Developmental genetic analysis of troponin T mutations in striated and nonstriated muscle cells of Caenorhabditis elegans.
We have been investigating a set of genes, collectively called mups, that are essential to striated body wall muscle cell positioning in Caenorhabditis elegans. Here we report our detailed characterization of the mup-2 locus, which encodes troponin T (TnT). Mutants for a heat-sensitive allele, called mup-2(e2346ts), and for a putative null, called mup-2(up1), are defective for embryonic body wall muscle cell contraction, sarcomere organization, and cell positioning. Characterizations of the heat-sensitive allele demonstrate that mutants are also defective for regulated muscle contraction in larval and adult body wall muscle, defective for function of the nonstriated oviduct myoepithelial sheath, and defective for epidermal morphogenesis. We cloned the mup-2 locus and its corresponding cDNA. The cDNA encodes a predicted 405-amino acid protein homologous to vertebrate and invertebrate TnT and includes an invertebrate-specific COOH-terminal tail. The mup-2 mutations lie within these cDNA sequences: mup-2(up1) is a termination codon near NH2 terminus (Glu94) and mup-2(e2346ts) is a termination codon in the COOH-terminal invertebrate-specific tail (Trp342). TnT is a muscle contractile protein that, in association with the thin filament proteins tropomyosin, troponin I and troponin C, regulates myosin-actin interaction in response to a rise in intracellular Ca2+. Our findings demonstrate multiple essential functions for TnT and provide a basis to investigate the in vivo functions and protein interactions of TnT in striated and nonstriated muscles.


Perinatal outcomes of cesarean deliveries in Sierra Leone: A prospective multicenter observational study.
To analyze the indications for cesarean deliveries and factors associated with adverse perinatal outcomes in Sierra Leone. Between October 2016 and May 2017, patients undergoing cesarean delivery performed by medical doctors and associate clinicians in nine hospitals were included in a prospective observational study. Data were collected perioperatively, at discharge, and during home visits after 30 days. In total, 1274 cesarean deliveries were included of which 1099 (86.3%) were performed as emergency surgery. Of the 1376 babies, 261 (19.0%) were perinatal deaths (53 antepartum stillbirths, 155 intrapartum stillbirths, and 53 early neonatal deaths). Indications with the highest perinatal mortality were uterine rupture (45 of 55 [81.8%]), abruptio placentae (61 of 85 [71.8%]), and antepartum hemorrhage (8 of 15 [53.3%]). In the group with cesarean deliveries performed for obstructed and prolonged labor, a partograph was filled out for 212 of 425 (49.9%). However, when completed, babies had 1.81-fold reduced odds for perinatal death (95% confidence interval 1.03-3.18, P-value 0.041). Cesarean deliveries in Sierra Leone are associated with an exceptionally high perinatal mortality rate of 190 per 1000 births. Late presentation in the facilities and lack of adequate fetal monitoring may be contributing factors.


Epidermal growth factor receptor targeted therapy in stages III and IV head and neck cancer.
What are the benefits associated with the use of anti-epidermal growth factor receptor (anti-EGFR) therapies in squamous cell carcinoma of the head and neck (HNSCC)? Anti-EGFR therapies of interest included cetuximab, gefitinib, lapatinib, zalutumumab, erlotinib, and panitumumab. Head-and-neck cancer includes malignant tumours arising from a variety of sites in the upper aerodigestive tract. The most common histologic type is squamous cell carcinoma, and most common sites are the oral cavity, the oropharynx, the hypopharynx, and the larynx. Worldwide, HNSCC is the sixth most common neoplasm, and despite advances in therapy, long-term survival in HNSCC patients is poor. Primary surgery followed by chemoradiation, or primary chemoradiation, are the standard treatment options for patients with locally advanced (stages III-IVB) HNSCC; however, meta-analytic data indicate that the benefit of concurrent platinum-based chemotherapy disappears in patients over the age of 70 years. Cetuximab is a monoclonal antibody approved for use in combination with radiation in the treatment of patients with untreated locally advanced HNSCC and as monotherapy for patients with recurrent or metastatic (stage IVC) HNSCC who have progressed on platinum-based therapy. Given the interest in anti-EGFR agents in advanced HNSCC, the Head and Neck Cancer Disease Site Group (DSG) of Cancer Care Ontario's Program in Evidence-Based Care (PEBC) chose to systematically review the literature pertaining to this topic so as to develop evidence-based recommendations for treatment. Outcomes of interest included overall and progression-free survival, quality of life, tumour response rate and duration, and the toxicity associated with the use of anti-EGFR therapies. The medline, embase, and Cochrane Library databases, the American Society of Clinical Oncology online conference proceedings, the Canadian Medical Association InfoBase, and the National Guidelines Clearinghouse were systematically searched to locate primary articles and practice guidelines. The reference lists from relevant review articles were searched for additional trials. All evidence was reviewed, and that evidence informed the development of the clinical practice guideline. The resulting recommendations were approved by the Report Approval Panel of the PEBC, and by the Head and Neck Cancer DSG. An external review by Ontario practitioners completed the final phase of the review process. Feedback from all parties was incorporated to create the final practice guideline. The electronic search identified seventy-four references that were reviewed for inclusion. Only four phase iii trials met the inclusion criteria for the present guideline. No practice guidelines, systematic reviews, or meta-analyses were found during the course of the literature search. The randomized controlled trials (RCTS) involved three distinct patient populations: those with locally advanced HNSCC being treated for cure, those with incurable advanced recurrent or metastatic HNSCC being treated with first-line platinum-based chemotherapy, and those with incurable advanced recurrent or metastatic HNSCC who had disease progression despite, or who were unsuitable for, first-line platinum-based chemotherapy. These recommendations apply to adult patients with locally advanced (nonmetastatic stages iii-ivb) or recurrent or metastatic (stage IVC) HNSCC. Platinum-based chemoradiation remains the current standard of care for treatment of locally advanced HNSCC. In patients with locally advanced HNSCC who are medically unsuitable for concurrent platinum based chemotherapy or who are over the age of 70 years (because concurrent chemotherapy does not appear to improve overall survival in this patient population), the addition of cetuximab to radical radiotherapy should be considered to improve overall survival, progression-free survival, and time to local recurrence.Cetuximab in combination with platinum-based combination chemotherapy is superior to chemotherapy alone in patients with recurrent or metastatic HNSCC, and is recommended to improve overall survival, progression-free survival, and response rate.The role of anti-EGFR therapies in the treatment of locally advanced HNSCC is currently under study in large randomized trials, and patients with HNSCC should continue to be offered clinical trials of novel agents aimed at improving outcomes. Chemoradiation is the current standard of care for patients with locally advanced HNSCC, and to date, there is no evidence that compares cetuximab plus radiotherapy with chemoradiation, or that examines whether the addition of cetuximab to chemoradiation is of benefit in these patients. However, five ongoing trials are investigating the effect of the addition of EGFR inhibitors concurrently with, before, or after chemoradiotherapy; those trials should provide direction about the best integration of cetuximab into standard treatment. In patients with recurrent or metastatic HNSCC who experience progressive disease despite, or who are unsuitable for, first-line platinum-based chemotherapy, gefitinib at doses of 250 mg or 500 mg daily, compared with weekly methotrexate, did not increase median overall survival [hazard ratio (hr): 1.22; 96% confidence interval (ci): 0.95 to 1.57; p = 0.12 (for 250 mg daily vs. weekly methotrexate); hr: 1.12; 95% ci: 0.87 to 1.43; p = 0.39 (for 500 mg daily vs. weekly methotrexate)] or objective response rate (2.7% for 250 mg and 7.6% for 500 mg daily vs. 3.9% for weekly methotrexate, p > 0.05). As compared with methotrexate, gefitinib was associated with an increased incidence of tumour hemorrhage (8.9% for 250 mg and 11.4% for 500 mg daily vs. 1.9% for weekly methotrexate).


Plasticity of plant defense and its evolutionary implications in wild populations of Boechera stricta.
Phenotypic plasticity is thought to impact evolutionary trajectories by shifting trait values in a direction that is either favored by natural selection ("adaptive" plasticity) or disfavored ("nonadaptive" plasticity). However, it is unclear how commonly each of these types of plasticity occurs in natural populations. To answer this question, we measured glucosinolate defensive chemistry and reproductive fitness in over 1500 individuals of the wild perennial mustard Boechera stricta, planted in four common gardens across central Idaho, United States. Glucosinolate profiles-including total glucosinolate concentration as well as the relative abundances and overall diversity of different compounds-were strongly plastic both among habitats and within habitats. Patterns of glucosinolate plasticity varied greatly among genotypes. Plasticity among sites was predicted to affect fitness in 27.1% of cases; more often than expected by chance, glucosinolate plasticity increased rather than decreased relative fitness. In contrast, we found no evidence for within-habitat selection on glucosinolate reaction norm slopes (i.e., plasticity along a continuous environmental gradient). Together, our results indicate that glucosinolate plasticity may improve the ability of B. stricta populations to persist after migration to new habitats.


[A longitudinal analysis on the association of serum lipids and lipoproteins concentrations with blood polychlorinated biphenyls level in chronic "Yusho" patients].
We examined the association between blood PCB level and the serum concentrations of total cholesterol, high-density lipoprotein cholesterol and triglycerides. The data was retrieved from the dataset of the nationwide health examination for Yusho patients. We longitudinally analyze the laboratory data of the officially identified Yusho patients who underwent the health examination in Fukuoka and Nagasaki prefectures five times or more during the years from 1986 to 2000. For the longitudinal analysis, the generalized estimating equation model was used adjusting for the age as of 1986, the year of taking the health examination, smoking and drinking habits, body mass index and the site of the examination (Fukuoka or Nagasaki). Ten-fold increase in blood PCB level was associated with the elevation in serum concentration of total cholesterol by 18.4 mg/dL (95% CI, 7.8 to 29.0, P < 0.001) in men and 19.7 mg/dL (95% CI, 8.3 to 31.2, P < 0.001) in women, and the elevation of serum concentration of triglycerides by 43.4% (95% CI, 17.5 to 74.9, P < 0.001) in men and 42.8% (95% CI, 25.7 to 62.1, P < 0.001) in women. Association of blood PCB level with serum concentration of high-density lipoprotein cholesterol was not statistically significant in both men and women. Hypercholesterolemia is a well known risk factor of coronary heart disease. It might be suggested that the high blood PCB level in Yusho patients has some possible health effects on the incidence of coronary heart disease.


