Multicystic peritoneal mesothelioma treated with complete cytoreductive surgery, peritonectomy and hyperthermic intra-peritoneal chemotherapy-A case report.
Multicystic Peritoneal mesothelioma is a rare and distinct variety of peritoneal mesothelioma with borderline malignant potential. Conventional Tumor bulking has been associated with recurrence of 45-50 %. Hence a comprehensive treatment with Complete cytoreductive surgery with involved field peritonectomy (CRS) and Hyperthermic Intra-peritoneal chemotherapy (HIPEC) is being increasingly adopted for MCPM. A 47 year old lady evaluated for peri-menopausal disturbance was diagnosed to have a multicystic lesion in the pelvis. With a preoperative suspicion of diagnosis of pseudomyxoma peritonei, CRS with HIPEC was planned. On exploration a diffuse multicystic mass was found in omentum and pouch of douglas with typical morphological features of MCPM. Complete cytoreduction was achieved with anterolateral and sub-diaphragmatic peritonectomy, omentectomy and panhystrectomy. HIPEC was performed with cisplatin 50 mg/m2 for 40 min. Pathological examination revealed MCPM of omentum and uterine surface with focal clusters of mesothelial proliferation. However there was low proliferative activity 1-2 %. MCPM presents with wide spread peritoneal spread but with relative sparing of visceral invasion. Literature review suggests the disease spread is similar to PMP and treatment with CCRS and HIPEC has yielded long term survivals in MCPM. This patient with voluminous disease burden in abdomen required surgical management and HIPEC for her condition. Whether CCRS alone without HIPEC can be an alternative for limited disease will be interesting research for future clinical reports.


Rituximab in lymphocyte-predominant Hodgkin disease: results of a phase 2 trial.
Lymphocyte-predominant Hodgkin disease (LPHD) is a unique clinical entity characterized by indolent nodal disease that tends to relapse after standard radiotherapy or chemotherapy. The malignant cells of LPHD are CD20+ and therefore rituximab may have activity with fewer late effects than standard therapy. In this phase 2 trial, 22 patients with CD20+ LPHD received 4 weekly doses of rituximab at 375 mg/m2. Ten patients had previously been treated for Hodgkin disease, while 12 patients had untreated disease. All 22 patients responded to rituximab (overall response rate, 100%) with complete response (CR) in 9 (41%), unconfirmed complete response in 1 (5%), and partial response in 12 (54%). Acute treatment-related adverse events were minimal. With a median follow-up of 13 months, 9 patients had relapsed, and estimated median freedom from progression was 10.2 months. Progressive disease was biopsied in 5 patients: 3 had recurrent LPHD, while 2 patients had transformation to large-cell non-Hodgkin lymphoma (LCL). All 3 patients with recurrent LPHD were retreated with rituximab, with a second CR seen in 1 patient and stable disease in 2. Rituximab induced prompt tumor reduction in each of 22 LPHD patients with minimal acute toxicity; however, based on the relatively short response duration seen in our trial and the concerns about transformation, rituximab should be considered investigational treatment for LPHD. Further clinical trials are warranted to determine the optimal dosing schedule of rituximab, the potential for combination treatment, and the possible relationship of rituximab treatment to the development of LCL.


Is alloparenting helpful for Mednyi Island arctic foxes, Alopex lagopus semenovi?
The Arctic Fox Alopex lagopus semenovi population on Mednyi Island is completely isolated and subsists largely by scavenging on seabird colonies, which have remained abundant and spatio-temporally predictable for many years. We compared population data at the beginning of 1976/1978 and some time after 1994-2005, finding an 85% decline in fox numbers due to disease, to assess the effect of population size on social structure. A total of 81 groups of known size and composition was observed during this 29-year period. Overall, helpers (usually non-lactating yearling females) occurred in 25.7% of groups, and in 32.4% of groups there were two or three lactating females. Female engagement in alloparental behaviour decreased, but not statistically significantly, after the decline in population density. Total food availability was apparently constant throughout the study period, and therefore, the amount available per individual was much higher later in the study. Both communally nursing females and helpers brought food and helped to guard the litter. However, the benefits of communal rearing were unclear. While cubs were left without guards significantly more rarely in the groups with an additional adult, the number of cubs weaned per lactating female was greater in groups with one (3.93 +/- 1.60), as opposed to two or three (3.06 +/- 0.92), lactating females. Survival of cubs to 1 year of age in the groups with two lactating females and/or with helpers was lower than that in the families with one lactating female without helpers (22.2% vs 32.2%). Fewer second-generation litters were born to foxes produced by composite families than to those produced by pairs. Reproductive adults producing by pairs had, on average, 1.23 (+/-1.72) second-generation litters. In groups that initially included additional adults, the average number of second-generation litters per reproductive female was 0.21 (+/-0.49) and 0.46 (+/-0.81) litters per male. Thus, according to three measures, increased group size had no apparent positive impact on reproductive success. The increased parental investment and enhanced guarding of the cubs in the larger families could be beneficial under conditions of high population density and a saturated biotope to which the island fox population was presumably adapted before the population crash in the late 1970s.


Effect of aerosol fenoterol on the severity of bronchial hyperreactivity in patients with asthma.
Beta adrenergic agents given by aerosol decrease the responsiveness of the airways to histamine and methacholine in subjects with asthma, causing a shift of the dose response curve to the right. To find out whether the shift is related to the dose of beta adrenergic agent given and to determine the duration of the reduced responsiveness, eight subjects with asthma were given histamine inhalation tests after inhaled saline and after increasing doses of inhaled fenoterol on different days. The histamine inhalation tests were repeated at hourly intervals for five hours after a selected dose of fenoterol. Fenoterol caused a dose related shift to the right of the histamine dose response curve in each subject and in some the dose response relationship reached the "non-symptomatic range." The shift in the dose response curve was short lived and had returned towards the control position within three hours in all subjects. There was no change in shape of the curves at the time of maximal shift. The results show that inhaled fenoterol greatly reduces the airway responsiveness to histamine, but up to 400 micrograms of fenoterol every four to five hours may be needed to keep the responsiveness of the airways in the non-symptomatic range.


Chromosomally mediated beta-lactamase production and gentamicin resistance in Enterococcus faecalis.
We have analyzed four distinct strains of multiply resistant, beta-lactamase-producing enterococci isolated during an outbreak of colonization with these strains on an infant-toddler surgical ward at The Children's Hospital in Boston, Mass. All four strains were resistant to erythromycin, penicillin, and tetracycline and to high levels of gentamicin and streptomycin. One strain was also resistant to chloramphenicol. Plasmid profiles revealed four different plasmid patterns, with the number of identified plasmids ranging from zero to three. The gene coding for beta-lactamase production could be transferred at low frequency (less than 10(-8)) to an enterococcal recipient from one strain in conjunction with all of the other resistance determinants. Probes derived from the staphylococcal beta-lactamase gene and gentamicin resistance gene failed to hybridize with any of the detectable plasmids, but both genes were present on restriction fragments of genomic DNA in all strains. Our results indicate that the beta-lactamase genes and gentamicin resistance genes in these strains are integrated into the bacterial chromosome. The cotransmissibility of the resistance determinants raises the possibility of their incorporation into a multiresistance transposable genetic element.


