in the survey and 189 responded (19 %). The majority of trainees think that the placebo effect is real (88 %), has therapeutic benefits (88 %) and that placebo manipulations are permissible (98 %). Sixty per cent of respondents agree that placebo can be used outside of research, most commonly, to distinguish between organic and non-organic symptoms (36 %). Trainees are more likely than senior surgeons to use placebo for pain management (34 % vs. 12 %). They are mainly concerned about the risk of side effects associated with the use of placebo (80 %) and prefer placebo interventions with minimal invasiveness. Seventy-three per cent respondents would recruit patients into the proposed randomised controlled surgical trial. The views regarding efficacy, permissibility and indications for placebo among trainees are similar to those of orthopaedic consultants. Orthopaedic trainees regard placebo as permissible and show willingness to recruit into placebo-controlled trials. However, they seem to have limited understanding of mechanisms of placebo effect and underestimate its ubiquity.


Frailty is associated with in-hospital mortality in older hospitalised COVID-19 patients in the Netherlands: the COVID-OLD study.
During the first wave of the coronavirus disease 2019 (COVID-19) pandemic, older patients had an increased risk of hospitalisation and death. Reports on the association of frailty with poor outcome have been conflicting. The aim of the present study was to investigate the independent association between frailty and in-hospital mortality in older hospitalised COVID-19 patients in the Netherlands. This was a multicentre retrospective cohort study in 15 hospitals in the Netherlands, including all patients aged ≥70 years, who were hospitalised with clinically confirmed COVID-19 between February and May 2020. Data were collected on demographics, co-morbidity, disease severity and Clinical Frailty Scale (CFS). Primary outcome was in-hospital mortality. A total of 1,376 patients were included (median age 78 years (interquartile range 74-84), 60% male). In total, 499 (38%) patients died during hospital admission. Parameters indicating presence of frailty (CFS 6-9) were associated with more co-morbidities, shorter symptom duration upon presentation (median 4 versus 7 days), lower oxygen demand and lower levels of C-reactive protein. In multivariable analyses, the CFS was independently associated with in-hospital mortality: compared with patients with CFS 1-3, patients with CFS 4-5 had a two times higher risk (odds ratio (OR) 2.0 (95% confidence interval (CI) 1.3-3.0)) and patients with CFS 6-9 had a three times higher risk of in-hospital mortality (OR 2.8 (95% CI 1.8-4.3)). The in-hospital mortality of older hospitalised COVID-19 patients in the Netherlands was 38%. Frailty was independently associated with higher in-hospital mortality, even though COVID-19 patients with frailty presented earlier to the hospital with less severe symptoms.


The RNA World as a Model System to Study the Origin of Life.
Understanding how life arose is a fundamental problem of biology. Much progress has been made by adopting a synthetic and mechanistic perspective on originating life. We present a current view of the biochemistry of the origin of life, focusing on issues surrounding the emergence of an RNA World in which RNA dominated informational and functional roles. There is cause for optimism on this difficult problem: the prebiotic chemical inventory may not have been as nightmarishly complex as previously thought; the catalytic repertoire of ribozymes continues to expand, approaching the goal of self-replicating RNA; encapsulation in protocells provides evolutionary and biophysical advantages. Nevertheless, major issues remain unsolved, such as the origin of a genetic code. Attention to this field is particularly timely given the accelerating discovery and characterization of exoplanets.


Prenatal exposure to di-(2-ethylhexyl) phthalate and decreased skeletal muscle mass in 6-year-old children: A prospective birth cohort study.
Phthalate is a well-known endocrine-disrupting chemical that has anti-androgenic effects. Although there are several studies on the relationship between body composition and phthalate, studies that investigated the effects of phthalate on skeletal muscle during childhood are lacking. We analyzed data from 481 mother-and-child pairs enrolled in the Environment and Development of Children cohort in South Korea. We examined the association between phthalate metabolites (mono [2-ethyl-5-hydroxyhexyl] phthalate [MEHHP], mono [2-ethyl-5-oxohexyl] phthalate [MEOHP], molar sum of MEHHP and MEOHP [Σ DEHP], and mono-n-butyl phthalate [MnBP]) in prenatal maternal urine and children's urine at the age of 6, and body composition indices (body mass index [BMI] z-score, percentage of fat mass, fat mass index, percentage of skeletal muscle, and the skeletal muscle index [SMI]) measured when the child was 6 years using a bioelectrical impedance analyzer. A 2-fold increase in Σ DEHP and MnBP in the prenatal maternal urine was significantly associated with a -0.07 unit (95% CI: -0.11, -0.03) and -0.09 unit (95% CI: -0.14, -0.03) change in SMI, respectively, in 6-year old girls alone. BMI z-score was also negatively associated with a 2-fold increase in MEHHP and MnBP in prenatal maternal urine as -0.11 unit (95% CI: -0.22, -0.01) and -0.15 unit (95% CI: -0.28, -0.02) change, respectively, only among girls. Among boys, phthalate metabolites in the prenatal and children's urine were not significantly associated with any body composition indices. Our longitudinal study shows that high levels of prenatal exposure to phthalates are significantly associated with decreased SMI among girls. We can postulate that anti-androgenic effects of phthalates during pregnancy may affect girl offspring's muscle growth.