Herpesvirus seropositivity in childhood associates with decreased monocyte-induced NK cell IFN-gamma production.
EBV infection is inversely associated with IgE sensitization in children, and this association is further enhanced by CMV coinfection. In mice, herpesvirus latency causes systemic innate activation and protection from bacterial coinfection, implying the importance of herpesviruses in skewing immune responses during latent infection. Early control of viral infections depends on IFN-gamma release by NK cells, which generally requires the presence of accessory cells. We investigated IFN-gamma production by NK cells in PBMCs from children seropositive (SP) for EBV alone, for both EBV and CMV, or seronegative for both viruses. The ability of classical (CD14(++)CD16(-)) and proinflammatory (CD14(+)CD16(+)) monocytes to induce autologous NK cell IFN-gamma was studied by coculture experiments with enriched CD3(-)CD56(+) cells. Transwell experiments were used to evaluate how monocytes interact with NK cells to induce IFN-gamma synthesis. SP children had a significantly reduced proportion of IFN-gamma(+) NK cells and cognate intracellular IFN-gamma levels, which was more pronounced in CMV-coinfected subjects. Also, resting PBMCs of SP children displayed lower proportions of proinflammatory monocytes. IFN-gamma production by NK cells was dependent on interactions with monocytes, with the proinflammatory subset inducing the highest IFN-gamma. Finally, SP children had markedly lower levels of plasma IFN-gamma, concurrent with in vitro findings. Herpesvirus infections could be one contributing factor for maturation toward balanced Th1-Th2 responses. Our data indicate that early infection by herpesviruses may affect NK cell and monocyte interactions and thereby also influence the development of allergies.


Visual acuity and increased mortality: the role of allostatic load and functional status.
Poor vision may detrimentally impact functional status and affect allostatic load (AL), a measure of cumulative physiological wear and tear on the body's regulatory systems. We examined the direct effects of visual acuity (VA) on mortality and its indirect effect on mortality through its impact on functional status and AL in older adults. Data from 4981 participants (age ≥ 60 years) from the 1999-2004 National Health and Nutrition Examination Survey (NHANES) with mortality linkage through 2006 were analyzed. Functional status was assessed by activities of daily living (ADL) and instrumental activities of daily living (IADL). The AL index was composed of 10 biomarkers: systolic and diastolic blood pressures, body mass index (BMI), glycosylated hemoglobin, total cholesterol, triglycerides, albumin, C-reactive protein, homocysteine, and creatinine clearance. Visual acuity was categorized as no (20/20-20/25), mild (20/30-20/40), moderate (20/50-20/80), or severe (≥20/200) visual impairment. Structural equation modeling using three mediating variables representing ADL, IADL, and AL examined the effects of VA on all-cause and cardiovascular disease (CVD)-related mortality. Adjusting for all covariates, a one-unit change in VA category increased mortality risk (hazard ratio [HR] = 1.17; 95% confidence interval [CI] 1.05, 1.32); IADL and AL predicted mortality (HR = 1.15; CI 1.10, 1.20 and HR = 1.13; CI 1.06, 1.20, respectively). Activities of daily living did not predict mortality (HR = 0.98; CI 0.91, 1.05). Worse VA was associated with increased AL (β = 0.11; P = 0.013) and worse IADL (β = 1.06; P < 0.001). Worse VA increased mortality risk indirectly through AL (HR = 1.01; CI 1.00, 1.03) and IADL (HR = 1.16; CI 1.09, 1.23). The total effect of VA on mortality including through IADL and AL was HR = 1.38 (CI 1.23, 1.54). Similar but slightly stronger patterns of association were found when examining CVD-related mortality, but not cancer-related mortality. Allostatic load and particularly IADL may function as mediators between VA impairment and mortality. Older adults with VA impairment could potentially benefit from interventions designed to prevent IADL functional status decline to reduce the risk of mortality.


Injury Prevalence of the Lower Limbs in Handball Players: A Systematic Review.
Lower limb injuries are frequent in handball and a serious hindrance to athletic performance. The aim of this systematic review was to synthesize the available research on the prevalence of lower limb injuries in handball players according to sex and competitive level. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis, 19 studies were selected after a systematic search and selection process of three digital databases: Scopus, PubMed, and Web of Science. Furthermore, a study quality analysis using an 'Extension for Sports Injury and Illness Surveillance of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE-SIIS)' was carried out. The sample consisted of 7110 male and female handball players registering 4483 injuries in their lower limbs. The results showed a high incidence of knee injuries (30.23%) and ankle injuries (24.80%), especially in the ligaments, such as the talofibular and the anterior cruciate ligaments. Considering sex and competitive level, knee injuries accounted for 47.02% of injuries among women, while among men, ankle injuries were most prevalent (34.22%) in international competitions. Additionally, the most common cause of injuries was trauma (85.61%). The findings highlighted that the prevalence of lower limb injuries varies greatly according to the characteristics of the sample and injury. Therefore, the study underlines the importance that sports practitioners (physical trainers, readapters, and physiotherapists) adapt training protocols to reduce injury incidence in the most affected body areas or tissues.


Efficient inversion of multiple-scattering model for optical diffraction tomography.
Optical diffraction tomography relies on solving an inverse scattering problem governed by the wave equation. Classical reconstruction algorithms are based on linear approximations of the forward model (Born or Rytov), which limits their applicability to thin samples with low refractive-index contrasts. More recent works have shown the benefit of adopting nonlinear models. They account for multiple scattering and reflections, improving the quality of reconstruction. To reduce the complexity and memory requirements of these methods, we derive an explicit formula for the Jacobian matrix of the nonlinear Lippmann-Schwinger model which lends itself to an efficient evaluation of the gradient of the data-fidelity term. This allows us to deploy efficient methods to solve the corresponding inverse problem subject to sparsity constraints.


County variation in children's and adolescent's health status and school district performance in California.
We examined the association between county-level estimates of children's health status and school district performance in California. We used 3 data sources: the California Health Interview Survey, district archives from the California Department of Education, and census-based estimates of county demographic characteristics. We used logistic regression to estimate whether a school district's failure to meet adequate yearly progress goals in 2004 to 2005 was a function of child and adolescent's health status. Models included district- and county-level fixed effects and were adjusted for the clustering of districts within counties. County-level changes in children's and adolescent's health status decreased the likelihood that a school district would fail to meet adequate yearly progress goals during the investigation period. Health status did not moderate the relatively poor performance of predominantly minority districts. We found empirical support that area variation in children's and adolescent's health status exerts a contextual effect on school district performance. Future research should explore the specific mechanisms through which area-level child health influences school and district achievement.


Spinal accessory neuropathy following dual tunneling of lead extensions for motor cortex stimulation.
Spinal accessory nerve (SAN) injury is a known complication of surgery involving the posterior cervical triangle. Because the nerve lies in a plane that is traversed by extension leads for neuromodulation, the SAN is at risk during tunneling for these procedures. We report a 50-year-old man who developed spinal accessory neuropathy after tunneling of two sets of extension leads through his neck to connect to the pulse generator at the chest wall. Immediately postoperatively, he developed severe right shoulder pain and trapezius weakness manifested as decreased shoulder abduction and scapular winging. Electromyography 2 months later confirmed a SAN injury. Ultrasonography demonstrated the SAN to be angulated between the two sets of extension leads in the posterior cervical triangle. Operative exploration confirmed this finding. Neurolysis was performed and the deep extension lead was relocated superficial to the nerve. Postoperatively, the patient had immediate resolution of his shoulder pain and an improved range of motion. As the indications for neuromodulation continue to grow, tunneling may be performed more frequently. It is our belief that the second pass through the neck of a dual extension lead system may inadvertently be directed deeply and poses an increased risk to the SAN.


Potential Impact of a Paper About COVID-19 and Smoking on Twitter Users' Attitudes Toward Smoking: Observational Study.
A cross-sectional study (Miyara et al, 2020) conducted by French researchers showed that the rate of current daily smoking was significantly lower in patients with COVID-19 than in the French general population, implying a potentially protective effect of smoking. We aimed to examine the dissemination of the Miyara et al study among Twitter users and whether a shift in their attitudes toward smoking occurred after its publication as preprint on April 21, 2020. Twitter posts were crawled between April 14 and May 4, 2020, by the Tweepy stream application programming interface, using a COVID-19-related keyword query. After filtering, the final 1929 tweets were classified into three groups: (1) tweets that were not related to the Miyara et al study before it was published, (2) tweets that were not related to Miyara et al study after it was published, and (3) tweets that were related to Miyara et al study after it was published. The attitudes toward smoking, as expressed in the tweets, were compared among the above three groups using multinomial logistic regression models in the statistical analysis software R (The R Foundation). Temporal analysis showed a peak in the number of tweets discussing the results from the Miyara et al study right after its publication. Multinomial logistic regression models on sentiment scores showed that the proportion of negative attitudes toward smoking in tweets related to the Miyara et al study after it was published (17.07%) was significantly lower than the proportion in tweets that were not related to the Miyara et al study, either before (44/126, 34.9%; P<.001) or after the Miyara et al study was published (68/198, 34.3%; P<.001). The public's attitude toward smoking shifted in a positive direction after the Miyara et al study found a lower incidence of COVID-19 cases among daily smokers.


Methodology for treatment evaluation in patients with cancer metastatic to bone.
Patients with cancer metastatic to bone experience several adverse and clinically important skeletal-related events, including pathologic fractures, vertebral compressions with fracture, the need for surgery to treat or prevent fractures, and the need for radiation therapy for the treatment of bone pain. We present appropriate methods for describing and modeling the clinical course of skeletal-related events and comparing treatments for such events. On the basis of data from a recently completed randomized, placebo-controlled trial involving 380 breast cancer patients with bone metastases, we tested the validity of the "events-per-person-years" method, one of the most commonly used techniques, for the analysis of skeletal-related events. We then used more robust methods of analysis that are based on fewer assumptions, including a random-effects Poisson model, and contrasted the inferences about skeletal-related event rates and treatment effects for the different analytic methods. All statistical tests were two-sided. The events-per-person-years analysis underestimated substantially the variation in the data and is not appropriate to summarize the incidence rate of skeletal-related events. A random-effects Poisson model did provide a valid basis for analyzing such data. The underestimation of variability in data associated with the use of the events-per-person-years analysis leads to unduly narrow confidence intervals for complication rates and inflated false-positive error rates in treatment comparisons. A random-effects Poisson model provides a valid, robust basis for describing the clinical course of bone complications and evaluating treatment effects.