Oxytocin and pair compatibility in adult male rhesus macaques (Macaca mulatta).
Pair housing is considered one of the best ways of promoting psychological wellbeing for caged macaques. However, incompatible partnerships can result in stress or aggression. Though previous studies have analyzed the role of variables such as age, weight, gender, and temperament on pair compatibility, few have examined the relationship between physiological parameters and pair compatibility. Oxytocin is known to promote prosocial nonsexual behavior in various primate species and may serve as an indicator of pair compatibility. In this study, we examined the association between peripheral oxytocin levels and prosocial behaviors in isosexual pairs of male rhesus macaques. We hypothesized that animals that demonstrated high levels of prosocial behaviors would have higher oxytocin levels than those showing low levels of the behavior. In addition, to elucidate the relationship between oxytocin and compatibility, we compared peripheral oxytocin between the highly affiliative animals and single-housed males identified as having multiple unsuccessful pair attempts with multiple partners. We collected plasma oxytocin on 40 pairs of monkeys that had lived together for at least 1 month and 20 single-housed animals. Further, we simultaneously collected behavioral data on the pairs, recording prosocial interactions (e.g., groom, play). Oxytocin varied among individuals, but was highly correlated between members of a pair (r = 0.58, p < .001). Additionally, prosocial behavior was positively correlated with plasma oxytocin (r = 0.38, p < .02). However, contrary to our expectations, oxytocin did not differ between single and highly affiliative pair-housed animals (F(1,38) = 0.71, p = .40). Our results suggest that oxytocin may be associated with the quality of isosexual pairs of male macaques. More work is needed to determine the nature of this relationship.


The liver: a model of organ-specific lymphocyte recruitment.
The liver is constantly exposed to gut-derived antigens that enter via the portal vein, and it must modulate immune responses so that harmful pathogens are cleared but necessary food antigens are ignored. The liver contains a large resident and migratory population of lymphocytes and macrophages that provide immune surveillance against foreign antigen. This population of cells can be rapidly expanded in response to infection or injury by recruiting leukocytes from the circulation, a process that is dependent on the ability of lymphocytes to recognise, bind to and migrate across the endothelial cells that line the vasculature. Lymphocytes can enter the liver at several sites: the vascular endothelium in the portal tracts (comprising the hepatic artery, portal vein and bile ductule), the sinusoids (through which the blood percolates past the hepatocytes) or the central hepatic veins (through which the blood exits). The requirements and physical conditions at each site vary and there is evidence that different combinations of adhesion proteins are involved at these different sites. This article discusses the expression and function of adhesion molecules within the liver and demonstrates how specific populations of effector lymphocytes can be selectively recruited to the liver.


Tracheobronchitis with stridor in a patient with ulcerative colitis.
Bronchopulmonary involvement is a rare but well documented extraintestinal manifestation of inflammatory bowel disease (IBD). IBD-related pulmonary disease can range from subglottic stenosis to tracheobronchitis to interstitial lung disease and is often misdiagnosed on initial presentation. We present a case of tracheobronchitis with stridor in a 23-year-old-woman with well controlled ulcerative colitis (UC).


To "grow" or "go": TMEM16A expression as a switch between tumor growth and metastasis in SCCHN.
Tumor metastasis is the leading cause of death in patients with cancer. However, the mechanisms that underlie metastatic progression remain unclear. We examined TMEM16A (ANO1) expression as a key factor shifting tumors between growth and metastasis. We evaluated 26 pairs of primary and metastatic lymph node (LN) tissue from patients with squamous cell carcinoma of the head and neck (SCCHN) for differential expression of TMEM16A. In addition, we identified mechanisms by which TMEM16A expression influences tumor cell motility via proteomic screens of cell lines and in vivo mouse studies of metastasis. Compared with primary tumors, TMEM16A expression decreases in metastatic LNs of patients with SCCHN. Stable reduction of TMEM16A expression enhances cell motility and increases metastases while decreasing tumor proliferation in an orthotopic mouse model. Evaluation of human tumor tissues suggests an epigenetic mechanism for decreasing TMEM16A expression through promoter methylation that correlated with a transition between an epithelial and a mesenchymal phenotype. These effects of TMEM16A expression on tumor cell size and epithelial-to-mesenchymal transition (EMT) required the amino acid residue serine 970 (S970); however, mutation of S970 to alanine does not disrupt the proliferative advantages of TMEM16A overexpression. Furthermore, S970 mediates the association of TMEM16A with Radixin, an actin-scaffolding protein implicated in EMT. Together, our results identify TMEM16A, an eight transmembrane domain Ca2+-activated Cl- channel, as a primary driver of the "Grow" or "Go" model for cancer progression, in which TMEM16A expression acts to balance tumor proliferation and metastasis via its promoter methylation.


In vitro antimicrobial activities against cariogenic streptococci and their antioxidant capacities: A comparative study of green tea versus different herbs.
The antimicrobial activity against cariogenic bacteria, total antioxidant capacity and phenolic constituents of methanolic extracts from 11 herbs were investigated and compared with those of green tea (Camellia sinensis). Among the 12 tested herbs, eight herbal extracts could inhibit the growth of Streptococcus sanguinis. Jasmine, jiaogulan, and lemongrass were the most potent, with minimum inhibitory concentrations (MIC) of 1mg/ml, while green tea was less effective, with a MIC of 4mg/ml. Among them, only rosemary could inhibit the growth of S. mutans at a MIC of 4mg/ml. Total antioxidant capacities of herbal extracts were analyzed by three different assays, including 2,2-diphenyl-1-picrylhydrazyl (DPPH·) radical scavenging activity, trolox equivalent antioxidant capacity (TEAC) and oxygen radical absorbance capacity (ORAC). Regardless of the assays used, green tea exhibited the highest antioxidant capacity, followed by osmanthus. Wide variations in total phenolics and total flavonoids of herbal tea extracts were observed. Chlorogenic acid was detected in high amount in honeysuckle and duzhong. These data suggest that rosemary is a potent inhibitor of oral streptococci, and green tea and osmanthus may be effective potential sources of natural antioxidants.


Artificial recharge through a thick, heterogeneous unsaturated zone.
Thick, heterogeneous unsaturated zones away from large streams in desert areas have not previously been considered suitable for artificial recharge from ponds. To test the potential for recharge in these settings, 1.3 x 10(6) m(3) of water was infiltrated through a 0.36-ha pond along Oro Grande Wash near Victorville, California, between October 2002 and January 2006. The pond overlies a regional pumping depression 117 m below land surface and is located where thickness and permeability of unsaturated deposits allowed infiltration and saturated alluvial deposits were sufficiently permeable to allow recovery of water. Because large changes in water levels caused by nearby pumping would obscure arrival of water at the water table, downward movement of water was measured using sensors in the unsaturated zone. The downward rate of water movement was initially as high as 6 m/d and decreased with depth to 0.07 m/d; the initial time to reach the water table was 3 years. After the unsaturated zone was wetted, water reached the water table in 1 year. Soluble salts and nitrate moved readily with the infiltrated water, whereas arsenic and chromium were less mobile. Numerical simulations done using the computer program TOUGH2 duplicated the downward rate of water movement, accumulation of water on perched zones, and its arrival at the water table. Assuming 10 x 10(6) m(3) of recharge annually for 20 years, a regional ground water flow model predicted water level rises of 30 m beneath the ponds, and rises exceeding 3 m in most wells serving the nearby urban area.