Fuzzy bi-objective preventive health care network design.
Preventive health care is unlike health care for acute ailments, as people are less alert to their unknown medical problems. In order to motivate public and to attain desired participation levels for preventive programs, the attractiveness of the health care facility is a major concern. Health economics literature indicates that attractiveness of a facility is significantly influenced by proximity of the clients to it. Hence attractiveness is generally modelled as a function of distance. However, abundant empirical evidence suggests that other qualitative factors such as perceived quality, attractions nearby, amenities, etc. also influence attractiveness. Therefore, a realistic measure should incorporate the vagueness in the concept of attractiveness to the model. The public policy makers should also maintain the equity among various neighborhoods, which should be considered as a second objective. Finally, even though the general tendency in the literature is to focus on health benefits, the cost effectiveness is still a factor that should be considered. In this paper, a fuzzy bi-objective model with budget constraints is developed. Later, by modelling the attractiveness by means of fuzzy triangular numbers and treating the budget constraint as a soft constraint, a modified (and more realistic) version of the model is introduced. Two solution methodologies, namely fuzzy goal programming and fuzzy chance constrained optimization are proposed as solutions. Both the original and the modified models are solved within the framework of a case study in Istanbul, Turkey. In the case study, the Microsoft Bing Map is utilized in order to determine more accurate distance measures among the nodes.


MR arthrography of the hip: differentiation between an anterior sublabral recess as a normal variant and a labral tear.
To retrospectively evaluate imaging characteristics of surgically proved sublabral recesses and labral tears in the anterior portion of the acetabulum at magnetic resonance (MR) arthrography. Institutional review board approval was obtained; informed consent was waived. The study included 57 patients (36 women [mean age, 37 years], 21 men [mean age, 32 years]) who underwent MR arthrography and either surgery or arthroscopy as reference standard. On MR images, location of sublabral contrast material interposition and depth, shape, and extension into the labral substance of contrast material interpositions were described. Abnormal labral signal intensity (areas of high signal intensity), acetabular cartilage lesions, osseous abnormalities, and perilabral cysts were noted. Mann-Whitney U and Fisher exact tests were performed; interobserver agreement was calculated (kappa statistic and intraclass correlation coefficient). Surgical procedures revealed that 10 (18%) of 57 patients had recesses and 44 (77%) of 57 had tears. Locations of recesses and tears, respectively, were as follows: seven and none, in the 8-o'clock position; two of each, in the 9-o'clock position; one and 22, in the 10-o'clock position; and none and 20, in the 11-o'clock position. None of the recesses extended into the substance of the labrum or through the full thickness of the labral base; 51% (22 of 43) of tears extended into the substance and 49% (21 of 43) of tears extended along the entire labral base. Shape of sublabral contrast material interposition was linear in five (83%) of six recesses and 21 (49%) of 43 tears. Recesses were not associated with abnormal signal intensity of the labrum, cartilage lesions, osseous abnormalities, or perilabral cysts. Of 43 tears, 32 (74%) were associated with abnormal signal of the labrum; 23 (53%), with cartilage damage; 11 (26%), with osseous abnormalities; and eight (19%), with perilabral cysts. Recesses occur as normal variants in the anteroinferior part of the acetabulum. Location in the 8-o'clock position, linear shape of contrast material interposition, partial separation of the labrum, and absence of perilabral abnormalities are characteristics of a recess.


Analytic inverse radiative transfer equations for atmospheric and hydrologic optics.
Two new sets of analytical equations are derived with which the albedo of single scattering and the coefficients of a Legendre polynomial expansion of the scattering phase function can be determined for a source-free, homogeneous plane-parallel medium uniformly illuminated over the surfaces. The equations, essentially linear in the unknowns, require measurements of the radiance in the interior of the medium, but no iterative forward-problem calculations are needed. Sets of equations for both unpolarized and polarized radiation applications are given, as well as a side-by-side comparison with previously known sets of analytic inversion equations. Applications of the equations are suggested.


Measurement of two-photon excitation spectrum used to photoconvert a fluorescent protein (Kaede) by nonlinear Fourier-transform spectroscopy.
We demonstrate the measurement of two-photon excitation (TPE) spectra, used not only for fluorescence but also for photoconversion in green-to-red photoconvertible Kaede, using nonlinear Fourier-transform spectroscopy. It was found that in unphotoconverted Kaede, the TPE spectrum for photoconversion is much different to that for green-fluorescence. This is similar to the difference between the one-photon excitation of photoconversion in the neutral form and that of green-fluorescence in the ionized form.


The human RNA surveillance factor UPF1 is required for S phase progression and genome stability.
The eukaryotic nonsense-mediated mRNA decay (NMD) pathway degrades mRNAs carrying premature stop codons (PTC). In humans, NMD depends on the RNA- and DNA-dependent 5'-3' helicase UPF1 and six other gene products referred to as SMG1, UPF2, UPF3, EST1A/SMG6, EST1B/SMG5, and EST1C/SMG7. The NMD machinery is also thought to coordinate mRNA nuclear export and translation and to regulate the levels of several physiologic transcripts. Furthermore, in a process named SMD, UPF1 promotes degradation of mRNAs that are bound by Staufen 1. Intriguingly, SMG1 and EST1A/SMG6 function also in DNA repair and telomere maintenance, respectively. Here, we show that UPF1 is also required for genome stability. shRNA-mediated depletion of UPF1 causes human cells to arrest early in S phase, inducing an ATR-dependent DNA-damage response. A fraction of hyperphosphorylated UPF1 associates with chromatin of unperturbed cells, and chromatin association increases in S phase and upon gamma irradiation. ATR phosphorylates UPF1 both in vitro and in vivo, and shRNA-mediated downregulation of ATR diminished the association of UPF1 with chromatin, although it did not affect NMD. Physical interaction of UPF1 with DNA polymerase delta suggests a role for human UPF1 in DNA synthesis during replication or repair.