Smokers' brains compute, but ignore, a fictive error signal in a sequential investment task.
Addicted individuals pursue substances of abuse even in the clear presence of positive outcomes that may be foregone and negative outcomes that may occur. Computational models of addiction depict the addicted state as a feature of a valuation disease, where drug-induced reward prediction error signals steer decisions toward continued drug use. Related models admit the possibility that valuation and choice are also directed by 'fictive' outcomes (outcomes that have not been experienced) that possess their own detectable error signals. We hypothesize that, in addiction, anomalies in these fictive error signals contribute to the diminished influence of potential consequences. Using a simple investment game and functional magnetic resonance imaging in chronic cigarette smokers, we measured neural and behavioral responses to error signals derived from actual experience and from fictive outcomes. In nonsmokers, both fictive and experiential error signals predicted subjects' choices and possessed distinct neural correlates. In chronic smokers, choices were not guided by error signals derived from what might have happened, despite ongoing and robust neural correlates of these fictive errors. These data provide human neuroimaging support for computational models of addiction and suggest the addition of fictive learning signals to reinforcement learning accounts of drug dependence.


Potentials of ion trap collisional spectrometry for liquid chromatography/electrospray ionization tandem mass spectrometry determination of buprenorphine and nor-buprenorphine in urine, blood and hair samples.
A liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method has been developed for the analysis of buprenorphine (BUP) and nor-buprenorphine (NBUP) in biological fluids. Analytes are isolated from urine and blood, after addition of d4-buprenorphine (d4-BUP) as internal standard, by solid-phase extraction. Preparation of hair involves external decontamination, mechanical pulverization, overnight incubation in acidic medium, and neutralization prior to extraction. Enzymatic hydrolysis with beta-glucuronidase may be performed to distinguish between free and total BUP. Chromatographic separation is accomplished by gradient elution on a cyanopropyl 2.1 x 150 mm column. Positive ion ESI and MS analyses are carried out in an ion trap mass spectrometer. The use of this mass analyzer allows effective collisional experiments to be performed on ESI-generated MH+ species. Abundant product ions are produced, which can be monitored together with precursor ions without losing sensitivity. Thus, assay selectivity is definitely increased with respect to LC/ESI-MS/MS methods in which only precursor ions are monitored. The method has good linearity (calibration curves were linear in the range 0.1-10 ng/mL in urine and blood, in the range 10-160 pg/mg in hair) and limits of detection of 0.05 ng/mL for both BUP and NBUP in blood and urine samples, of 4 pg/mg for both analytes in hair. Both intra- and inter-assay precision and accuracy were satisfactory at three concentrations studied: relative standard deviations were <13.7% in urine, <17.3% in blood, <17.8% in hair; percent deviation of the mean from the true value was always <10.5% in urine and blood, <16.1% in hair. The method can be used to determine both analytes in the urine and hair of drug addicts on replacement therapy, and in post-mortem blood specimens when there is suspicion of drug-related death.


An effective fluoroscopic shield for angiographic equipment.
The need to reduce the dose of radiation to radiologists and technologists involved in peripheral angiography at the University of Cincinnati Hospital resulted in the development of a radiation shield. This shield is lightweight, transparent, and adequately reduces the level of scatter radiation produced during fluoroscopy without interfering with the angiographer or the sterile field. The shield is effective, fairly inexpensive, and simple to construct.


Starchless mutants of Chlamydomonas reinhardtii lack the small subunit of a heterotetrameric ADP-glucose pyrophosphorylase.
ADP-glucose synthesis through ADP-glucose pyrophosphorylase defines the major rate-controlling step of storage polysaccharide synthesis in both bacteria and plants. We have isolated mutant strains defective in the STA6 locus of the monocellular green alga Chlamydomonas reinhardtii that fail to accumulate starch and lack ADP-glucose pyrophosphorylase activity. We show that this locus encodes a 514-amino-acid polypeptide corresponding to a mature 50-kDa protein with homology to vascular plant ADP-glucose pyrophosphorylase small-subunit sequences. This gene segregates independently from the previously characterized STA1 locus that encodes the large 53-kDa subunit of the same heterotetramer enzyme. Because STA1 locus mutants have retained an AGPase but exhibit lower sensitivity to 3-phosphoglyceric acid activation, we suggest that the small and large subunits of the enzyme define, respectively, the catalytic and regulatory subunits of AGPase in unicellular green algae. We provide preliminary evidence that both the small-subunit mRNA abundance and enzyme activity, and therefore also starch metabolism, may be controlled by the circadian clock.


The impact of a newly designed resilience-enhancing programme on parent- and teacher-perceived resilience environment among Health Promoting Schools in Hong Kong.
The Health Promoting School (HPS) approach provides a strong foundation to improve students' overall health, including psychological well-being, which has its roots in resilience. The present study evaluates the effectiveness of a resilience-enhancing programme, building on the concept of HPS among a Chinese population. All mainstream schools in a socially disadvantaged region of Hong Kong were eligible, and stratified random sampling was used to recruit both HPS as intervention schools and non-HPS as control schools. The participants included teachers and parents of grade 3 and 5 primary and grade 1 secondary school students (aged 8, 10 and 12 respectively). Validated surveys were used to assess resilience scores in both groups of schools before and after a series of resilience-enhancing activities in HPS, and ANOVA was used to compare the score changes between the two groups. Five primary and four secondary HPS and four primary and four secondary non-HPS were recruited, involving 4918 parents and 602 teachers. Among primary and secondary parents, the HPS group did not report a higher score than the non-HPS group. Among secondary teachers, the HPS group showed significantly higher scores than the non-HPS group (p = 0.023 to < 0.001) The present study is the first to demonstrate the positive synergistic effect of a newly designed resilience-enhancing intervention programme, building on the concept of HPS in schools among secondary teachers in Hong Kong. It was suggested that future initiatives may involve parent networking and school-family collaboration in fostering an even more resilient school environment.


An innovative ultrasound, Fe(2+) and TiO(2) photoassisted process for bisphenol A mineralization.
This paper explores the degradation of a model pollutant, bisphenol A, by an advanced oxidation process that combines sonolysis, Fe(2+), and TiO(2) in a photoassisted process. Experiments were done under saturated oxygen conditions. The effect of different Fe(2+) (0.56 and 5.6 mg/L) and TiO(2) (10 and 50 mg/L) concentrations was investigated on both the elimination and mineralization of the pollutant. A pronounced synergistic effect that led to the complete and rapid elimination of dissolved organic carbon (DOC) was observed even at low catalyst loadings. In this system, almost a complete removal of DOC (93%) was observed after 4 h using 10 and 5.6 mg/L of TiO(2) and Fe(2+), respectively, whereas at the same time, only 5, 6, and 22% of DOC was removed by an individual process alone (TiO(2) photocatalysis, ultrasound, and photo-Fenton, respectively). In this system, ultrasound has the principal role of eliminating the initial substrate and providing hydrogen peroxide for the photocatalytic systems, while photo-Fenton and TiO(2) photocatalysis are mainly responsible for the transformation of the intermediates in CO(2) and H(2)O. The role of H(2)O(2) generated from the sonochemical process is also discussed.


Effects of ocean acidification on early life stages of shrimp (Pandalus borealis) and mussel (Mytilus edulis).
Ocean acidification (OA) resulting from anthropogenic emissions of carbon dioxide (CO(2)) has already lowered and is predicted to further lower surface ocean pH. There is a particular need to study effects of OA on organisms living in cold-water environments due to the higher solubility of CO(2) at lower temperatures. Mussel larvae (Mytilus edulis) and shrimp larvae (Pandalus borealis) were kept under an ocean acidification scenario predicted for the year 2100 (pH 7.6) and compared against identical batches of organisms held under the current oceanic pH of 8.1, which acted as a control. The temperature was held at a constant 10°C in the mussel experiment and at 5°C in the shrimp experiment. There was no marked effect on fertilization success, development time, or abnormality to the D-shell stage, or on feeding of mussel larvae in the low-pH (pH 7.6) treatment. Mytilus edulis larvae were still able to develop a shell in seawater undersaturated with respect to aragonite (a mineral form of CaCO(3)), but the size of low-pH larvae was significantly smaller than in the control. After 2 mo of exposure the mussels were 28% smaller in the pH 7.6 treatment than in the control. The experiment with Pandalus borealis larvae ran from 1 through 35 days post hatch. Survival of shrimp larvae was not reduced after 5 wk of exposure to pH 7.6, but a significant delay in zoeal progression (development time) was observed.


Critical care resources utilized in high-risk adenotonsillectomy patients.
Children at high risk for respiratory complication after adenotonsillectomy are often admitted to a pediatric intensive care unit (PICU) postoperatively. Although many patients receive care in such units, it is unknown how many utilize critical care resources. A review was conducted to audit intensive care needs of postadenotonsillectomy patients admitted to the PICU at a tertiary, academic, pediatric hospital between July 2013, and March 2017. Demographic information, ICU indication, polysomnogram results, and comorbidities were collected. Patients were defined as needing ICU resources based on supplemental oxygen requirements greater than 2 L between 2 to 24 hours postoperatively, more than two desaturation events in a 2-hour period, or more than hourly nursing intervention. Factors associated with utilization of ICU resources were assessed. One hundred and ten patients were admitted to the PICU after adenotonsillectomy. Median age was 4.2 years, median body mass index was 90.8 percentile, and median apnea hypopnea index (AHI) was 34.3. Twenty patients (18.2%) utilized ICU resources by criteria defined. Of these patients, 14 were known to need such resources by 2 hours postoperatively (70%, negative predictive value 93.8%). Neither AHI nor obesity status was correlated with need for resources; however, resource need was associated with young age, gastrostomy tube status, and neuromuscular disorders (P = 0.048, P = 0.002 and 0.013, respectively). Most high-risk adenotonsillectomy patients do not utilize critical care resources despite their increased perioperative risk. Patients with respiratory complications are frequently identifiable within the first 2 hours of surgery. 4 Laryngoscope, 129:1229-1234, 2019.