Determination of ascorbic acid and isoascorbic acid by capillary zone electrophoresis: application to fruit juices and to a pharmaceutical formulation.
Capillary zone electrophoresis was applied to the determination of ascorbic and isoascorbic acid, analysing the various parameters of influence such as the separation voltage, the buffer pH and concentration, the type of separation capillary or the loading conditions. Both analytes could be adequately determined within 5 min. The proposed method uses a 20 cm x 25 microns i.d. coated column, 0.1 M phosphate buffer pH 5.0, 8 kV separation voltage and light absorption detection at 265 nm. Linear calibration curves were obtained in the 0-1 mg mi-1 range, with detection limits of 0.5 micrograms ml-1. This method proved to be very rapid, simple and practical for the qualitative and quantitative determination of ascorbic acid in lemon and orange juices, as well as in a commercially available pharmaceutical formulation.


Recovery from disturbance requires resynchronization of ecosystem nutrient cycles.
Nitrogen (N) and phosphorus (P) are tightly cycled in most terrestrial ecosystems, with plant uptake more than 10 times higher than the rate of supply from deposition and weathering. This near-total dependence on recycled nutrients and the stoichiometric constraints on resource use by plants and microbes mean that the two cycles have to be synchronized such that the ratio of N:P in plant uptake, litterfall, and net mineralization are nearly the same. Disturbance can disrupt this synchronization if there is a disproportionate loss of one nutrient relative to the other. We model the resynchronization of N and P cycles following harvest of a northern hardwood forest. In our simulations, nutrient loss in the harvest is small relative to postharvest losses. The low N:P ratio of harvest residue results in a preferential release of P and retention of N. The P release is in excess of plant requirements and P is lost from the active ecosystem cycle through secondary mineral formation and leaching early in succession. Because external P inputs are small, the resynchronization of the N and P cycles later in succession is achieved by a commensurate loss of N. Through succession, the ecosystem undergoes alternating periods of N limitation, then P limitation, and eventually co-limitation as the two cycles resynchronize. However, our simulations indicate that the overall rate and extent of recovery is limited by P unless a mechanism exists either to prevent the P loss early in succession (e.g., P sequestration not stoichiometrically constrained by N) or to increase the P supply to the ecosystem later in succession (e.g., biologically enhanced weathering). Our model provides a heuristic perspective from which to assess the resynchronization among tightly cycled nutrients and the effect of that resynchronization on recovery of ecosystems from disturbance.


High-power sub-terahertz source with a record frequency stability at up to 1 Hz.
Many state-of-the-art fundamental and industrial projects need the use of terahertz radiation with high power and small linewidth. Gyrotrons as radiation sources provide the desired level of power in the sub-THz and THz frequency range, but have substantial free-running frequency fluctuations of the order of 10-4. Here, we demonstrate that the precise frequency stability of a high-power sub-THz gyrotron can be achieved by a phase-lock loop in the anode voltage control. The relative width of the frequency spectrum and the frequency stability obtained for a 0.263 THz/100 W gyrotron are 4 × 10-12 and 10-10, respectively, and these parameters are better than those demonstrated so far with high-power sources by almost three orders of magnitude. This approach confirms its potential for ultra-high precision spectroscopy, the development of sources with large-scale radiating apertures, and other new projects.


Exploring status and determinants of prenatal and postnatal visits in western China: in the background of the new health system reform.
Prenatal and postnatal visits are two effective interventions for protection and promotion of maternal health by reducing maternal mortality and improving the quality of birth. There is limited nationally representative data regarding the changes of prenatal and postnatal visits since the latest health system reform initiated in 2009 in Shaanxi, China. The aim of this study was to explore the current status and determinants of prenatal and postnatal visits in the background of new health system reform. Data were drawn from two waves of National Health Service Surveys in Shaanxi Province which were conducted prior and post the health system reform in 2008 and 2013, respectively. A concentration index was employed to measure the degree of income-related inequality of maternal health services utilization. Multilevel mix-effects logistic regressions were applied to study the factors associated with prenatal and postnatal visits. The study sample consists of 2398 women aged 15-49 years old. The data of the 5th National Health Services Survey in 2013 showed in the criterion of the World Health Organization (WHO), the percentage of women receiving ≥4 prenatal visits was 84.79% for urban women and 82.20% for rural women, with women receiving ≥3 postnatal visits were 26.48 and 25.29% for urban and rural women respectively. In the criterion of China's ≥ 5 prenatal visits the percentages were 72.25% for urban women and 70.33% for rural women; 61.69% of urban women and 71.50% of rural women received ≥1 postnatal visits. As for urban women, the concentration index of postnatal visit utilization was -0.075 (95% CI:-0.148, -0.020) after the health system reform. The determinants related to prenatal and postnatal visits were the change of reform, women's education, parity and the delivery institution. This study showed the utilization of prenatal and postnatal visits met the requirement of the WHO, higher than other areas in China and other developing countries after the new health system reform. The new health system reform increased the utilization of postnatal visits in poor urban women and improved the frequency of prenatal and postnatal visits in rural women.


A Novel BaEVRless-Pseudotyped γ-Globin Lentiviral Vector Drives High and Stable Fetal Hemoglobin Expression and Improves Thalassemic Erythropoiesis In Vitro.
It has previously been demonstrated that the self-inactivating γ-globin lentiviral vector GGHI can significantly increase fetal hemoglobin (HbF) in erythroid cells from thalassemia patients and thus improve the disease phenotype in vitro. In the present study, the GGHI vector was improved further by incorporating novel enhancer elements and also pseudotyping it with the baboon endogenous virus envelope glycoprotein BaEVRless, which efficiently and specifically targets human CD34+ cells. We evaluated the hypothesis that the newly constructed vector designated as GGHI-mB-3D would increase hCD34+ cell tropism and thus transduction efficiency at low multiplicity of infection, leading to increased transgene expression. High and stable HbF expression was demonstrated in thalassemic cells for the resulting GGHI-mB-3D/BaEVRless vector, exhibiting increased transduction efficiency compared to the original GGHI-mB-3D/VSVG vector, with a concomitant 91% mean HbF increase at a mean vector copy number per cell of 0.86 and a mean transduction efficiency of 56.4%. Transduced populations also exhibited a trend toward late erythroid, orthochromatic differentiation and reduced apoptosis, a further indication of successful gene therapy treatment. Monitoring expression of ATG5, a key link between autophagy and apoptosis, it was established that this correction correlates with a reduction of enhanced autophagy activation, a typical feature of thalassemic polychromatophilic normoblasts. This work provides novel mechanistic insights into gene therapy-mediated correction of erythropoiesis and demonstrates the beneficial role of BaEVRless envelope glycoprotein compared to VSVG pseudotyping and of the novel GGHI-mB-3D/BaEVRless lentiviral vector for enhanced thalassemia gene therapy.