Combined Effects of Three High-Energy Charged Particle Beams Important for Space Flight on Brain, Behavioral and Cognitive Endpoints in B6D2F1 Female and Male Mice.
The radiation environment in deep space includes the galactic cosmic radiation with different proportions of all naturally occurring ions from protons to uranium. Most experimental animal studies for assessing the biological effects of charged particles have involved acute dose delivery for single ions and/or fractionated exposure protocols. Here, we assessed the behavioral and cognitive performance of female and male C57BL/6J × DBA2/J F1 (B6D2F1) mice 2 months following rapidly delivered, sequential irradiation with protons (1 GeV, 60%), 16O (250 MeV/n, 20%), and 28Si (263 MeV/n, 20%) at 0, 25, 50, or 200 cGy at 4-6 months of age. Cortical BDNF, CD68, and MAP-2 levels were analyzed 3 months after irradiation or sham irradiation. During the dark period, male mice irradiated with 50 cGy showed higher activity levels in the home cage than sham-irradiated mice. Mice irradiated with 50 cGy also showed increased depressive behavior in the forced swim test. When cognitive performance was assessed, sham-irradiated mice of both sexes and mice irradiated with 25 cGy showed normal responses to object recognition and novel object exploration. However, object recognition was impaired in female and male mice irradiated with 50 or 200 cGy. For cortical levels of the neurotrophic factor BDNF and the marker of microglial activation CD68, there were sex × radiation interactions. In females, but not males, there were increased CD68 levels following irradiation. In males, but not females, there were reduced BDNF levels following irradiation. A significant positive correlation between BDNF and CD68 levels was observed, suggesting a role for activated microglia in the alterations in BDNF levels. Finally, sequential beam irradiation impacted the diversity and composition of the gut microbiome. These included dose-dependent impacts and alterations to the relative abundance of several gut genera, such as Butyricicoccus and Lachnospiraceae. Thus, exposure to rapidly delivered sequential proton, 16O ion, and 28Si ion irradiation significantly affects behavioral and cognitive performance, cortical levels of CD68 and BDNF in a sex-dependent fashion, and the gut microbiome.


Design and Usability Evaluation of Social Mobile Diabetes Management System in the Gulf Region.
The prevalence of diabetes in the Gulf States is one of the highest globally. It is estimated that 20% of the population in the region has been diagnosed with diabetes and according to the International Diabetes Federation (IDF), five of the IDF's "top 10" countries for diabetes prevalence in 2011 and projected for 2030 are in this region. In recent years, there have been an increasing number of clinical studies advocating the use of mobile phone technology for diabetes self-management with improved clinical outcomes. However, there are few studies to date addressing the application of mobile diabetes management in the Gulf region, particularly in the Kingdom of Saudi Arabia (KSA), where there is exponential increase in mobile phone usage and access to social networking. The objective of this paper is to present the design and development of a new mobile health system for social behavioral change and management tailored for Saudi patients with diabetes called Saudi Arabia Networking for Aiding Diabetes (SANAD). A usability study for the SANAD system is presented to validate the acceptability of using mobile technologies among patients with diabetes in the KSA and the Gulf region. The SANAD system was developed using mobile phone technology with diabetes management and social networking modules. For the usability study the Questionnaire for User Interaction Satisfaction was used to evaluate the usability aspect of the SANAD system. A total of 33 users with type 2 diabetes participated in the study. The key modules of the SANAD system consist of (1) a mobile diabetes management module; (2) a social networking module; and (3) a cognitive behavioral therapy module for behavioral change issues. The preliminary results of the usability study indicated general acceptance of the patients in using the system with higher usability rating in patients with type 2 diabetes. We found that the acceptability of the system was high among Saudi patients with diabetes, and ongoing work in this research area is underway to conduct a clinical pilot study in the KSA for patients with type 2 diabetes. The wide deployment of such a system is timely and required in the Gulf region due to the wide use of mobile phones and social networking mediums.


Gender disparities in mental health service use of Puerto Rican children and adolescents.
Differences in service utilization indicating that boys use more mental health services than girls were analyzed to see if they could be explained by known correlates of service use. These correlates were arranged into individual (severe emotional disturbance, level of impairment and externalizing disorders), family (parental education, psychopathology and parental concern) and school factors (difficulties with school work). The objectives were to understand and identify the factors accounting for gender differences in mental health service utilization in order to develop alternatives to promote equity in service delivery. A representative sample of 1,896 children 4 to 17 years of age and their primary caretakers were interviewed for this study. Reports of service use were obtained using the Service Assessment for Children and Adolescents. Logistic regression was used to assess the relationship between gender and service use, adjusting for known correlates. Our results showed that, except for impairment, other individual, family and school factors did not explain gender differences in service utilization. Males with impairment were 2.87 times more likely to receive services than impaired females (p <or= .01), and this result continued to hold true for impaired undiagnosed boys compared to impaired diagnoses-free girls (p <or= .001). Our findings showed a service disparity between impaired boys and girls who did not meet criteria for a DSM IV diagnosis, but no observed differences in service use between boys and girls who met criteria for severe emotional disturbance (SED). Continued investigations are necessary to analyze, assess and understand the different circumstances that bring boys and girls into treatment, followed by the development of appropriate intervention programs at the school and community levels.


Eugenics--a side effect of progressivism? analysis of the role of scientific and medical elites in the rise and fall of eugenics in pre-war Poland.
The eminent geneticist, Benno Muller-Hill, described eugenics as"explosive mixture between something we might call hard science, that is, human genetics, and the sphere of political action. On the one hand, geneticists needed politicians to implement their ideas. On the other hand, Hitler and the Nazis needed scientists who could say that anti-Semitism has scientific theoretical foundations." For some Polish eugenicists, the Third Reich was not the home of the Nuremberg Laws, but a country that "boldly embarked on racial hygiene." This enthusiastic attitude of Polish intellectual circles towards Nazi eugenic laws was characteristic of the status of pre-war science in Poland, which in many areas, such as anthropology and psychiatry, remained strongly influenced by the paradigm of German science. While the professional and scientific context of the day promoted eugenic and racist ideas within the framework of the academic milieu and the curriculum of the medical and scientific community, eugenicists in Poland tended to refrain from anti-Semitic and racist phraseology. Indeed, the Polish eugenic movement was class- rather than race-orientated. The hybrid language of eugenics, combining social sensitivity with repulsion and contempt for the sick and the weak, illustrated the ambiguous stance of the Polish eugenicists on politics and science in Nazi Germany, for the Third Reich provided the German eugenicists with what had always been an unfulfilled dream to the Polish eugenicists--political power and the ability to implement their ideas.