Cytochrome oxidase and neurofilament reactivity in monocularly deprived human primary visual cortex.
Previous studies of human primary visual cortex (V1) have demonstrated a significant eye-specific decrease in cytochrome oxidase (CO) staining following monocular enucleation. We have extended these results by examining CO staining and neurofilament labeling in V1 from a patient with long-standing monocular blindness. A pattern of reduced neurofilament reactivity was found to align with pale CO-stained ocular dominance columns. Neurons located within deprived ocular dominance columns were significantly smaller compared with those in nondeprived columns. A spatial analysis of the relationship between CO blobs and ocular dominance columns revealed that both deprived and nondeprived blobs tended to align with the centers of ocular dominance columns.


Microwave spectrum and molecular structure of the carbon monoxide-hydrogen bromide molecular complex.
Rotational spectra have been assigned for five isotopic species of the OC...HBr hydrogen-bonded molecular complex by using pulsed microwave Fourier transform spectroscopy in a Fabry-Perot cavity and a pulsed supersonic nozzle as the molecular source. The rotational constants, centrifugal distortion constants, Br nuclear-quadrupole-coupling constants, and Br spin-rotation constants were determined and from them, the vibrationally averaged structure of OCHBr was derived. This structure is consistent with a linear geometry at equilibrium and an atomic arrangement as written above. The intermolecular potential binding CO to HBr is discussed.


Children and adolescents - who can give consent?
Case histories are based on actual medical negligence claims or medicolegal referrals; however certain facts have been omitted or changed by the author to ensure the anonymity of the parties involved. Can children and adolescents consent to their own medical treatment? Do general practitioners owe teenagers a duty of confidentiality? This article examines the legal obligations of GPs when obtaining consent to medical treatment from patients who are under 18 years of age.


Peptic ulcer: (Analysis of predisposing and associated causes).
Age incidence, food habits and socio-economic condition were studied in a series of 478 predominantly male peptic ulcer patients. Age incidence of peptic ulcer increased in the second decade of life, reached a peak at the third decade and tapered off towards the end of fourth decade. As many as 57% of the patients belonged to the low socio-economic group and 78% were having only two meals a day. A ratio of 21 : 1 for duodenal ulcer to gastric ulcer was revealed from laparotomy findings.


Structural and biochemical characterization of ZhuI aromatase/cyclase from the R1128 polyketide pathway.
Aromatic polyketides comprise an important class of natural products that possess a wide range of biological activities. The cyclization of the polyketide chain is a critical control point in the biosynthesis of aromatic polyketides. The aromatase/cyclases (ARO/CYCs) are an important component of the type II polyketide synthase (PKS) and help fold the polyketide for regiospecific cyclizations of the first ring and/or aromatization, promoting two commonly observed first-ring cyclization patterns for the bacterial type II PKSs: C7-C12 and C9-C14. We had previously reported the crystal structure and enzymological analyses of the TcmN ARO/CYC, which promotes C9-C14 first-ring cyclization. However, how C7-C12 first-ring cyclization is controlled remains unresolved. In this work, we present the 2.4 Å crystal structure of ZhuI, a C7-C12-specific first-ring ARO/CYC from the type II PKS pathway responsible for the production of the R1128 polyketides. Though ZhuI possesses a helix-grip fold shared by TcmN ARO/CYC, there are substantial differences in overall structure and pocket residue composition that may be important for directing C7-C12 (rather than C9-C14) cyclization. Docking studies and site-directed mutagenesis coupled to an in vitro activity assay demonstrate that ZhuI pocket residues R66, H109, and D146 are important for enzyme function. The ZhuI crystal structure helps visualize the structure and putative dehydratase function of the didomain ARO/CYCs from KR-containing type II PKSs. The sequence-structure-function analysis described for ZhuI elucidates the molecular mechanisms that control C7-C12 first-ring polyketide cyclization and builds a foundation for future endeavors into directing cyclization patterns for engineered biosynthesis of aromatic polyketides.


A transition scoring system of caries increment with adjustment of reversals in longitudinal study: evaluation using primary tooth surface data.
The aim of this paper is to evaluate a new comprehensive scoring system for longitudinal studies using the International Caries Detection and Assessment System (ICDAS). A sample of 638 children were examined in 2002-2003 and again in 2007. Caries was assessed using the ICDAS criteria which assess six clinical stages of dental caries. Based on a transition matrix matching the baseline and follow-up ICDAS scores, we developed transition weights to best describe the progression, regression, or no progression nor regression of dental caries. Differential weights were assigned to transitions involved with noncavitated, cavitated, filled, crowned, or missing lesions. This method [transitional scoring system (TSS)] differentiated biologically plausible reversals from those because of examiner's misclassification. We computed and compared mean dmfs (decayed, missing, and filled tooth surfaces) increment scores including (d(t) mfs) or excluding the noncavitated stage (d(c) mfs) from TSS and another adjustment method proposed by Beck (modified Beck's method). The coefficients of variation (CV) of the two methods were also compared. Mean d(t) mfs from TSS was slightly higher than that from modified Beck's method. There was no difference in mean d(c) mfs between two methods. The ratios of CV indicated that the CV of TSS was significantly smaller than those from modified Beck's method. There were differences in caries increment scores between the two methods when we accounted for the transition of noncavitated lesions. The evaluation of CV concluded that TSS was more efficient because it requires less sample size compared with the modified Beck's method to detect a treatment effect. Both methods can be used to compute caries increments for populations with similar distribution of the dmfs scores to the sample used in this study.


Zinc Deficiency and Arsenic Exposure Can Act Both Independently or Cooperatively to Affect Zinc Status, Oxidative Stress, and Inflammatory Response.
The negative health impact of zinc deficiency overlaps significantly with arsenic exposure, and is associated with increased risk for chronic diseases. Arsenic contamination in the groundwater often co-exists in regions of the world that are prone to zinc deficiency. Notably, low zinc status shares many hallmarks of arsenic exposure, including increased oxidative stress and inflammation. Despite their common targets and frequent co-distribution in the population, little is known regarding the interaction between zinc deficiency and arsenic exposure. In this study, we tested the effect of arsenic exposure at environmentally relevant doses in combination with a physiologically relevant level of zinc deficiency (marginal zinc deficiency) on zinc status, oxidative damage, and inflammation. In cell culture, zinc-deficient THP-1 monocytes co-exposed with arsenic resulted in further reduction in intracellular zinc, as well as further increase in oxidative stress and inflammatory markers. In an animal study, zinc-deficient mice had further decrease in zinc status when co-exposed to arsenic. Zinc deficiency, but not arsenic exposure, resulted in an increase in baseline transcript abundance of inflammatory markers in the liver. Upon lipopolysaccharide challenge to elicit an acute inflammatory response, arsenic exposure, but not zinc deficiency, resulted in an increase in proinflammatory response. In summary, zinc deficiency and arsenic exposure can function independently or cooperatively to affect zinc status, oxidant stress, and proinflammatory response. The results highlight the need to consider both nutritional status and arsenic exposures together when considering their impact on health outcomes in susceptible populations.


Protocol for a systematic review and meta-analysis of human exposure to pesticide residues in honey and other bees' products.
The presence of pesticides in honey and related products is an increasing concern for consumers and producers, although there is lack of data on the current burden of exposure of the general human population through these products. We present a protocol for a systematic review and meta-analysis of contamination to insecticides, herbicides and fungicides of products from honeybees, and an estimation of how much the consumption of these products contributes to the ADI (Acceptable Daily Intake) of selected substances. We aim to systematically review and meta-analyse studies on the contamination to plant protection products in honey, royal jelly, beeswax and propolis, applying the Navigation Guide and WHO-ILO systematic review methodology as an organizing framework. We will search electronic academic databases for potentially relevant records from PubMed, TOXNET and EMBASE. We will include quantitative studies analysing the contamination from insecticides, herbicides and fungicides in honey, propolis, royal jelly and beeswax. In particular, we will evaluate the presence of the following substances and classes of pesticides: Glyphosate, Chlorpyrifos, pyrethroid and neonicotinoid pesticides, fungicides and acaricides. At least two authors will independently screen titles and abstracts at a first stage of review, and full texts at a second stage, of potentially eligible records against the eligibility criteria; data extraction of included studies will then be performed by at least two authors, in blind. At least two authors will assess risk of bias and the quality of evidence, using the most suited tools currently available. The data on prevalence of contaminated samples and concentration of pesticides in the products will be combined using meta-analysis: when more than three studies reporting the necessary measures to fit the models are available, meta-analysis will be performed separately by product and by exposure; otherwise, weighted descriptive analysis will be performed. We will report the results using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA).


[Histopathological features of carcinomas of the bladder treated with radiotherapy. Anatomo-clinical correlation].
We evaluated the effects of radiotherapy (total dose 6,100 rads; 1,500 intraoperative and 4,600 external irradiation) on urothelial carcinomas in 16 patients. Tumor response and the histopathological changes were evaluated. All but one of the patients were men. Mean patient age was 58 years. The urothelial tumors were graded from I-III according to the histological features and degree of invasion. Two were classed as grade I, 6 grade II and 8 grade III. The post-irradiation cystectomy specimens revealed no tumor cells in 9 cases (56%); 2 grade II and 7 grade III tumors. All cystectomy specimens revealed histopathological changes following radiotherapy: edema and congestion (16 cases), squamous metaplasia (11 cases), multinucleated giant cells (7 cases), fibroblast proliferation (6 cases), dystrophic calcification (4 cases), macrophages with lipids (3 cases) and osseous formation (1 case). The mean patient follow-up was 18 months. Four patients died (3 from the tumor). Mean patient survival was 12 months. The foregoing findings indicate that radiotherapy appears to be more effective in destroying the more undifferentiated and deeper urothelial carcinoma.