Albumin effects on drug absorption and metabolism in reconstructed epidermis and excised pig skin.
To replace animal experiments for the risk assessment in cutaneous absorption European and Non-European regulatory authorities urge to develop in vitro test systems. A variety of methods have been established which, however, vary in several respects, such as the nature of the barrier and used media. Since both affect drug uptake we have compared the influence of albumin (BSA) in the acceptor medium on the permeation and metabolism of highly lipophilic steroidal drugs, testosterone and prednicarbate (PC). Surprisingly, the addition of BSA to the acceptor medium slightly reduced the steroid permeation, especially when formulations of poor PC uptake were tested. Moreover, with slow drug permeation the metabolite pattern changed as compared to PC metabolites to be found in albumin-free acceptor medium. This was clearly less the case with PC incorporated into newly developed solid lipid nanoparticles accelerating PC uptake about fourfold. The penetration of testosterone was not influenced by BSA in the acceptor medium. Summarising, these results contribute essentially to the development of appropriate in vitro methods for testing of the cutaneous absorption of drugs, ingredients of cosmetics and for the risk assessment of xenobiotics, pesticides and biozides.


Enrichment in the Sucker and Weaner Phase Altered the Performance of Pigs in Three Behavioural Tests.
We tested the hypothesis that provision of enrichment in the form of enrichment blocks during the sucker and weaner phases would affect the behaviour of pigs. We measured the performance of pigs in an open field/novel object test, a maze test, an executive function test and the cortisol response of the pigs after exposure to an open field test. The provision of enrichment blocks altered the behaviour of the pigs in all three tests and these changes suggest an increased willingness to explore and possibly an increased ability to learn. The behavioural tests highlighted that young pigs have the capacity to learn complex tasks. Our findings support the notion that the benefits of enrichment cannot be evaluated by measuring the interactions the animal has with the enrichments in the home pen and it may simply be beneficial to live in a more complex environment. We have highlighted that the early rearing environment is important and that the management and husbandry at an early age can have long-term implications for pigs. The enrichment we used in this study was very simple, an enrichment block, and we provide evidence suggesting the provision of enrichment effected pig behavioural responses. Even the simplest of enrichments may have benefits for the welfare and development of young pigs and there is merit in developing enrichment devices that are suitable for use in pig production.


Intraoperative tremor in surgeons and trainees.
Tremor may be expected to interfere with the performance of fine motor tasks such as surgery. While tremor is readily quantified in inactive subjects, it is more challenging to measure tremor as the subjects perform complex tasks. The objective of this work was to quantify tremor during the performance of a realistic simulated surgery. Our novel surgical simulator incorporates a force sensor that allows identification and quantification of the intraoperative effects of tremor on the manipulandum. We have collected preliminary data from trainees and experienced surgeons carrying out multiple simulated anastomoses on silicone vessels, mimicking a procedure such as distal coronary anastomosis. We calculated transient and overall tremor intensity, and tested for a hypothesized 'learning effect'. Several of the recordings of intraoperative force data manifested distinctive features corresponding to substantial oscillation in the range of 8-12 Hz. We attribute this to enhanced physiological tremor. These early results indicate a significant reduction in the transmission of surgeon's tremor to the operative field from the first attempt to later attempts (P = 0.039, standardized effect size = 0.91), which may be associated with increasing confidence. This new method does not just quantify tremor, but quantifies the transmission of tremor to a manipulandum in the operative field during high-fidelity simulated coronary surgery. This may be used to assess and provide feedback on the performance of trainees and experienced surgeons, along with other fields in which fine motor skills are of vital importance.


Consequences of ionizing radiation-induced damage in human neural stem cells.
Cranial irradiation remains a frontline treatment for brain cancer, but also leads to normal tissue damage. Although low-dose irradiation (≤10 Gy) causes minimal histopathologic change, it can elicit variable degrees of cognitive dysfunction that are associated with the depletion of neural stem cells. To decipher the mechanisms underlying radiation-induced stem cell dysfunction, human neural stem cells (hNSCs) subjected to clinically relevant irradiation (0-5 Gy) were analyzed for survival parameters, cell-cycle alterations, DNA damage and repair, and oxidative stress. hNSCs showed a marked sensitivity to low-dose irradiation that was in part due to elevated apoptosis and the inhibition of cell-cycle progression that manifested as a G2/M checkpoint delay. Efficient removal of DNA double-strand breaks was indicated by the disappearance of γ-H2AX nuclear foci. A dose-responsive and persistent increase in oxidative and nitrosative stress was found in irradiated hNSCs, possibly the result of a higher metabolic activity in the fraction of surviving cells. These data highlight the marked sensitivity of hNSCs to low-dose irradiation and suggest that long-lasting perturbations in the CNS microenvironment due to radiation-induced oxidative stress can compromise the functionality of neural stem cells.


Never enough sleep: a brief history of sleep recommendations for children.
There is a common belief that children are not getting enough sleep and that children's total sleep time has been declining. Over the century, many authors have proposed sleep recommendations. The aim of this study was to describe historical trends in recommended and actual sleep durations for children and adolescents, and to explore the rationale of sleep recommendations. A systematic literature review was conducted to identify recommendations for children's sleep requirements and data reporting children's actual total sleep time. For each recommendation identified, children's actual sleep time was determined by identifying studies reporting the sleep duration of children of the same age, gender, and country in the same years. Historical trends in age-adjusted recommended sleep times and trends in children's actual sleep time were calculated. A thematic analysis was conducted to determine the rationale and evidence-base for recommendations. Thirty-two sets of recommendations were located dating from 1897 to 2009. On average, age-specific recommended sleep decreased at the rate of -0.71 minute per year. This rate of decline was almost identical to the decline in the actual sleep duration of children (-0.73 minute per year). Recommended sleep was consistently ∼37 minutes greater than actual sleep, although both declined over time. A lack of empirical evidence for sleep recommendations was universally acknowledged. Inadequate sleep was seen as a consequence of "modern life," associated with technologies of the time. No matter how much sleep children are getting, it has always been assumed that they need more.


Anthropological perspectives on use of the areca nut.
This paper first reviews the identity of historical and contemporary users of the areca nut. It then considers the reasons given by users for indulging in areca consumption, drawing upon historical, ethnographic and experimental sources of evidence for the effects which users have sought to derive from it. Particularly important is the social context in which consumption occurs, and the social meanings attached to areca use and exchange. Finally, a possible evolutionary hypothesis is postulated to explain the origins of areca use as a form of behaviour indicating reproductive availability. However, diverse culturally explicit reasons underlie usage and what may once have been a sufficient rationale for consumption may no longer justify this pattern of behaviour.


18F-Fluorodeoxyglucose PET/CT and dynamic contrast-enhanced MRI as imaging biomarkers in malignant pleural mesothelioma.
The purpose of this study was to compare the use of fluorine-18-fluorodeoxyglucose (F-FDG) PET with computed tomography (CT) and dynamic contrast-enhanced (DCE) MRI to predict prognosis and monitor treatment in malignant pleural mesothelioma. F-FDG PET/CT and DCE-MRI studies carried out as part of the South West Area Mesothelioma Pemetrexed trial were used. F-FDG PET/CT and DCE-MRI studies were carried out before treatment, and after two cycles of chemotherapy, on patients treated with pemetrexed and cisplatin. A total of 73 patients were recruited, of whom 65 had PET/CT and DCE-MRI scans. Baseline measurements from F-FDG PET/CT (maximum standardized uptake value, metabolic tumour volume and total lesion glycolysis) and DCE-MRI (integrated area under the first 90s of the curve and washout slope) were compared with overall survival (OS) using Kaplan-Meier and Cox regression analyses, and changes in imaging measurements were compared with disease progression. PET/CT and DCE-MRI measurements were not correlated with each other. Maximum standardized uptake value, metabolic tumour volume and total lesion glycolysis were significantly related to OS with Cox regression analysis and Kaplan-Meir analysis, and DCE-MRI washout curve shape was significantly related to OS. DCE-MRI curve shape can be combined with F-FDG PET/CT to give additional prognostic information. Changes in measurements were not related to progression-free survival. F-FDG PET/CT and DCE-MRI give prognostic information in malignant pleural mesothelioma. Neither PET/CT nor DCE-MRI is useful for monitoring disease progression.