Botulinum neurotoxins for post-stroke spasticity in adults: a systematic review.
The aim of this systematic review was to determine whether botulinum neurotoxin (BoNT) reduce spasticity or improve function in adult patients after stroke. Eleven double-blind randomized placebo-controlled trials met inclusion criteria. They encompassed 782 patients, 767 (98%) of whom received BoNT/A, and 15 (2%) BoNT/B. Most studies used the Ashworth scale as primary outcome measure. Differences between treated and control groups were assessed as categorical or continuous comparisons. The overall effect on upper limb spasticity was in favor of BoNT/A. A significantly higher number of patients had a reduction of upper limb spasticity at 4-week and 8-week evaluations in the treatment group compared with placebo. Mean changes in joint spasticity revealed improvement 3 to 6 weeks and 9 to 12 weeks after treatment. There were insufficient data to establish BoNT/A efficacy on lower limb spasticity or the effect of BoNT/B on the upper and lower limbs. Because of inconsistency and heterogeneity of the available data, it was not possible to perform a meta-analysis on disability and patients' reported outcomes. There was an overlapping safety profile between the treatment and the placebo groups. BoNT/A reduces upper limb spasticity in patients post-stroke, but the improvement in functional ability remains to be established. This gap needs to be filled by new studies to assess the effect of BoNT in the context of multidisciplinary patient management.


Forage breeding and management to increase the beneficial fatty acid content of ruminant products.
The declining consumption of ruminant products has been partly associated with their high proportion (but not necessarily content) of saturated fatty acids. Recent studies have focused on the less prominent fact that they are also important sources of beneficial fatty acids, including n-3 fatty acids and conjugated linoleic acids. alpha-Linolenic acid (18 : 3n-3) is of particular interest because it also contributes to improved flavour of beef and lamb. Many recent studies showed large effects of special concentrates on levels of fatty acids in milk and meat. However, the 'rumen protection' treatments, needed to ensure a worthwhile level of fatty acid in products, are expensive. Herbage lipids are the cheapest and safest source of these fatty acids and so breeding to increase delivery of fatty acids from plants into ruminant products is an important long-term strategy. Plant lipids usually contain high levels of polyunsaturated fatty acids, particularly 18 : 2n-6 and 18 : 3n-3 which are the precursors of beneficial fatty acids. Whilst some plants are particularly rich in individual fatty acids (e.g. 18 : 3n-3 in linseed), there are also useful levels in grass and clover (Trifolium Spp.). Levels of fatty acids in forages in relation to species and varieties are considered, as well as management and conservation methods. Relationships between levels of fatty acids and existing traits and genetic markers are identified. The effects of forage treatments on the fatty acid content of ruminant products are reviewed. The higher levels of polyunsaturated fatty acids in milk from cows fed clover silages show that the level of fatty acids in herbage is not the only factor affecting levels of fatty acids in ruminant products. Further effort is needed to characterise susceptibility of unsaturated fatty acids to oxidative loss during field wilting and biohydrogenation losses in the rumen, and the relative importance of plant and microbial processes in these losses. The pathways of lipolysis and lipid oxidation are reviewed and other plant factors which offer potential to breed for reduced losses are considered.


The influence of urbanisation on macroinvertebrate biodiversity in constructed stormwater wetlands.
The construction of wetlands in urban environments is primarily carried out to assist in the removal of contaminants from wastewaters; however, these wetlands have the added benefit of providing habitat for aquatic invertebrates, fish and waterbirds. Stormwater quantity and quality is directly related to impervious area (roads, sealed areas, roofs) in the catchment. As a consequence, it would be expected that impervious area would be related to contaminant load and biodiversity in receiving waters such as urban wetlands. This study aimed to establish whether the degree of urbanisation and its associated changes to stormwater runoff affected macroinvertebrate richness and abundance within constructed wetlands. Urban wetlands in Melbourne's west and south east were sampled along a gradient of urbanisation. There was a significant negative relationship between total imperviousness (TI) and the abundance of aquatic invertebrates detected for sites in the west, but not in the south east. However macroinvertebrate communities were relatively homogenous both within and between all study wetlands. Chironomidae (non-biting midges) was the most abundant family recorded at the majority of sites. Chironomids are able to tolerate a wide array of environmental conditions, including eutrophic and anoxic conditions. Their prevalence suggests that water quality is impaired in these systems, regardless of degree of urbanisation, although the causal mechanism is unclear. These results show some dependency between receiving wetland condition and the degree of urbanisation of the catchment, but suggest that other factors may be as important in determining the value of urban wetlands as habitat for wildlife.


Fatty acid composition, antioxidant and antibacterial properties of the microwave aqueous extract of three varieties of Labisia pumila Benth.
The present study was conducted in order to evaluate the fatty acid profile, anti-oxidant and anti-bacterial activities from the microwave aqueous extract of the leaves of three different varieties of Labisia pumila Benth. The chemical analysis of the extract showed that fatty acids (palmitic, palmitoleic, stearic, oleic, linoleic and α-linolenic) acid as the main components in three varieties of L. pumila leaves. Furthermore, the obtained results of the anti-oxidant revealed that L. pumila var. alata contained higher anti-oxidative activities compared to var. pumila and var. lanceolata. However, these values were lower than the tested anti-oxidant standards. On the other hand, the aqueous leaf extracts in all three varieties of L. pumila were also found to inhibit a variable degree of antibacterial activities against eight bacteria (four Gram-positive and four Gram-negative bacteria). In this study, it was observed the leaves of three varieties of L. pumila exhibited variable patterns of fatty acids and the microwave aqueous extraction possess anti-oxidant and anti-bacterial activities.