Biophysical separation of Staphylococcus epidermidis strains based on antibiotic resistance.
Electrophoretic and dielectrophoretic approaches to separations can provide unique capabilities. In the past, capillary and microchip-based approaches to electrophoresis have demonstrated extremely high-resolution separations. More recently, dielectrophoretic systems have shown excellent results for the separation of bioparticles. Here we demonstrate resolution of a difficult pair of targets: gentamicin resistant and susceptible strains of Staphylococcus epidermidis. This separation has significant potential implications for healthcare. This establishes a foundation for biophysical separations as a direct diagnostic tool, potentially improving nearly every figure of merit for diagnostics and antibiotic stewardship. The separations are performed on a modified gradient insulator-based dielectrophoresis (g-iDEP) system and demonstrate that the presence of antibiotic resistance enzymes (or secondary effects) produces a sufficient degree of electrophysical difference to allow separation. The differentiating factor is the ratio of electrophoretic to dielectrophoretic mobilities. This factor is 4.6 ± 0.6 × 10(9) V m(-2) for the resistant strain, versus 9.2 ± 0.4 × 10(9) V m(-2) for the susceptible strain. Using g-iDEP separation, this difference produces clear and easily discerned differentiation of the two strains.


The Promise of Electronic Health Records to Promote Shared Decision Making: A Narrative Review and a Look Ahead.
Shared decision making (SDM) involves the sharing of best available evidence between patients and providers in the face of difficult decisions. We examine outcomes that occur when electronic health records (EHRs) are purposefully used with the goal of improving SDM and detail which EHR functions can benefit SDM. A systematic search of PubMed yielded 1369 articles. Studies were included only if they used EHR interventions to support SDM and included results that showed impact on SDM. Articles were excluded if they did not measure the impact of the intervention on SDM or did not discuss how SDM had been supported by the EHR. Five studies demonstrated improved clinical outcomes, positive lifestyle behavior changes, more deliberation from patients regarding use of imaging, and less decisional conflict about medication use among patients with use of EHRs aiding SDM. Few EHRs have integrated SDM, and even fewer evaluations of these exist. EHRs have potential in supporting providers during all steps of SDM. The promise of EHRs to support SDM has yet to be fully exploited.


Crystal structure of eukaryotic ribosome and its complexes with inhibitors.
A high-resolution structure of the eukaryotic ribosome has been determined and has led to increased interest in studying protein biosynthesis and regulation of biosynthesis in cells. The functional complexes of the ribosome crystals obtained from bacteria and yeast have permitted researchers to identify the precise residue positions in different states of ribosome function. This knowledge, together with electron microscopy studies, enhances our understanding of how basic ribosome processes, including mRNA decoding, peptide bond formation, mRNA, and tRNA translocation and cotranslational transport of the nascent peptide, are regulated. In this review, we discuss the crystal structure of the entire 80S ribosome from yeast, which reveals its eukaryotic-specific features, and application of X-ray crystallography of the 80S ribosome for investigation of the binding mode for distinct compounds known to inhibit or modulate the protein-translation function of the ribosome. We also refer to a challenging aspect of the structural study of ribosomes, from higher eukaryotes, where the structures of major distinctive features of higher eukaryote ribosome-the high-eukaryote-specific long ribosomal RNA segments (about 1MDa)-remain unresolved. Presently, the structures of the major part of these high-eukaryotic expansion ribosomal RNA segments still remain unresolved.This article is part of the themed issue 'Perspectives on the ribosome'.


Electrodermal activity in hypothyroid patients and healthy subjects.
The involvement of the central nervous system either in hypothyroidism or in hyperthyroidim has previously been shown on the basis of visual, auditory, somatosensory, and central motor evoked potential studies by some investigators. In to our previous study, we found that abnormal electrodermal activity in nonmedicated hyperthyroid patients was not associated with psychiatric symptoms. In this study, our purpose was to investigate whether hypothyroidism results in electrodermal abnormalities in the absence of measurable psychiatric symptoms. Electrodermal activity was recorded with a skin conductance unit connected to a personal computer. Basal levels of electrodermal activity and responsiveness to repeated acoustic stimulation were studied in 14 nonmedicated hypothyroid patients and 14 healthy controls. Psychiatric rating scores indicated that patients and healthy controls had normal levels of anxiety and depression. Hypothyroid patients had lower skin conductance levels, lower fluctation rates and prolonged onset latencies compared with controls. None of the hypothyroid patients had amplitude changes. In conclusion, hypothyroid patients may have abnormal electrodermal activity that is related to the change of hypothalamic-pituitary-thyroid axis function, without associated psychiatric symptoms.


Quantitative enhanced Raman scattering of labeled DNA from gold and silver nanoparticles.
Surface-enhanced resonance Raman scattering (SERRS) from silver nanoparticles using 514.5-nm excitation has been shown to offer huge potential for applications in highly sensitive multiplexed DNA assays. If the technique is to be applied to real biological samples and integrated with other methods, then the use of gold nanoparticles and longer wavelengths of excitation are desirable. The data presented here demonstrate that dye-labeled oligonucleotide sequences can be directly detected by SERRS using gold nanoparticles in a quantitative manner for the first time. The performance of gold and silver nanoparticles as SERRS substrates was assessed using 514.5-, 632.8-, and 785-nm excitation and a range of 13 commercially available dye-labeled oligonucleotides. The quantitative response allowed the limit of detection to be determined for each case and demonstrates that the technique is highly effective, sensitive, and versatile. The possibility of excitation at multiple wavelengths further enhances the multiplexing potential of the technique. The importance of effectively combining the optical properties of the nanoparticle and the dye label is demonstrated. For example, at 632.8-nm excitation, the dye BODIPY TR-X and gold nanoparticles make a strong SERRS combination with very little background fluorescence. This study allows the choice of nanoparticle and dye label for particular experimental setups, and significantly expands the applicability of enhanced Raman scattering for use in many disciplines.


Attenuation of beryllium induced hepatorenal dysfunction and oxidative stress in rodents by combined effect of gallic acid and piperine.
We determined a minimum effective dose of gallic acid (3,4,5-trihydroxy benzoic acid; 50 mg/ kg, i.p.) and piperine (10 mg/kg, p.o.) through their therapeutic potential and further evaluated them individually and in combination against beryllium-induced biochemical alterations and oxidative stress consequences in female albino rats. The administration of beryllium altered blood biochemical variables by significantly depleting hemoglobin, albumin and urea, whereas it enhanced bilirubin and creatinine. The release of serum transaminase, lactate dehydrogenase and gamma-glutamyl transpeptidase was significantly greater, and was concomitant with a decrease in serum alkaline phosphatase. A significant increase in lipid peroxidation and a decrease in glutathione, superoxide dismutase and catalase in the liver and kidney was an indication of oxidative stress due to beryllium exposure. Individual administration of gallic acid and piperine moderately reversed the altered biochemical variables, whereas the combination of these was found to completely reverse the beryllium-induced biochemical alterations and oxidative stress consequences. We concluded that gallic acid exerts a synergistic effect when administered with piperine and provides a more pronounced therapeutic potential in reducing beryllium-induced hepatorenal dysfunction and oxidative stress consequences.


Influence of pregnancy perceptions on patterns of seeking antenatal care among women in reproductive age of Masaka District, Uganda.
Maternal mortality remains a challenge in Sub-Saharan Africa including Uganda. Antenatal Care (ANC) is one of the recommended measures to improve maternal and child health. However, the influence of pregnancy definition and perception on patterns of seeking regular and timely antenatal care among women in the reproductive age group (15-49 years) is not known. The objectives of this study were to: (i) understand the women's social definitions and perceptions on their pregnancy; (ii) understand the socio-cultural beliefs related to pregnancy among women of the reproductive age group; and, (iii) examine the influence of social definitions, perceptions and beliefs about pregnancy on women's antenatal care seeking behaviour patterns to inform the decentralised health care delivery system in Uganda. A total of 45 women, mothers and expectant women who were purposively selected from Kimanya sub county of Masaka district in Uganda participated in the study. Ten key informant interviews and four Focus Group Discussions (FGDs) were also conducted. Key findings indicate that the women's socio-definitions and perceptions of pregnancy influence their seeking behaviour on antenatal health care. To the women with a positive orientation towards antenatal care, pregnancy provides joy, happiness, pride, promotes their social status and safe-guards their marriage. Pregnancy is rewarding with care, love, support and gifts. Women who shun antenatal care perceive pregnancy to be a source of misery, sadness, pain and suffering. It is an uncomfortable and regrettable experience. Women also hold socio-cultural beliefs on pregnancy, which are culturally constructed and rooted in taboos, rituals and practices of their communities. It is therefore important to sensitise women and those who attend to them when they are pregnant to understand these perceptions and definitions to motivate them to seek antenatal and postnatal care for better maternal and child health.


Spontaneous differentiation of adult rat marrow stromal cells in a long-term culture.
It is well recognized that bone marrow stromal cells (MSCs) can differentiate into neuron-like cells when supplemented with growth factors and/or chemical treatments. We demonstrated that primary MSCs obtained from adult rats could spontaneously differentiate into neural precursor cells after long-term culture. During the outset of in vitro culture, less than 0.1% of adult rat primary MSCs expressed nestin, the common protein of neural precursors. These MSCs didn't show neuronal morphology nor express neuronal antigens. In contrast, after continuous maintenance for 6 weeks, a significant subpopulation of MSCs formed cellular clumps and expressed nestin (32.3 +/- 6.3%). Less than 0.1% of cells expressing immature neuron marker betaIII-tubulin could be detected in these prolonged cultured MSCs. After serum deprivation and growth factor supplement, these nestin-positive cells could express neuron-like morphology and neuron-specific markers NF-H, betaIII-tubulin, tau, and neurotransmitter GABA. In contrast, the MSCs without prolonged culture didn't show neuronal morphology nor neuronal markers even after serum withdrawal and growth factors stimulation. These results demonstrated that neural precursors could be obtained from long-term cultured MSCs, and suggested that MSCs should be useful as a potential source for treatment of neurological disease.


Clinical efficacy of sublingual immunotherapy tablets for allergic rhinitis is unlikely to be derived from in vitro allergen-release data.
Introduction: Allergen bioavailability underpins the efficacy and safety of SLIT tablets. Three product-related factors are likely to influence this: tablet potency, formulation and sublingual holding time. Areas covered: Tablet formulation determines the rate and extent of solubilized allergen release. Using validated in vitro dissolution assays, the two licensed grass pollen SLIT tablets are shown to release ≥85% of their total allergenic activity within several minutes. Sublingual holding time affects the contact duration between solubilized allergens and sublingual tissue. Maximal uptake of allergens by sublingual tissue requires ~5 minutes, with little uptake occurring within the first minute. A higher potency tablet with longer sublingual holding time would provide higher bioavailability, while faster rates of allergen release in vitro are unlikely to translate to a greater increase in bioavailability. Differences in dissolution times cannot serve as a surrogate of in vivo bioavailability, and are not related to differences in efficacy at the marketed tablet dosages. Rapid in vitro dissolution is likely not a key requirement for inducing a potent immune response. Expert opinion: In vitro dissolution cannot predict the clinical efficacy of SLIT tablets but could be important in immune tolerance and safety. In addition, a discontinuous administration regimen may have benefits for adherence and cost without compromising efficacy.