Sex-Dependent Prescription Patterns and Clinical Outcomes Associated With the Use of Two Oral Cannabis Formulations in the Multimodal Management of Chronic Pain Patients in Colombia.
To date, the therapeutic use of cannabinoids in chronic pain management remains controversial owing to the limited clinical evidence found in randomized clinical trials (RCTs), the heterogeneous nature of the clinical indication, and the broad range of cannabis-based medicinal products (CBMPs) used in both experimental and observational clinical studies. Here we evaluate patient-reported clinical outcomes (PROMS) in a cohort of adult patients, diagnosed with chronic pain of diverse etiology, who received adjuvant treatment with oral, cannabis-based, magistral formulations between May and September 2021 at the Latin American Institute of Neurology and Nervous System (ILANS-Zerenia) in Bogotá, Colombia. During this period, 2,112 patients completed a PROMS questionnaire aimed at capturing the degree of clinical improvement of their primary symptom and any potential side effects. Most participants were female (76.1%) with an average age of 58.7 years old, and 92.5% (1,955 patients) reported some improvement in their primary symptom (p < 0.001). Two monovarietal, full-spectrum, cannabis formulations containing either cannabidiol (CBD 30 mg/mL; THC <2 mg/mL) or a balanced composition (THC 12 mg/mL; CBD 14 mg/mL) accounted for more than 99% of all prescriptions (59.5 and 39.8%, respectively). The degree of improvement was similar between both formulations, although males reported less effectiveness in the first 4 weeks of treatment. Sex-specific differences were also found in prescription patterns, with male patients increasing the intake of the balanced chemotype overtime. For many patients (71.7%) there were no adverse side effects associated to the treatment and those most reported were mild, such as somnolence (13.0%), dizziness (8.1%) and dry mouth (4.2%), which also appeared to fade over time. Our results constitute the first real-world evidence on the clinical use of medicinal cannabis in Colombia and suggest that cannabis-based oral magistral formulations represent a safe and efficacious adjuvant therapeutic option in the management of chronic pain.


Gut microbiota and pediatric disease.
Researchers have made every effort to assess the role of gut microbiota in pediatric diseases like inflammatory bowel disease (IBD), celiac disease, asthma, allergy, and autism. The leading hypothesis is that an altered microbial composition is present (other than the presence of a specific pathogen) and that it could be involved in the pathogenesis or progression of such disorders. Cultural, molecular, metabolomic, and metagenomic approaches are trying to define the pediatric gut microbiota imbalances in different diseases. In pediatric IBD, a marked increase in aerobes and facultative anaerobes was found, along with an increase in Enterobacteriaceae members (Escherichia coli). In both pediatric IBD and celiac disease (Th1-mediated disorders), higher bacterial cell counts were observed, jointly with a general gain of biodiversity. A preponderance of Bacteroidetes and a parallel decrease of Firmicutes was also reported in IBD, celiac disease and autism. Contrarily, dietary changes due to Western lifestyles increase Firmicutes populations and lower short-chain fatty acids production, possibly exposing 'developed' children to the infectious challenge (Escherichia and Shigella spp.). Lactobacillus and Bifidobacterium species could be protective agents for atopic diseases, while Clostridia, Enterobacteriaceae, and staphylococci can be associated with an increased risk of such Th2-mediated disorders. In the brain-gut axis view, gut microbiota could also play a role in autism.


General formalism for vibronic Hamiltonians in tetragonal symmetry and beyond.
We derive general expansion formulas in vibrational coordinates for all bimodal Jahn-Teller and pseudo-Jahn-Teller Hamiltonians in tetragonal symmetry. Symmetry information of all the vibronic Hamiltonian matrix elements is fully carried by up to only 4 eigenvalues of symmetry operators. This problem-to-eigenvalue reduction enables us to handle thousands of vibronic problems in one work. The derived bimodal formulas can be easily extended to cover problems with one or more than two vibrational modes. They lay a solid foundation for future vibronic coupling studies of tetragonal systems. More importantly, the efficient derivation can be applied to handle (pseudo-)Jahn-Teller Hamiltonians for all problems with one principal symmetry axis.


Associations of HDL, HDL(2), and HDL(3) cholesterol and apolipoproteins A-I and B with lifestyle factors in healthy women and men: the Stanford Five City Project.
Measures of the two major high-density lipoprotein (HDL) subfractions, HDL(2) and HDL(3), and the major apolipoproteins of HDL and low-density lipoprotein (LDL), Apo A-I and Apo B, may be etiologically important factors in the development of coronary artery disease. The association of lifestyle factors with these lipoprotein-related variables remains unclear. HDL-C, HDL(2)-C, HDL(3)-C, Apo A-I, and Apo B levels were determined in a population-based sample of 1,027 healthy women and men aged 25-64 years, from four California cities who participated in the 1989/1990 survey of the Stanford Five City Project. In this cross-sectional study we examined the independent associations of these lipoprotein-related variables with body mass index (BMI), cigarette smoking, daily energy expenditure, alcohol intake, dietary intake, and hormone use (oral contraceptives and estrogen replacement therapy). In general, BMI and alcohol intake were the strongest independent predictors of the lipoprotein-related variables. The negative association of BMI with HDL-C was attributable primarily to the association with the HDL(2)-C subfraction, while for alcohol intake the positive association with HDL-C was attributable primarily to the association with HDL(3)-C, particularly in men. Among men, but not women, energy expenditure was a significant independent predictor of each of the lipoprotein-related variables, with positive associations observed for HDL-C, HDL(2)-C, HDL(2)-C, and Apo A-I and a negative association observed for Apo B (P < 0.005). Data from this population-based sample suggest that specific lifestyle factors are more strongly associated with some lipoprotein-related variables than with others, with notable gender differences.


The accessory gene regulator (agr) controls Staphylococcus aureus virulence in a murine arthritis model.
We have studied the role of the accessory gene regulator (agr) of Staphylococcus aureus as a virulence determinant in the pathogenesis of septic arthritis. At least 15 genes coding for potential virulence factors in Staphylococcus aureus are regulated by a putative multicomponent signal transduction system encoded by the agr/hld locus. agr and hld mutants show a decreased synthesis of extracellular toxins and enzymes, such as alpha-, beta-, and delta-hemolysin, leucocidin, lipase, hyaluronate lyase, and proteases, and at the same time an increased synthesis of coagulase and protein A as compared with the wild-type counterpart. We have used a recently described murine model of S. aureus-induced arthritis to study the virulence of S. aureus 8325-4 and two agr/hld mutants derived from it. Sixty percent of the mice injected with the wild-type strain developed arthritis, whereas agrA and hld mutants displayed joint involvement in only 10 and 30%, respectively. In addition, 40% of the mice inoculated with the wild-type strain displayed an erosive arthropathy; such changes were not detectable at all in mice inoculated with the agrA mutant. Serum levels of interleukin-6, a potent B-cell differentiation factor, were significantly higher (P < 0.001) in the mice inoculated with the wild-type strain than in those inoculated with the agrA mutant counterpart. Overall, our results suggest that the agr system of S. aureus is an important virulence determinant in the induction and progression of septic arthritis in mice.