Engaging cancer patients in clinical practice guideline development: a pilot study.
Patient engagement is a key quality component of cancer guideline development; however, the optimal strategy for engaging patients in guideline development remains unclear. The feasibility and efficacy of two patient engagement models was tested by Cancer Care Ontario's cancer guideline development program, the Program in Evidence-Based Care (pebc). In model 1, patients participated in the guideline development process as active members of a working group. In model 2, patients formed a separate consultation group to review project plans and recommendations generated by multiple working groups. Training included online resources (model 1) and an in-person orientation (model 2). The pebc's standard patient engagement process acted as a control. The study was conducted for 1 year. Surveys measured the satisfaction of patients and members of the guideline working groups with the process and the outcome of each model. Three guideline projects used model 1 to engage patients, six projects used model 2 to receive feedback, and one project was used as a control group (14 patients total). Most participants, whatever the model, reported satisfaction with their experience. Key challenges to implementation included patient recruitment and long wait times between meetings (model 1), and difficulty focusing on the discussion topic and poor meeting attendance on the part of patients (model 2). The pilot study demonstrated that, although both models are feasible and effective for the engagement of patients in cancer guideline development, modifications are required to optimize their continued interest. The pebc will use the study results to inform the implementation of a patient engagement strategy for its program.


Further validation of the Multidimensional Fatigue Inventory in a US adult population sample.
The Multidimensional Fatigue Inventory (MFI-20) was developed in 1995. Since then, it has been widely used in cancer research and cancer-related illnesses but has never been validated in fatiguing illnesses or in a large US population-selected sample. In this study, we sought to examine the reliability and validity of the MFI-20 in the population of the state of Georgia, USA. Further, we assessed whether the MFI-20 could serve as a complementary diagnostic tool in chronically fatigued and unwell populations. The data derive from a cross-sectional population-based study investigating the prevalence of chronic fatigue syndrome (CFS) in Georgia. The study sample was comprised of three diagnostic groups: CFS-like (292), chronically unwell (269), and well (222). Participants completed the MFI-20 along with several other measures of psychosocial functioning, including the Medical Outcomes Survey Short Form-36 (SF-36), the Zung Self-Rating Depression Scale (SDS), and the Spielberger State-Trait Anxiety Inventory (STAI). We assessed the five MFI-20 subscales using several criteria: inter-item correlations, corrected item-total correlations, internal consistency reliability (Cronbach's alpha coefficients), construct validity, discriminant (known-group) validity, floor/ceiling effects, and convergent validity through correlations with the SF-36, SDS, and STAI instruments. Averaged inter-item correlations ranged from 0.38 to 0.61, indicating no item redundancy. Corrected item-total correlations for all MFI-20 subscales were greater than 0.30, and Cronbach's alpha coefficients achieved an acceptable level of 0.70. No significant floor/ceiling effect was observed. Factor analysis demonstrated factorial complexity. The MFI-20 also distinguished clearly between three diagnostic groups on all subscales. Furthermore, correlations with depression (SDS), anxiety (STAI), and functional impairment (SF-36) demonstrated strong convergent validity. This study provides support for the MFI-20 as a valuable tool when used in chronically unwell and well populations. It also suggests that the MFI-20 could serve as a complementary diagnostic tool in fatiguing illnesses, such as CFS.


Enhancer of zeste homolog 2 (Ezh2) controls bone formation and cell cycle progression during osteogenesis in mice.
Epigenetic mechanisms control skeletal development and osteoblast differentiation. Pharmacological inhibition of the histone 3 Lys-27 (H3K27) methyltransferase enhancer of zeste homolog 2 (EZH2) in WT mice enhances osteogenesis and stimulates bone formation. However, conditional genetic loss of Ezh2 early in the mesenchymal lineage (i.e. through excision via Prrx1 promoter-driven Cre) causes skeletal abnormalities due to patterning defects. Here, we addressed the key question of whether Ezh2 controls osteoblastogenesis at later developmental stages beyond patterning. We show that Ezh2 loss in committed pre-osteoblasts by Cre expression via the osterix/Sp7 promoter yields phenotypically normal mice. These Ezh2 conditional knock-out mice (Ezh2 cKO) have normal skull bones, clavicles, and long bones but exhibit increased bone marrow adiposity and reduced male body weight. Remarkably, in vivo Ezh2 loss results in a low trabecular bone phenotype in young mice as measured by micro-computed tomography and histomorphometry. Thus, Ezh2 affects bone formation stage-dependently. We further show that Ezh2 loss in bone marrow-derived mesenchymal cells suppresses osteogenic differentiation and impedes cell cycle progression as reflected by decreased metabolic activity, reduced cell numbers, and changes in cell cycle distribution and in expression of cell cycle markers. RNA-Seq analysis of Ezh2 cKO calvaria revealed that the cyclin-dependent kinase inhibitor Cdkn2a is the most prominent cell cycle target of Ezh2 Hence, genetic loss of Ezh2 in mouse pre-osteoblasts inhibits osteogenesis in part by inducing cell cycle changes. Our results suggest that Ezh2 serves a bifunctional role during bone formation by suppressing osteogenic lineage commitment while simultaneously facilitating proliferative expansion of osteoprogenitor cells.


Meta-analysis challenges a textbook example of status signalling and demonstrates publication bias.
The status signalling hypothesis aims to explain within-species variation in ornamentation by suggesting that some ornaments signal dominance status. Here, we use multilevel meta-analytic models to challenge the textbook example of this hypothesis, the black bib of male house sparrows (Passer domesticus). We conducted a systematic review, and obtained primary data from published and unpublished studies to test whether dominance rank is positively associated with bib size across studies. Contrary to previous studies, the overall effect size (i.e. meta-analytic mean) was small and uncertain. Furthermore, we found several biases in the literature that further question the support available for the status signalling hypothesis. We discuss several explanations including pleiotropic, population- and context-dependent effects. Our findings call for reconsidering this established textbook example in evolutionary and behavioural ecology, and should stimulate renewed interest in understanding within-species variation in ornamental traits.