Speech and language abnormalities in myotonic dystrophy: An overview.
Myotonic dystrophy (DM) is an autosomal dominant neuromuscular and multisystem disease that is divided into two types, DM1 and DM2, according to mutations in DMPK and CNBP genes, respectively. DM patients may manifest with various speech and language abnormalities. In this review, we had an overview on speech and language abnormalities in both DM1 and DM2. Our literature search highlights that irrespective of age, all DM patients (i.e. congenital, juvenile, and adult onset DM1 as well as DM2 patients) exhibit various degrees of speech impairments. These problems are related to both cognitive dysfunction (e.g. difficulties in written and spoken language) and bulbar/vocal muscles weakness and myotonia. DM1 adult patients have also a significant decrease in speech rate and performance due to myotonia and flaccid dysarthria, which can improve with warming up. Weakness, tiredness, and hypotonia of oral and velopharyngeal muscles can cause flaccid dysarthria. Hearing impairment also plays a role in affecting speech recognition in DM2. A better understanding of different aspects of speech and language abnormalities in DM patients may provide better characterization of these abnormalities as markers that can be potentially used as outcome measures in natural history studies or clinical trials.


Immunomodulatory and Anti-Inflammatory Potential of Curcumin for the Treatment of Allergic Asthma: Effects on Expression Levels of Pro-inflammatory Cytokines and Aquaporins.
Curcumin is well known for possessing anti-inflammatory properties and for its beneficial effects in the treatment of asthma. Current study investigates the immunomodulatory and anti-inflammatory effects of curcumin using mouse model of ovalbumin-induced allergic asthma. BALB/c mice were immunized with ovalbumin on day 0 and 14 to induce allergic asthma. Animals were treated with two different doses of curcumin (20 mg/kg and 100 mg/kg) and methylprednisolone from day 21 to 28. Mice were also daily challenged intranasally with ovalbumin during treatment period, and all groups were sacrificed at day 28. Histopathological examination showed amelioration of allergic asthma in treated groups as evident by the attenuation of infiltration of inflammatory cells, goblet cell hyperplasia, alveolar thickening, and edema and vascular congestion. Curcumin significantly reduced total and differential leukocyte counts in both bronchoalveolar lavage fluid and blood. Reverse transcription polymerase chain reaction analysis showed significantly suppressed mRNA expression levels of IL-4 and IL-5 (pro-inflammatory cytokines), TNF-α, TGF-β (pro-fibrotic cytokines), eotaxin (chemokine), and heat shock protein 70 (marker of airway obstruction) in treated groups. Attenuation of these pro-inflammatory markers might have led to the suppression of airway inflammation. The expression levels of aquaporin-1 (AQP) and AQP-5 were found significantly elevated in experimental groups which might be responsible for reduction of pulmonary edema. In conclusion, curcumin significantly ameliorated allergic asthma. The anti-asthmatic effect might be attributed to the suppression of pro-inflammatory cytokines, and elevation of aquaporin expression levels, suggesting further studies and clinical trials to establish its candidature in the treatment of allergic asthma.


Scalable Fabrication of Porous Microchannel Nerve Guidance Scaffolds with Complex Geometries.
Microchannel scaffolds accelerate nerve repair by guiding growing neuronal processes across injury sites. Although geometry, materials chemistry, stiffness, and porosity have been shown to influence nerve growth within nerve guidance scaffolds, independent tuning of these properties in a high-throughput manner remains a challenge. Here, fiber drawing is combined with salt leaching to produce microchannels with tunable cross sections and porosity. This technique is applicable to an array of biochemically inert polymers, and it delivers hundreds of meters of porous microchannel fibers. Employing these fibers as filaments during 3D printing enables the production of microchannel scaffolds with geometries matching those of biological nerves, including branched topographies. Applied to sensory neurons, fiber-based porous microchannels enhance growth as compared to non-porous channels with matching materials and geometries. The combinatorial scaffold fabrication approach may advance the studies of neural regeneration and accelerate the development of nerve repair devices.


Tuning and Persistent Switching of Graphene Plasmons on a Ferroelectric Substrate.
We characterized plasmon propagation in graphene on thin films of the high-κ dielectric PbZr0.3Ti0.7O3 (PZT). Significant modulation (up to ±75%) of the plasmon wavelength was achieved with application of ultrasmall voltages (< ±1 V) across PZT. Analysis of the observed plasmonic fringes at the graphene edge indicates that carriers in graphene on PZT behave as noninteracting Dirac Fermions approximated by a semiclassical Drude response, which may be attributed to strong dielectric screening at the graphene/PZT interface. Additionally, significant plasmon scattering occurs at the grain boundaries of PZT from topographic and/or polarization induced graphene conductivity variation in the interior of graphene, reducing the overall plasmon propagation length. Lastly, through application of 2 V across PZT, we demonstrate the capability to persistently modify the plasmonic response of graphene through transient voltage application.


Transcatheter aortic valve implantation in patients with severe aortic valve stenosis and large aortic annulus, using the self-expanding 31-mm Medtronic CoreValve prosthesis: first clinical experience.
With the introduction of the 31-mm Medtronic CoreValve prosthesis, patients with large aortic annulus have become eligible for transcatheter aortic valve implantation. The aim of this study was to evaluate the feasibility, efficacy, and safety of transcatheter aortic valve implantation using the 31-mm Medtronic CoreValve in patients with severe aortic valve stenosis and large aortic annulus. Five institutions in the Netherlands and Italy participated in a retrospective multicenter registry. Clinical, procedural, and imaging data of patients treated with the 31-mm Medtronic CoreValve were retrospectively collected in accordance with the Valve Academic Research Consortium-2 criteria. Between August 2011 and November 2012, 47 patients (44 men, mean age 77.6 ± 8.9 years) received the 31-mm Medtronic CoreValve prosthesis for severe aortic stenosis. Device success (correct positioning of a single valve with intended performance and no all-cause 30-day mortality) was achieved in 31 patients (66.0%). Reasons for failing the device success criteria were significant prosthetic aortic regurgitation in 3 patients (6.4%), second valve implantation in 10 patients (21.2%) (8 cases of malpositioning with high-grade aortic regurgitation, 1 acute valve dislocation, and 1 delayed valve dislocation), 1 of whom died intrahospital, and in-hospital mortality in a further 3 patients (6.4%). Peak and mean transaortic gradients decreased significantly (P < .01). The rate of new pacemaker implantations was 41.7%. In this retrospective multicenter registry, transcatheter treatment of severe aortic valve stenosis with the 31-mm Medtronic CoreValve seemed to be challenging, even in experienced hands. If the prosthesis is properly implanted, it offers adequate valve hemodynamics and proper functioning.


Genome-based phylogenetic analysis of Streptomyces and its relatives.
Streptomyces is one of the best-studied genera of the order Actinomycetales due to its great importance in medical science, ecology and the biotechnology industry. A comprehensive, detailed and robust phylogeny of Streptomyces and its relatives is needed for understanding how this group emerged and maintained such a vast diversity throughout evolution and how soil-living mycelial forms (e.g., Streptomyces s. str.) are related to parasitic, unicellular pathogens (e.g., Mycobacterium tuberculosis) or marine species (e.g., Salinispora tropica). The most important application area of such a phylogenetic analysis will be in the comparative re-annotation of genome sequences and the reconstruction of Streptomyces metabolic networks for biotechnology. Classical 16S-rRNA-based phylogenetic reconstruction does not guarantee to produce well-resolved robust trees that reflect the overall relationship between bacterial species with widespread horizontal gene transfer. In our study we therefore combine three whole genome-based phylogenies with eight different, highly informative single-gene phylogenies to determine a new robust consensus tree of 45 Actinomycetales species with completely sequenced genomes. None of the individual methods achieved a resolved phylogeny of Streptomyces and its relatives. Single-gene approaches failed to yield a detailed phylogeny; even though the single trees are in good agreement among each other, they show very low resolution of inner branches. The three whole genome-based methods improve resolution considerably. Only by combining the phylogenies from single gene-based and genome-based approaches we finally obtained a consensus tree with well-resolved branches for the entire set of Actinomycetales species. This phylogenetic information is stable and informative enough for application to the system-wide comparative modeling of bacterial physiology.


Robot Assisted Cystectomy With Holmium Laser Debridement for Osteomyelitis of the Pubic Symphysis With Urinary Fistula.
To assess the success of robot-assisted holmium laser debridement of the pubic symphysis for osteomyelitis of the pubic symphysis with associated urosymphyseal fistula. Traditionally, excision of the fistulous tract and concomitant cystectomy with urinary diversion and pubic symphyseal debridement has been done using an open approach. This paper presents patients who were successfully managed with this approach. Between January 2007 and January 2018, all patients who underwent pubic symphyseal debridement with or without cystectomy were identified. We reviewed patients who underwent planned robot-assisted cystectomy with holmium laser debridement for osteomyelitis of the pubic symphysis as a result of urinary fistula. Data on clinical presentation, perioperative outcomes, and recurrence of urinary tract fistula and symptoms were collected. Twelve patients underwent holmium laser debridement of the pubic symphysis during robot-assisted cystectomy for urinary fistula. Eleven patients had prior radiation treatments for prostate cancer with all having failed prior conservative management. Median operative time was 270 minutes with median length of stay of 5 days. At last follow-up, 11 (91.7%) of patients had complete resolution of their urinary fistula at median follow-up of 29 months. No patients developed osteonecrosis of the bone or complications from their urinary diversion at last follow-up. Definitive surgical treatment with holmium laser debridement of the pubic symphysis with concomitant robot-assisted cystectomy and urinary diversion is a safe and durable approach to the complex problem of urinary fistula with pubic symphysis osteomyelitis.