Universal Approach to FRAP Analysis of Arbitrary Bleaching Patterns.
The original approach to calculating diffusion coefficients of a fluorescent probe from Fluorescence Recovery After Photobleaching (FRAP) measurements assumes bleaching with a circular laser beam of a Gaussian intensity profile. This method was used without imaging the bleached cell. An empirical equation for calculating diffusion coefficients from a rectangular bleaching geometry, created in a confocal image, was later published, however a single method allowing the calculation of diffusion coefficients for arbitrary geometry does not exist. Our simulation approach allows computation of diffusion coefficients regardless of bleaching geometry used in the FRAP experiment. It accepts a multiple-frame TIFF file, representing the experiment as input, and simulates the (pure) diffusion of the fluorescent probes (2D random walk) starting with the first post-bleach frame of the actual data. It then fits the simulated data to the real data and extracts the diffusion coefficient. We validate our approach using a well characterized diffusing molecule (DiIC18) against well-established analytical procedures. We show that the algorithm is able to calculate the absolute value of diffusion coefficients for arbitrary bleaching geometries, including exaggeratedly large ones. It is provided freely as an ImageJ plugin, and should facilitate quantitative FRAP measurements for users equipped with standard fluorescence microscopy setups.


Comparative analysis of kabuli chickpea transcriptome with desi and wild chickpea provides a rich resource for development of functional markers.
Chickpea (Cicer arietinum L.) is an important crop legume plant with high nutritional value. The transcriptomes of desi and wild chickpea have already been sequenced. In this study, we sequenced the transcriptome of kabuli chickpea, C. arietinum (genotype ICCV2), having higher commercial value, using GS-FLX Roche 454 and Illumina technologies. The assemblies of both Roche 454 and Illumina datasets were optimized using various assembly programs and parameters. The final optimized hybrid assembly generated 43,389 transcripts with an average length of 1065 bp and N50 length of 1653 bp representing 46.2 Mb of kabuli chickpea transcriptome. We identified a total of 5409 simple sequence repeats (SSRs) in these transcript sequences. Among these, at least 130 and 493 SSRs were polymorphic with desi (ICC4958) and wild (PI489777) chickpea, respectively. In addition, a total of 1986 and 37,954 single nucleotide polymorphisms (SNPs) were predicted in kabuli/desi and kabuli/wild genotypes, respectively. The SNP frequency was 0.043 SNP per kb for kabuli/desi and 0.821 SNP per kb for kabuli/wild, reflecting very low genetic diversity in chickpea. Further, SSRs and SNPs present in tissue-specific and transcription factor encoding transcripts have been identified. The experimental validation of a selected set of polymorphic SSRs and SNPs exhibited high intra-specific polymorphism potential between desi and kabuli chickpea, suggesting their utility in large-scale genotyping applications. The kabuli chickpea gene index assembled, and SSRs and SNPs identified in this study will serve as useful genomic resource for genetic improvement of chickpea.


In vivo phosphoproteomics analysis reveals the cardiac targets of β-adrenergic receptor signaling.
β-Blockers are widely used to prevent cardiac arrhythmias and to treat hypertension by inhibiting β-adrenergic receptors (βARs) and thus decreasing contractility and heart rate. βARs initiate phosphorylation-dependent signaling cascades, but only a small number of the target proteins are known. We used quantitative in vivo phosphoproteomics to identify 670 site-specific phosphorylation changes in murine hearts in response to acute treatment with specific βAR agonists. The residues adjacent to the regulated phosphorylation sites exhibited a sequence-specific preference (R-X-X-pS/T), and integrative analysis of sequence motifs and interaction networks suggested that the kinases AMPK (adenosine 5'-monophosphate-activated protein kinase), Akt, and mTOR (mammalian target of rapamycin) mediate βAR signaling, in addition to the well-established pathways mediated by PKA (cyclic adenosine monophosphate-dependent protein kinase) and CaMKII (calcium/calmodulin-dependent protein kinase type II). We found specific regulation of phosphorylation sites on six ion channels and transporters that mediate increased ion fluxes at higher heart rates, and we showed that phosphorylation of one of these, Ser(92) of the potassium channel KV7.1, increased current amplitude. Our data set represents a quantitative analysis of phosphorylated proteins regulated in vivo upon stimulation of seven-transmembrane receptors, and our findings reveal previously unknown phosphorylation sites that regulate myocardial contractility, suggesting new potential targets for the treatment of heart disease and hypertension.


A Liquid Chromatography - Tandem Mass Spectrometry Approach for the Identification of Mebendazole Residue in Pork, Chicken, and Horse.
A confirmatory and quantitative method of liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the determination of mebendazole and its hydrolyzed and reduced metabolites in pork, chicken, and horse muscles was developed and validated in this study. Anthelmintic compounds were extracted with ethyl acetate after sample mixture was made alkaline followed by liquid chromatographic separation using a reversed phase C18 column. Gradient elution was performed with a mobile phase consisting of water containing 10 mM ammonium formate and methanol. This confirmatory method was validated according to EU requirements. Evaluated validation parameters included specificity, accuracy, precision (repeatability and within-laboratory reproducibility), analytical limits (decision limit and detection limit), and applicability. Most parameters were proved to be conforming to the EU requirements. The decision limit (CCα) and detection capability (CCβ) for all analytes ranged from 15.84 to 17.96 μgkg-1. The limit of detection (LOD) and the limit of quantification (LOQ) for all analytes were 0.07 μgkg-1 and 0.2 μgkg-1, respectively. The developed method was successfully applied to monitoring samples collected from the markets in major cities and proven great potential to be used as a regulatory tool to determine mebendazole residues in animal based foods.


PCNA is required for initiation of recombination-associated DNA synthesis by DNA polymerase delta.
Genetic recombination ensures proper chromosome segregation during meiosis and is essential for genome stability and tumor suppression. DNA synthesis after Rad51-mediated DNA strand invasion is a crucial step during recombination. PCNA is known as the processivity clamp for DNA polymerases. Here, we report the surprising observation that PCNA is specifically required to initiate recombination-associated DNA synthesis in the extension of the 3' end of the invading strand in a D loop. We show using a reconstituted system of yeast Rad51, Rad54, RPA, PCNA, RFC, and DNA polymerase delta that loading of PCNA by RFC targets DNA polymerase delta to the D loop formed by Rad51 protein, allowing efficient utilization of the invading 3' end and processive DNA synthesis. We conclude that PCNA has a specific role in the initiation of recombination-associated DNA synthesis and that DNA polymerase delta promotes recombination-associated DNA synthesis.