Prehispanic use of chili peppers in Chiapas, Mexico.
The genus Capsicum is New World in origin and represents a complex of a wide variety of both wild and domesticated taxa. Peppers or fruits of Capsicum species rarely have been identified in the paleoethnobotanical record in either Meso- or South America. We report here confirmation of Capsicum sp. residues from pottery samples excavated at Chiapa de Corzo in southern Mexico dated from Middle to Late Preclassic periods (400 BCE to 300 CE). Residues from 13 different pottery types were collected and extracted using standard techniques. Presence of Capsicum was confirmed by ultra-performance liquid chromatography (UPLC)/MS-MS Analysis. Five pottery types exhibited chemical peaks for Capsicum when compared to the standard (dihydrocapsaicin). No peaks were observed in the remaining eight samples. Results of the chemical extractions provide conclusive evidence for Capsicum use at Chiapas de Corzo during a 700 year period (400 BCE-300 CE). Presence of Capsicum in different types of culinary-associated pottery raises questions how chili pepper could have been used during this early time period. As Pre-Columbian cacao products sometimes were flavored using Capsicum, the same pottery sample set was tested for evidence of cacao using a theobromine marker: these results were negative. As each vessel that tested positive for Capsicum had a culinary use we suggest here the possibility that chili residues from the Chiapas de Corzo pottery samples reflect either paste or beverage preparations for religious, festival, or every day culinary use. Alternatively, some vessels that tested positive merely could have been used to store peppers. Most interesting from an archaeological context was the presence of Capsicum residue obtained from a spouted jar, a pottery type previously thought only to be used for pouring liquids.


Prototype Positive Control Wells for Malaria Rapid Diagnostic Tests: Prospective Evaluation of Implementation Among Health Workers in Lao People's Democratic Republic and Uganda.
Rapid diagnostic tests (RDTs) are widely used for malaria diagnosis, but lack of quality control at point of care restricts trust in test results. Prototype positive control wells (PCW) containing recombinant malaria antigens have been developed to identify poor-quality RDT lots. This study assessed community and facility health workers' (HW) ability to use PCWs to detect degraded RDTs, the impact of PCW availability on RDT use and prescribing, and preferred strategies for implementation in Lao People's Democratic Republic (Laos) and Uganda. A total of 557 HWs participated in Laos (267) and Uganda (290). After training, most (88% to ≥ 99%) participants correctly performed the six key individual PCW steps; performance was generally maintained during the 6-month study period. Nearly all (97%) reported a correct action based on PCW use at routine work sites. In Uganda, where data for 127,775 individual patients were available, PCW introduction in health facilities was followed by a decrease in antimalarial prescribing for RDT-negative patients ≥ 5 years of age (4.7-1.9%); among community-based HWs, the decrease was 12.2% (P < 0.05) for all patients. Qualitative data revealed PCWs as a way to confirm RDT quality and restore confidence in RDT results. HWs in malaria-endemic areas are able to use prototype PCWs for quality control of malaria RDTs. PCW availability can improve HWs' confidence in RDT results, and benefit malaria diagnostic programs. Lessons learned from this study may be valuable for introduction of other point-of-care diagnostic and quality-control tools. Future work should evaluate longer term impacts of PCWs on patient management.


Zinc finger protein Wiz links G9a/GLP histone methyltransferases to the co-repressor molecule CtBP.
G9a is a SET-domain mammalian histone methyltransferase responsible for mono- and dimethylation of lysine 9 in histone H3 (H3K9) at euchromatic regions. Recently we reported that G9a forms a stoichiometric heteromeric complex with another SET-domain-containing molecule, GLP/Eu-HMTase1. Although G9a and GLP can independently methylate H3K9 in vitro, G9a/GLP heteromeric formation seems to be essential for their function as a euchromatic H3K9 methyltransferase in vivo. To further elucidate how G9a/GLP-mediated histone methylation and transcriptional regulation are controlled, we purified and characterized G9a complexes from mouse embryonic stem cells. We identified a novel G9a/GLP-associating zinc finger molecule named Wiz that can interact with G9a and GLP independently but is more stable in the G9a/GLP heteromeric complexes. Interestingly, Wiz small inhibitory RNA knocks down not only Wiz but also G9a. GLP deficiency also decreases G9a levels, suggesting that the Wiz/G9a/GLP tri-complex may protect G9a from degradation and that Wiz plays a major role in G9a/GLP heterodimer formation. Furthermore, amino acid sequence analysis of Wiz predicted two potential CtBP binding sites, and indeed CtBP binding to Wiz and association of CtBP with the Wiz/G9a/GLP complex was observed. These data indicate that Wiz not only contributes to the stability of G9a but also links the G9a/GLP heteromeric complex to the CtBP co-repressor machinery.


Failure of Tooth Formation Mediated by miR-135a Overexpression via BMP Signaling.
MicroRNAs (miRNAs) are known to regulate a variety of gene functions in many tissues and organs, but their expression and function in tooth development are not well-understood. A specific miRNA, miR-135a, was determined to be highly expressed at the bud stage. Interestingly, after the cap stage, miR-135a was expressed in the epithelium and mesenchyme but not in the inner enamel epithelium. To identify the relationship between miR-135a and its putative target genes, Bmpr-Ia and Bmpr-Ib, in early tooth development, miR-135a was ectopically overexpressed with a lentivirus. This overexpression resulted in the repression of Bmpr-Ia and Bmpr-Ib. Furthermore, miR-135a inhibited both Bmpr-Ia and Bmpr-Ib transcription. BMP2 proteins were expressed ectopically in tooth germs during the cap stage to determine the relationship between miR-135a and BMP signaling in early tooth development. When miR-135a was ectopically expressed, no tooth formation was observed after 4 wk of incubation in the kidney capsule. This study suggested that Bmp signaling, specifically Bmpr-Ia and Bmpr-Ib, regulates tooth formation via miR-135a.