Directed mutagenesis identifies amino acid residues involved in elongation factor Tu binding to yeast Phe-tRNAPhe.
The co-crystal structure of Thermus aquaticus elongation factor Tu.guanosine 5'- [beta,gamma-imido]triphosphate (EF-Tu.GDPNP) bound to yeast Phe-tRNA(Phe) reveals that EF-Tu interacts with the tRNA body primarily through contacts with the phosphodiester backbone. Twenty amino acids in the tRNA binding cleft of Thermus Thermophilus EF-Tu were each mutated to structurally conservative alternatives and the affinities of the mutant proteins to yeast Phe-tRNA(Phe) determined. Eleven of the 20 mutations reduced the binding affinity from fourfold to >100-fold, while the remaining ten had no effect. The thermodynamically important residues were spread over the entire tRNA binding interface, but were concentrated in the region which contacts the tRNA T-stem. Most of the data could be reconciled by considering the crystal structures of both free EF-Tu.GTP and the ternary complex and allowing for small (1.0 A) movements in the amino acid side-chains. Thus, despite the non-physiological crystallization conditions and crystal lattice interactions, the crystal structures reflect the biochemically relevant interaction in solution.


Gastroprotection by pentoxyfilline against stress-induced gastric damage. Role of lipid peroxidation, antioxidizing enzymes and proinflammatory cytokines.
Impairment of blood perfusion in gastric mucosa results in the formation of erosions and ulcers. Nitric oxide (NO), produced via activity of NO-synthase (NOS), appears to be a one of major factors, involved in the regulation of the gastric blood flow (GBF). Inhibition of this enzyme by N-nitro-L-arginine (L-NNA) results in local decrease of NO production, reduces GBF and impairs gastric mucosal integrity, the effects that can be reversed by the pretreatment with L-arginine, the NOS substrate. However, little information is available regarding the contribution of reactive oxygen species (ROS)-induced lipid peroxidation and NO to the mechanism of gastric mucosal integrity. Therefore, the aim of our present study was to determine the action of pentoxyfilline (PTX), an inhibitor of tumor necrosis factor alpha (TNFalpha) with or without NOS inhibition by L-NNA administration in rats with water immersion and restraint stress (WRS)-induced gastric lesions. Experiments were carried out on 100 male Wistar rats. The gastric blood flow (GBF) was measured using laser Doppler flowmeter. The area of gastric lesions was determined by planimetry and the levels of proinflammatory cytokines (IL-1beta and TNFalpha) were measured by ELISA. Colorimetric assays were employed to determine gastric mucosal levels of lipid peroxidation products, such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) and antioxidant enzymes including superoxide dismutase (SOD) activity, as well as tissue concentration of reduced glutathione (GSH). Administration of PTX significantly attenuated the gastric lesions, induced by 3.5 h of WRS and this was accompanied by the rise in the GBF and a significant decrease in plasma proinflammatory cytokines (IL-1beta and TNFalpha) levels, as well as the reduction of lipid peroxidation. Exposure of rats to WRS suppressed the SOD and GSH activities and these effects were reversed by PTX. The protective and hyperemic effects of PTX, as well as an increase in mucosal SOD activity and GSH concentration were counteracted by pretreatment with L-NNA, but restored by the pretreatment with L-arginine, a NOS substrate. We conclude that PTX exerts beneficial, gastroprotective effect against WRS-induced gastric lesions due to enhancement in gastric microcirculation, possibly mediated by the enhanced NOS activity as well as local action of NO and by the attenuation of oxidative metabolism and generation proinflammatory cytokines.


Understanding Respiratory Restrictions as a Function of the Scoliotic Spinal Curve in Thoracic Insufficiency Syndrome: A 4D Dynamic MR Imaging Study.
Over the past 100 years, many procedures have been developed for correcting restrictive thoracic deformities which cause thoracic insufficiency syndrome. However, none of them have been assessed by a robust metric incorporating thoracic dynamics. In this paper, we investigate the relationship between radiographic spinal curve and lung volumes derived from thoracic dynamic magnetic resonance imaging (dMRI). Our central hypothesis is that different anteroposterior major spinal curve types induce different restrictions on the left and right lungs and their dynamics. Retrospectively, we included 25 consecutive patients with thoracic insufficiency syndrome (14 neuromuscular, 7 congenital, 4 other) who underwent vertical expandable prosthetic titanium rib surgery and received preimplantation and postimplantation thoracic dMRI for clinical care. We measured thoracic and lumbar major curves by the Cobb measurement method from anteroposterior radiographs and classified the curves as per Scoliosis Research Society (SRS)-defined curve types. From 4D dMRI images, we derived static volumes and tidal volumes of left and right lung, along with left and right chest wall and left and right diaphragm tidal volumes (excursions), and analyzed their association with curve type and major curve angles. Thoracic and lumbar major curve angles ranged from 0 to 136 and 0 to 116 degrees, respectively. A dramatic postoperative increase in chest wall and diaphragmatic excursion was seen qualitatively. All components of volume increased postoperatively by up to 533%, with a mean of 70%. As the major curve, main thoracic curve (MTC) was associated with higher tidal volumes (effect size range: 0.7 to 1.0) than thoracolumbar curve (TLC) in preoperative and postoperative situation. Neither MTC nor TLC showed any meaningful correlation between volumes and major curve angles preoperatively or postoperatively. Moderate correlations (0.65) were observed for specific conditions like volumes at end-inspiration or end-expiration. The relationships between component tidal volumes and the spinal curve type are complex and are beyond intuitive reasoning and guessing. TLC has a much greater influence on restricting chest wall and diaphragm tidal volumes than MTC. Major curve angles are not indicative of passive resting volumes or tidal volumes. Level II-diagnostic.


Contact and irritant stomatitis.
Contact stomatitis is rather uncommon because of the relative resistance of the oral mucosa to irritant agents and allergens. The clinical manifestations of contact stomatitis are extremely variable and include erythema, erosions, ulcerations, leukoplakia-like lesions, and lichenoid reactions. Clinical signs are frequently less pronounced than subjective symptoms, and patients commonly experience severe functional problems despite only mild mucosal alterations. Allergic stomatitis is rare and almost always attributable to metallic mercury and gold salts. A careful history and an accurate examination of the oral cavity, teeth, and dental restorations are essential for a correct diagnosis. Patch testing is indicated in all lesions that are not clearly related to trauma or physical injuries. Patch testing is not useful in the burning mouth syndrome. Evaluation of clinical relevance of patch test results is always very difficult and requires an interdisciplinary approach to the patient. Successful treatment requires the identification and elimination of the causative factor, when possible. It is important to bear in mind that replacement of dental restorations and prostheses may be very expensive and stressful for the patient and thus should not be recommended when their causative role is doubtful.


Antioxidant activity and protective effect of banana peel against oxidative hemolysis of human erythrocyte at different stages of ripening.
Phytochemicals such as polyphenols and carotenoids are gaining importance because of their contribution to human health and their multiple biological effects such as antioxidant, antimutagenic, anticarcinogenic, and cytoprotective activities and their therapeutic properties. Banana peel is a major by-product in pulp industry and it contains various bioactive compounds like polyphenols, carotenoids, and others. In the present study, effect of ripening, solvent polarity on the content of bioactive compounds of crude banana peel and the protective effect of peel extracts of unripe, ripe, and leaky ripe banana fruit on hydrogen peroxide-induced hemolysis and their antioxidant capacity were investigated. Banana (Musa paradisica) peel at different stages of ripening (unripe, ripe, leaky ripe) were treated with 70% acetone, which were partitioned in order of polarity with water, ethyl acetate, chloroform (CHCl₃), and hexane sequentially. The antioxidant activity of the samples was evaluated by the red cell hemolysis assay, free radical scavenging (1,1-diphenyl-2-picrylhydrazyl free radical elimination) and superoxide dismutase activities. The Folin-Ciocalteu's reagent assay was used to estimate the phenolic content of extracts. The findings of this investigation suggest that the unripe banana peel sample had higher antioxidant potency than ripe and leaky ripe. Further on fractionation, ethyl acetate and water soluble fractions of unripe peel displayed high antioxidant activity than CHCl₃ and hexane fraction, respectively. A positive correlation between free radical scavenging capacity and the content of phenolic compound were found in unripe, ripe, and leaky ripe stages of banana peel.


[Effect of dalargin on repair capacity of gastroduodenal mucosa in patients with duodenal ulcer].
Changes in the number of DNA-synthesizing nuclei of gastroduodenal mucosa in duodenal ulcer were monitored for patients treated with dalargin versus standard therapy (spasmolytics and antacids). In contrast to the standard treatment, dalargin 20-day administration produced a significant increase in the index of 3H-thymidine-labelled epithelial nuclei in fundal and duodenal bulb mucosa. The capacity for activating DNA synthesis in gastroduodenal mucosa may represent an essential mechanism of dalargin therapeutic action.


The Use of Short, Animated, Patient-Centered Springboard Videos to Underscore the Clinical Relevance of Preclinical Medical Student Education.
Medical students often struggle to appreciate the clinical relevance of material taught in the preclinical years. The authors believe videos could be effectively used to interweave a patient's illness script with foundational basic science concepts. In collaboration with four other U.S. medical schools, educators at the Stanford University School of Medicine created 36 short, animated, patient-centered springboard videos (third-person, narrated accounts of authentic patient cases conveying foundational pathophysiology) in 2014. The videos were used to introduce students to 36 content modules, created as part of a microbiology, immunology, and infectious diseases curriculum. The videos were created with input from faculty content experts and in some cases medical students, and were piloted using a flipped classroom pedagogical approach in January 2015-June 2016. Student feedback from course evaluations and focus groups was analyzed using a mixed-methods approach. On the course evaluations, the majority of students rated the patient-centered videos positively, and the majority of comments on the videos were positive, highlighting both enhanced engagement and enhanced learning and retention. Comments from focus groups mirrored the course evaluation comments and highlighted different usage patterns for the videos. The authors will continue to gather and analyze data from schools using the videos as part of their core preclinical curriculum, and will produce similar videos for use in other areas of undergraduate medical education. These videos could support students' review of content taught previously and be repurposed for use in continuing and graduate medical education, as well as patient education.