Prenatal programming of emotion regulation: neonatal reactivity as a differential susceptibility factor moderating the outcome of prenatal cortisol levels.
Hypothalamic-pituitary-adrenal (HPA) activation during pregnancy is linked to dysfunctional behavioral outcomes in the offspring. According to Belsky's differential susceptibility hypothesis, individuals vary regarding their developmental plasticity. Translating the differential susceptibility hypothesis to the field of fetal programming, we hypothesize that infants' temperament, as the constitutionally based reactivity to stimulation, moderates prenatal environmental effects on postnatal emotion regulation. Maternal HPA axis activity and stress-reactivity during pregnancy was estimated, by measuring cortisol concentrations in saliva, collected at 0, 30, 45 and 60 min after awakening and in blood, collected during a laboratory stress test (Trier Social Stress Test), respectively. Newborns reactivity to stimulation was evaluated between postnatal day 10 and 14 using the Neonatal Intensive Care Unit Network Neurobehavioral Scale. Infant's self-quieting-activities, as an indicator of emotion regulation, were evaluated at the age of six months during the still face paradigm. Maternal cortisol reactivity to stress during pregnancy was associated with infant's emotion regulation at the age of six months. Whereas cortisol levels after awakening in mid and late pregnancy were not associated with emotion regulation. Furthermore, regression analyses revealed that in interaction with neonatal reactivity, both, prenatal maternal HPA activity as well as prenatal maternal HPA reactivity to stress predicted emotion regulation. The findings indicate that newborns' reactivity to stimulation is moderating the association between prenatal exposure to maternal glucocorticoids and emotion regulation in infancy. Data suggests that temperamental characteristics of the newborn are a relevant differential susceptibility factor with regard to prenatal effects on emotion regulation.


Polymeric binders suppress gliadin-induced toxicity in the intestinal epithelium.
Celiac disease is a prevalent immune disorder caused by the ingestion of gliadin-containing grains. We investigated the ability of a polymeric binder to reverse the toxic effects induced by gliadin in human intestinal cells and gliadin-sensitive HCD4-DQ8 mice. Gliadin was neutralized by complexation to a linear copolymer of hydroxyethylmethacrylate (HEMA) and sodium 4-styrene sulfonate (SS). The ability of the polymeric binder to abrogate the damaging effect of gliadin on cell-cell contact was investigated in IEC-6, Caco-2/15, and primary cultured differentiated enterocytes. The efficacy of the polymeric binder in preventing gliadin-induced intestinal barrier dysfunction was assessed using gliadin-sensitive HLA-HCD4/DQ8 transgenic mice. Poly(hydroxyethylmethacrylate-co-styrene sulfonate) [P(HEMA-co-SS)] complexed with gliadin in a relatively specific fashion. Intestinal cells exposed to gliadin underwent profound alterations in morphology and cell-cell contacts. These changes were averted by complexing the gliadin with P(HEMA-co-SS). More importantly, the P(HEMA-co-SS) hindered the digestion of gliadin by gastrointestinal enzymes, thus minimizing the formation of immunogenic peptides. Coadministration of P(HEMA-co-SS) with gliadin to HLA-HCD4/DQ8 mice attenuated gliadin-induced changes in the intestinal barrier and reduced intraepithelial lymphocyte and macrophage cell counts. Polymeric binders can prevent in vitro gliadin-induced epithelial toxicity and intestinal barrier dysfunction in HCD4/DQ8 mice. They have a potential role in the treatment of patients with gluten-induced disorders.


Distinct radiation responses after in vitro mtDNA depletion are potentially related to oxidative stress.
Several clinically used drugs are mitotoxic causing mitochondrial DNA (mtDNA) variations, and thereby influence cancer treatment response. We hypothesized that radiation responsiveness will be enhanced in cellular models with decreased mtDNA content, attributed to altered reactive oxygen species (ROS) production and antioxidant capacity. For this purpose BEAS-2B, A549, and 143B cell lines were depleted from their mtDNA (ρ0). Overall survival after irradiation was increased (p<0.001) for BEAS-2B ρ0 cells, while decreased for both tumor ρ0 lines (p<0.05). In agreement, increased residual DNA damage was observed after mtDNA depletion for A549 and 143B cells. Intrinsic radiosensitivity (surviving fraction at 2Gy) was not influenced. We investigated whether ROS levels, oxidative stress and/or antioxidant responses were responsible for altered radiation responses. Baseline ROS formation was similar between BEAS-2B parental and ρ0 cells, while reduced in A549 and 143B ρ0 cells, compared to their parental counterparts. After irradiation, ROS levels significantly increased for all parental cell lines, while levels for ρ0 cells remained unchanged. In order to investigate the presence of oxidative stress upon irradiation reduced glutathione: oxidized glutathione (GSH:GSSG) ratios were determined. Irradiation reduced GSH:GSSG ratios for BEAS-2B parental and 143B ρ0, while for A549 this ratio remained equal. Additionally, changes in antioxidant responses were observed. Our results indicate that mtDNA depletion results in varying radiation responses potentially involving variations in cellular ROS and antioxidant defence mechanisms. We therefore suggest when mitotoxic drugs are combined with radiation, in particular at high dose per fraction, the effect of these drugs on mtDNA copy number should be explored.


Clinical trial design in fracture-healing research: meeting the challenge.
The rapidly growing global burden of road-traffic accidents and fragility fractures makes research on fracture repair a vital component of the efforts needed to face this rising public health challenge. The focus on developing new and innovative strategies to treat fractures is easily justifiable given the potential human benefit from such discoveries. Randomized trials remain the standard to which the evaluation of novel fracture-healing therapies must continue to evolve. This article reviews randomized controlled trials in the context of the hierarchy of evidence, special challenges to their conduct in the setting of surgical research, and lessons learned from fracture-healing trials published to date. Suggestions are made regarding the optimal characteristics of fracture models and logistical consideration for ensuring the success of future trials. The realization that surgical trials have unique methodological and interpretative challenges has fueled a renewed vision of the design and execution of large, definitive clinical trials with a meaningful impact on the lives of patients.


Clinical nursing leaders' perceptions of nutrition quality indicators in Swedish stroke wards: a national survey.
To describe nursing leaders' perceptions of nutrition quality in Swedish stroke wards. A high risk of undernutrition places great demand on nutritional care in stroke wards. Evidence-based guidelines exist, but healthcare professionals have reported low interest in nutritional care. The Donabedian framework of structure, process and outcome is recommended to monitor and improve nutrition quality. Using a descriptive cross-sectional design, a web-based questionnaire regarding nutritional care quality was delivered to eligible participants. Most clinical nursing leaders reported structure indicators, e.g. access to dieticians. Among process indicators, regular assessment of patients' swallowing was most frequently reported in comprehensive stroke wards compared with other stroke wards. Use of outcomes to monitor nutrition quality was not routine. Wards using standard care plans showed significantly better results. Using the structure, process and outcome framework to examine nutrition quality, quality-improvement needs became visible. To provide high-quality nutrition, all three structure, process and outcome components must be addressed. The use of care pathways, standard care plans, the Senior Alert registry, as well as systematic use of outcome measures could improve nutrition quality. To assist clinical nursing leaders in managing all aspects of quality, structure, process and outcome can be a valuable framework.