Patient-Reported Outcomes 1 Year After Immediate Breast Reconstruction: Results of the Mastectomy Reconstruction Outcomes Consortium Study.
Purpose The goals of immediate postmastectomy breast reconstruction are to minimize deformity and optimize quality of life as perceived by patients. We prospectively evaluated patient-reported outcomes (PROs) in women undergoing immediate implant-based or autologous reconstruction. Methods Women undergoing immediate postmastectomy reconstruction for invasive cancer and/or carcinoma in situ were enrolled at 11 sites. Women underwent implant-based or autologous tissue reconstruction. Patients completed the BREAST-Q, a condition-specific PRO measure for breast surgery patients, and Patient-Reported Outcomes Measurement Information System-29, a generic PRO measure, before and 1 year after surgery. Mean changes in PRO scores were summarized. Mixed-effects regression models were used to compare PRO scores across procedure types. Results In total, 1,632 patients (n = 1,139 implant, n = 493 autologous) were included; 1,183 (72.5%) responded to 1-year questionnaires. After analysis was controlled for baseline values, patients who underwent autologous reconstruction had greater satisfaction with their breasts than those who underwent implant-based reconstruction (difference, 6.3; P < .001), greater sexual well-being (difference, 4.5; P = .003), and greater psychosocial well-being (difference, 3.7; P = .02) at 1 year. Patients in the autologous reconstruction group had improved satisfaction with breasts (difference, 8.0; P = .002) and psychosocial well-being (difference, 4.6; P = .047) compared with preoperative baseline. Physical well-being of the chest was not fully restored in either the implant group (difference, -3.8; P = .001) or autologous group (-2.2; P = .04), nor was physical well-being of the abdomen in patients who underwent autologous reconstruction (-13.4; P < .001). Anxiety and depression were mitigated at 1 year in both groups. Compared with their baseline reports, patients who underwent implant reconstruction had decreased fatigue (difference, -1.4; P = .035), whereas patients who underwent autologous reconstruction had increased pain interference (difference, 2.0; P = .006). Conclusion At 1 year after mastectomy, patients who underwent autologous reconstruction were more satisfied with their breasts and had greater psychosocial and sexual well-being than those who underwent implant reconstruction. Although satisfaction with breasts was equal to or greater than baseline levels, physical well-being was not fully restored. This information can help patients better understand expected outcomes and may guide innovations to improve outcomes.


Predicting levels of Latino depression: acculturation, acculturative stress, and coping.
Past research has noted that aspects of living in the United States place Latinos at risk for experiencing psychological problems. However, the specific features of the adaptation process that contribute to depression remain unclear. The purpose of the present study was to investigate the ability of acculturation, acculturative stress, and coping to predict membership into low, medium, and high groups of depression among Latinos. Within a group of 148 Latino adults from the community, a multinomial logistic regression revealed that an Anglo orientation, English competency pressures, and active coping differentiated high from low depression and that a Latino orientation and, to some extent, the pressure to acculturate distinguished medium from low depression. These results highlight a pattern of characteristics that function as risk and protective factors in relation to level of symptom severity. The findings are discussed in terms of implications for Latino mental health, including considerations for intervention and prevention.


TLR8 and complement C5 induce cytokine release and thrombin activation in human whole blood challenged with Gram-positive bacteria.
We recently showed that TLR8 is critical for the detection of Gram-positive bacteria by human monocytes. Here, we hypothesized that TLR8 and complement together regulate antibacterial responses in human blood. Anticoagulated blood was treated with selective inhibitors of TLR8 and/or complement C5, and then challenged with live Streptococcus agalactiae (Group B streptococcus, GBS), Staphylococcus aureus, or Escherichia coli. Cytokine production, plasma membrane permeability, bacterial survival, phagocytosis, and activation of coagulation was examined. GBS and S. aureus, but not E. coli, triggered TLR8-dependent production of IL-12p70, IL-1β, TNF, and IL-6 in fresh human whole blood. In purified polymorphonuclear neutrophils (PMN), GBS and S. aureus induced IL-8 release in part via TLR8, whereas PMN plasma membrane leakage and extracellular DNA levels increased independently of TLR8. TLR8 was more important than C5 for bacteria-induced production of IL-12p70, IL-1β, and TNF in blood, whereas IL-8 release was more C5 dependent. Both TLR8 and C5 induced IL-6 release and activation of prothrombin cleavage, and here their combined effects were additive. Blocking of C5 or C5aR1 attenuated phagocytosis and increased the extracellular growth of GBS in blood, whereas TLR8 inhibition neither reduced phagocytosis nor intracellular killing of GBS and S. aureus. In conclusion, TLR8 is more important than C5 for production of IL-12p70, IL-1β, and TNF upon GBS and S. aureus infection in blood, whereas C5 is central for IL-8 release and phagocytosis. Both TLR8 and C5 mediate IL-6 release and activation of coagulation during challenge with Gram-positive bacteria in blood.


Long-stem shaped multifunctional molecular beacon for highly sensitive nucleic acids determination via intramolecular and intermolecular interactions based strand displacement amplification.
Occurrence and application of oligonucleotide probes have promoted great progress in the biochemical analysis field due to their unique biological and chemical properties. In this work, a long-stem shaped multifunctional molecular beacon (LS-MMB) that is responsive to a cancer-related gene, p53, is well-prepared. By designing the probe with long-paired bases at its two ends and short-paired bases between the middle region and the 3' end, the LS-MMB is intelligently endowed with the ability to recognize the target analyte, serve as the polymerization primer/template, and signal the hybridization event synchronously, which is distinctly advantageous over the traditional molecular beacons (MBs). Moreover, it is excitingly found that the LS-MMB can be employed to exert intramolecular and intermolecular interactions for strand displacement amplification (SDA) without the involvement of any assistant probes; this therapy results in a really easy and rapid sensing system that provides an extremely low background noise and high target output signal. In this case, an excellent sensitivity and specificity to detect target gene down to picomolar level and resolution to even one nucleotide variation are achieved, respectively. In addition, the application potential for real genomic DNA analysis is realized. We envision that the probe of LS-MMB can act as a universal platform for biosensing and biomedical research.