Relation of exploratory behavior of rats in elevated plus-maze to brain receptor binding properties and serum growth hormone levels.
Forty-five male Wistar rats were selected according to their behavior in the elevated plus-maze. They were separated as follows: animals with low exploratory activity ('anxious'), an 'intermediate' group and animals having high exploratory activity ('non-anxious'). Various receptor binding studies and hormonal assays were also performed in these selected rats. The affinity of 5-hydroxytryptamine 5-HT2A receptors in the frontal cortex was lower in the 'anxious' rats compared to home-cage controls and 'non-anxious' animals. Moreover, the number of cholecystokinin (CCK) receptors in the hippocampus was significantly elevated in the 'anxious' group compared to home-cage control animals. The blood levels of growth hormone (GH) were significantly lower in the 'non-anxious' rats compared to 'anxious' counterparts. In conclusion, it seems likely that the decreased exploratory activity of rats is related to the increased 5-hydroxytryptamine (5-HT) and CCK mediated neurotransmission in the brain. The different serum levels of GH in the selected rats probably reflect alterations in the activity of 5-HT and CCK.


Tandem transcription and translation regulatory sensing of uncharged tryptophan tRNA.
The Bacillus subtilis AT (anti-TRAP) protein inhibits the regulatory protein TRAP (trp RNA-binding attenuation protein), thereby eliminating transcription termination in the leader region of the trp operon. Transcription of the AT operon is activated by uncharged tryptophan transfer RNA (tRNATrp). Here we show that translation of AT also is regulated by uncharged tRNATrp. A 10-residue coding region containing three consecutive tryptophan codons is located immediately preceding the AT structural gene. Completion of translation of this coding region inhibits AT synthesis, whereas incomplete translation increases AT production. Tandem sensing of uncharged tRNATrp therefore regulates synthesis of AT, which in turn regulates TRAP's ability to inhibit trp operon expression.


Social Media and Pediatric Scoliosis: An Analysis of Patient and Surgeon Use.
The purpose of this observational study was to investigate and analyze the social media presence of both patients and surgeons in relation to pediatric scoliosis. First, patient Instagram (Instagram, Inc., San Francisco, California) posts were evaluated for 1) media format; 2) timing in relation to surgery; 3) tone; 4) perspective; 5) content; and 6) subject reference. To analyze reciprocal engagement, the presence and activity of pediatric scoliosis surgeons at five major academic centers were subsequently analyzed on Instagram, Twitter (Twitter Inc., San Francisco, California), and LinkedIn (LinkedIn Corporation, Sunnyvale, California). A search of public Instagram profiles was performed over a one-year period from February 2016 to February 2017. Posts related to pediatric scoliosis were selected for analysis using a hashtag search with 30 related terms. A total of 982 posts were retrieved, with 669 posts meeting the inclusion criteria. Each post was then evaluated for timing, tone, perspective, and content using a categorical scoring system. An additional analysis was performed using academic orthopaedic hospitals' websites, in which the names of scoliosis surgeons were found and searched for on Instagram, Twitter, and LinkedIn. Their profiles were analyzed for level and length of activity, number of followers or connections, and references to clinical practice. A total of 669 posts related to scoliosis were analyzed, the majority of which were temporally related to non-operative (74.7%) or post-operative (21.8%) settings. Patients (33.3%), friends and family (34.4%), and professional organizations (23.8%) were the most active contributors. The vast majority of posts were positive in nature (88.9 %) and highlighted the patient experience (79.2%), specifically related to bracing (33.1%), activities of daily living (31.7%), and surgical site or x-rays (25.5%). Of the social media sites analyzed, surgeons were found to have the highest presence on LinkedIn (55% have accounts with a mean of 175 connections) compared to Instagram (8%, 57 followers) and Twitter (33%, 61 followers). Surgeons were also noted to have more information regarding their practice, training, and clinical skills on LinkedIn. An analysis of Instagram posts related to scoliosis showed that the majority were shared by patients in the non-operative period and overwhelmingly had a positive tone. The content of the posts focused mainly on brace wear, activities of daily living, and post-operative appearance or x-rays. This information provides further insight into what patients deem important regarding pediatric scoliosis care. Analysis of the social media presence of scoliosis surgeons showed that they have an underwhelming presence on Instagram and Twitter, but are more active on LinkedIn, a site geared more toward professional development and networking than other social media options.


Extracellular Vesicle-Dependent Cross-Talk in Cancer-Focus on Pancreatic Cancer.
Extracellular vesicles (EVs) like exosomes and shed microvesicles are generated by many different cells. However, among all the cells, cancer cells are now recognized to secrete more EVs than healthy cells. Tumor-derived EVs can be isolated from biofluids such as blood, urine, ascitic fluid, and saliva. Their numerous components (nucleic acids, proteins, and lipids) possess many pleiotropic functions involved in cancer progression. The tumor-derived EVs generated under the influence of tumor microenvironment play distant roles and promote cellular communication by directly interacting with different cells. Moreover, they modulate extracellular matrix remodeling and tumor progression. Tumor-derived EVs are involved in pre-metastatic niche formation, dependent on the EV-associated protein receptors, and in cancer chemoresistance as they transfer drug-resistance-related genes to recipient cells. Recent advances in preclinical and clinical fields suggest their potential use as biomarkers for diagnosis and prognosis as well as for drug delivery in cancer. In this Review, we discuss EV characteristics and pro-tumor capacities, and highlight the future crucial impact of tumor-derived EVs in pancreatic cancer diagnosis and prognosis.


Ursodeoxycholic acid amides as novel glucocorticoid receptor modulators.
Ursodeoxycholic acid (UDCA) is used for the treatment of hepatic inflammatory diseases. Recent studies have shown that UDCA's biological effects are partly glucocorticoid receptor (GR) mediated. UDCA derivatives were synthesized and screened for ability to induce GR translocation in a high content analysis assay using the esophageal cancer SKGT-4 cell line. UDCA derivatives induced GR translocation in a time dependent manner with equal efficacy to that of dexamethasone (Dex) and with greatly increased potency relative to UDCA. The cyclopropylamide 1a suppressed TNF-α induced NF-κB activity and it induced GRE transactivation. 1a was unable to displace Dex from the GR ligand binding domain (LBD) in a competition experiment but was capable of coactivator recruitment in a time-resolved fluorescence energy transfer assay (TR-FRET). This represents a novel mechanism of action for a GR modulator. These derivatives could result in a new class of GR modulators.


Antihypertensive agents for primary prevention of diabetic nephropathy.
The objective of this study was to evaluate the comparative effects of antihypertensive agents in patients with diabetes and normoalbuminuria. Randomized, controlled trials that compared any antihypertensive agent with placebo or another agent in hypertensive or normotensive patients with diabetes and normoalbuminuria (albumin excretion rate <30 mg/d) were identified on Medline, in Embase, on the Cochrane Controlled Trials Register, in conference proceedings, and by contacting investigators. Two authors independently extracted data on renal outcomes and other patient-relevant outcomes (e.g., mortality, serious cardiovascular events) and assessed quality of trials. Analysis was by a random-effects model, and results were expressed as relative risk (RR) and 95% confidence intervals (CI). Sixteen trials (7603 patients) were identified, six of angiotensin-converting enzyme inhibitors (ACEi) versus placebo, six of ACEi versus calcium antagonists, one of ACEi versus calcium antagonists or combined ACEi and calcium antagonist, and three of ACEi versus other agents. Compared with placebo, ACEi significantly reduced the development of microalbuminuria (six trials, 3840 patients; RR 0.60; 95% CI 0.43 to 0.84) but not doubling of creatinine (three trials, 2683 patients; RR 0.81; 95% CI 0.24 to 2.71) or all-cause mortality (four trials, 3284 patients; RR 0.81; 95% CI 0.64 to 1.03). Compared with calcium antagonists, ACEi significantly reduced progression to microalbuminuria (four trials, 1210 patients; RR 0.58; 95% CI 0.40 to 0.84). A significant reduction in the risk for developing microalbuminuria in normoalbuminuric patients with diabetes has been demonstrated for ACEi only. It seems that the effect of ACEi is independent of baseline BP, renal function, and type of diabetes, but data are too sparse to be confident that these are not important effect modifiers, and an individual patient data meta-analysis is required.


Developing a general practice workforce for the future.
Australia continues to develop as a multicultural nation, with a population that is ageing and developing complex health needs. The world around us is changing, and the pace of change is increasing. These contextual changes pose challenges for general practice training. This paper explores the potential impact of these changes on the general practice workforce. General practitioners (GPs) will continue to have a central role in coordinating continuous, comprehensive care but are more likely to act as managers of multi-source, continuous monitoring data that facilitate personalised medical care. GPs will need to adapt rapidly to change, seizing opportunities offered by disruptive technology in a globalised world affected by climate change. The nature and impact of change is difficult to predict, and more research is needed to explore how change will affect healthcare and healthcare professionals. Ideally, training for general practice should include preparation for managing continuous change.


The effect of inoculation dose of a highly pathogenic avian influenza virus strain H5N1 on the infectiousness of chickens.
Highly pathogenic avian influenza is of major concern for the poultry industry, as the virus can spread rapidly in and between flocks, causing high mortality and severe economic losses. The aim of this study was to determine the probability of infection and to determine dose-dependent virus transmission (direct transmission) for various inoculation doses. Two transmission experiments with pair-wise housed layer type chickens were performed, in which one bird per pair was inoculated with an HPAI H5N1 virus and the other contact-exposed. Various inoculation doses were used to determine the susceptibility (ID(50)), and possible relation between ID(50), and infectiousness, expressed as the amount of virus shedding and the probability of contact birds becoming infected. The infectious H5N1 dose (CID(50)) in this study was an estimated 10(2.5) egg infectious dose (EID(50))(.) Increasing the dose increased the probability of infection but survival from infection was independent of dose. In addition, increasing the dose decreased the mean latent period in the inoculated chickens significantly. This could be important for determining the time of onset of infection in a flock and thus allowing more accurate identification of the source of infection. Moreover, the amount of virus shed in trachea and cloaca by the inoculated chickens in the time between inoculation and contact infection, also differed between the various dose groups. Despite differences in latent period and virus shedding, the transmission rate parameter β and reproduction ratio R(0) did not differ significantly between the various dose groups. This implies that in this experiment the amount of virus shedding is not a measure to predict transmission or the infectiousness of chickens.