In vitro and modelling approaches to risk assessment from the U.S. Environmental Protection Agency ToxCast programme.
A significant challenge in toxicology is the 'too many chemicals' problem. Human beings and environmental species are exposed to tens of thousands of chemicals, only a small percentage of which have been tested thoroughly using standard in vivo test methods. This study reviews several approaches that are being developed to deal with this problem by the U.S. Environmental Protection Agency, under the umbrella of the ToxCast programme (http://epa.gov/ncct/toxcast/). The overall approach is broken into seven tasks: (i) identifying biological pathways that, when perturbed, can lead to toxicity; (ii) developing high-throughput in vitro assays to test chemical perturbations of these pathways; (iii) identifying the universe of chemicals with likely human or ecological exposure; (iv) testing as many of these chemicals as possible in the relevant in vitro assays; (v) developing hazard models that take the results of these tests and identify chemicals as being potential toxicants; (vi) generating toxicokinetics data on these chemicals to predict the doses at which these hazard pathways would be activated; and (vii) developing exposure models to identify chemicals for which these hazardous dose levels could be achieved. This overall strategy is described and briefly illustrated with recent examples from the ToxCast programme.


Anticoagulant Reversal Strategies in the Emergency Department Setting: Recommendations of a Multidisciplinary Expert Panel.
Bleeding is the most common complication of anticoagulant use. The evaluation and management of the bleeding patient is a core competency of emergency medicine. As the prevalence of patients receiving anticoagulant agents and variety of anticoagulants with different mechanisms of action, pharmacokinetics, indications, and corresponding reversal agents increase, physicians and other clinicians working in the emergency department require a current and nuanced understanding of how best to assess, treat, and reverse anticoagulated patients. In this project, we convened an expert panel to create a consensus decision tree and framework for assessment of the bleeding patient receiving an anticoagulant, as well as use of anticoagulant reversal or coagulation factor replacement, and to address controversies and gaps relevant to this topic. To support decision tree interpretation, the panel also reached agreement on key definitions of life-threatening bleeding, bleeding at a critical site, and emergency surgery or urgent invasive procedure. To reach consensus recommendations, we used a structured literature review and a modified Delphi technique by an expert panel of academic and community physicians with training in emergency medicine, cardiology, hematology, internal medicine/thrombology, pharmacology, toxicology, transfusion medicine and hemostasis, neurology, and surgery, and by other key stakeholder groups.


Immunohistochemistry of Atlantic cod larvae Gadus morhua experimentally challenged with Vibrio anguillarum.
Farming of Atlantic cod Gadus morhua is one of the most rapidly growing sectors of Norwegian aquaculture. Classical vibriosis caused by Vibrio anguillarum is a problem in cod aquaculture. To prevent disease outbreaks, a thorough understanding of the infection route and the impact of the bacteria on the host is important. The intestinal tract, skin and gills have all been proposed as routes of entry for bacterial infections such as vibriosis. We aimed to further develop understanding of V anguillarum serotype O2alpha infections in cod larvae by elucidation of a possible route of entry, the pattern of infection and its histopathology. Cod eggs were transferred to a 24-well polystyrene multi-dish with 2 ml of sterile aerated 80% (28 per thousand salinity) seawater. Challenge doses were 10(4) and 10(6) CFU ml(-1). Unchallenged larvae were used as controls. Larvae for immunohistochemical examination were sampled daily from each group. In most of the larvae, either no or very few bacteria were observed. Typical findings were clusters of bacteria in the spaces between the primary gill lamellae. None of these bacteria seemed to have adhered to the gills. Intestines of 3 out of 161 larvae examined contained positively immunostained bacteria. Some bacteria appeared attached to the microvilli, but none was observed inside epithelial cells. Only 2 larvae from the low-challenge dose group showed clear signs of histopathology, which occurred in the intestine. It is not possible to draw any conclusions regarding the portal of entry.


Soluble endoglin regulates expression of angiogenesis-related proteins and induction of arteriovenous malformations in a mouse model of hereditary hemorrhagic telangiectasia.
Endoglin is a transmembrane glycoprotein expressed in vascular endothelium that plays a key role in angiogenesis. Mutations in the endoglin gene (ENG) cause hereditary hemorrhagic telangiectasia type 1 (HHT1), characterized by arteriovenous malformations (AVMs) in different organs. These vascular lesions derive from abnormal processes of angiogenesis, whereby aberrant vascular remodeling leads to focal loss of capillaries. Current treatments for HHT1 include antiangiogenic therapies. Interestingly, a circulating form of endoglin (also known as soluble endoglin, sEng), proteolytically released from the membrane-bound protein and displaying antiangiogenic activity, has been described in several endothelial-related pathological conditions. Using human and mouse endothelial cells, we find that sEng downregulates several pro-angiogenic and pro-migratory proteins involved in angiogenesis. However, this effect is much reduced in endothelial cells that lack endogenous transmembrane endoglin, suggesting that the antiangiogenic activity of sEng is dependent on the presence of endogenous transmembrane endoglin protein. In fact, sEng partially restores the phenotype of endoglin-silenced endothelial cells to that of normal endothelial cells. Moreover, using an established neonatal retinal model of HHT1 with depleted endoglin in the vascular endothelium, sEng treatment decreases the number of AVMs and has a normalizing effect on the vascular phenotype with respect to vessel branching, vascular density and migration of the vascular plexus towards the retinal periphery. Taken together, these data show that circulating sEng can influence vascular development and AVMs by modulating angiogenesis, and that its effect on endothelial cells depends on the expression of endogenous endoglin.This article has an associated First Person interview with the first author of the paper.