Therapeutic gene silencing strategies for polyglutamine disorders.
Dominantly inherited polyglutamine disorders are chronic neurodegenerative diseases therapeutically amenable to gene-specific silencing strategies. Several compelling nucleic acid-based approaches have recently been developed to block the expression of mutant proteins and prevent toxic neurodegenerative sequelae. With such approaches, avoiding potential side effects caused by the concomitant ablation of the normal protein is an important objective. Therefore, allele-specific gene silencing is highly desirable; however, retaining wild type function is complex given that the common CAG mutation cannot be directly targeted, and might not be necessary or justifiable in all cases. Insights from polyglutamine gene function studies and the further development of allele-specific and other gene silencing methodologies will be important to determine the optimal therapeutic strategy for each polyglutamine disorder.


Anatomic Evaluation of the Ophthalmic Artery in Optic Canal Decompression: A Cadaver Study of 20 Optic Canals.
A relationship was shown in this study between the optic canal and the ophthalmic artery by cadaver study. It is intended that the anatomical and histological values which we obtained can be used as a guide in surgery MATERIAL and METHODS: A surgical anatomical evaluation was made of twenty optic canals in ten cadavers fixed in 10% formaldehyde. These were evaluated together with measurements of the ophthalmic artery and histological sections of the surrounding structure. The ophthalmic artery separated from the carotid at different positions. In our material, eight (40%) left the carotid from the upper internal part, six (30%) from the front internal part, four (20%) from the upper central part, and two (10%) emerged at the end of the cavernous segment of the middle of the carotid at a steep angle. In none of the material did the ophthalmic artery originate from any other vascular structure than the carotid. Whatever position the ophthalmic artery was in within the canal on entry, it followed the outer walls of the canal and left the canal in the lower external section of the optic nerve. In the literature, work on this area has been limited to examining the anatomical values and variations in the optic canal. The results in the present study have been obtained by combining the data with surgical anatomy. This is a method of transcranial decompression of the optic canal which is safe for the vascular structures in and around the optic canal providing certain points are kept in mind.


Manganese speciation of laboratory-generated welding fumes.
The objective of this laboratory study was to identify and measure manganese (Mn) fractions in chamber-generated welding fumes (WF) and to evaluate and compare the results from a sequential extraction procedure for Mn fractions with that of an acid digestion procedure for measurement of total, elemental Mn. To prepare Mn-containing particulate matter from representative welding processes, a welding system was operated in short circuit gas metal arc welding (GMAW) mode using both stainless steel (SS) and mild carbon steel (MCS) and also with flux cored arc welding (FCAW) and shielded metal arc welding (SMAW) using MCS. Generated WF samples were collected onto polycarbonate filters before homogenization, weighing and storage in scintillation vials. The extraction procedure consisted of four sequential steps to measure various Mn fractions based upon selective solubility: (1) soluble Mn dissolved in 0.01 M ammonium acetate; (2) Mn (0,II) dissolved in 25 % (v/v) acetic acid; (3) Mn (III,IV) dissolved in 0.5% (w/v) hydroxylamine hydrochloride in 25% (v/v) acetic acid; and (4) insoluble Mn extracted with concentrated hydrochloric and nitric acids. After sample treatment, the four fractions were analyzed for Mn by inductively coupled plasma-atomic emission spectroscopy (ICP-AES). WF from GMAW and FCAW showed similar distributions of Mn species, with the largest concentrations of Mn detected in the Mn (0,II) and insoluble Mn fractions. On the other hand, the majority of the Mn content of SMAW fume was detected as Mn (III,IV). Although the concentration of Mn measured from summation of the four sequential steps was statistically significantly different from that measured from the hot block dissolution method for total Mn, the difference is small enough to be of no practical importance for industrial hygiene air samples, and either method may be used for Mn measurement. The sequential extraction method provides valuable information about the oxidation state of Mn in samples and allows for comparison to results from previous work and from total Mn dissolution methods.


Recurrent partial hydatidiform mole: a report of a patient with three consecutive molar pregnancies.
Hydatidiform mole (HM) is the most common form of gestational trophoblastic neoplasia and is characterized by atypical hyperplastic trophoblasts and hydropic villi. Recurrence of HM is extremely rare. Here, we report the case of a patient with three consecutive partial HMs without normal pregnancy. A 28-year-old woman with gravida 3, para 0, was referred to our hospital with a diagnosis of an invasive mole in December 2003. She had three consecutive molar pregnancies in 2000, 2001, and 2003. All three molar pregnancies were evacuated by suction curettage and the patient was followed by serial beta-human chorionic gonadotropin levels. All three moles were histologically confirmed as partial moles. In the first two molar events no additional treatment after evacuation was required, but in the last event, the beta-human chorionic gonadotropin levels increased and an invasive mole was suspected. Diagnostic workup ruled out an invasive mole and choriocarcinoma. Karyotypic analysis of the patient and her husband was normal. The patient required chemotherapy for treatment of persistent disease. Recurrent partial HM is a very rare clinical disorder. Repetitive molar pregnancy is not an indication for chemotherapy, but persistent disease does require chemotherapy.


Detection of blaCTX-M Extended Spectrum Beta-lactamase Producing Salmonella enterica Serotype Typhi in a Tertiary Care Centre.
Infections caused by Salmonella are an important public health threat in tropical and subtropical countries. Due to the emergence of resistance to ampicillin, chloramphenicol and trimethoprim/sulfamethoxazole (multidrug resistant salmonellae) in the late 1980s, fluoroquinolones and extended spectrum cephalosporins became the drugs of choice. Resistance to cefotaxime and ceftriaxone due to the production of Extended Spectrum Beta-Lactamase (ESBL) and reduced susceptibility to ciprofloxacin have emerged resulting in treatment failure. The Cefotaximase (CTX-M) type ESBLs are the most widespread beta lactamase among Enterobacteriaceae including salmonellae. To detect the presence of blaCTX-M in salmonellae causing human infections. Detection of qnr genes to identify the coexistence of blaCTX-M and qnr gene. The study included 103 consecutive, non-repetitive salmonellae isolated from clinical specimens obtained from July 2015- June 2016 which were identified up to species level by conventional/automated methods. Susceptibility to various classes of antimicrobial agents was determined by disc diffusion method. Minimum Inhibitory Concentration (MIC) to cefotaxime and ceftriaxone was determined by agar dilution method. The results were interpreted in accordance with Clinical & Laboratory Standard Institute (CLSI) (guidelines 2015. Detection of the ESBL phenotype was performed by the combined disk method. Polymerase Chain Reaction (PCR) amplification of all isolates was performed using group specific primers to characterize the presence of blaCTX-M, qnrA, qnrB and qnrS. Of the 103 study isolates two isolates of Salmonella typhi were resistant to cefotaxime and ceftriaxone and had a MIC of 128μg/ml. PCR amplification and sequencing detected the presence of blaCTX-M-15 in these two isolates. These two isolates exhibited resistance to ciprofloxacin in vitro but qnr gene was not detected in these isolates. Resistance to third generation cephalosporins among salmonellae is a cause for concern as it may lead to treatment failure. It is imperative to continuously monitor the susceptibility pattern as enteric fever is endemic in India.


Comparison of unsupervised feature selection methods for high-dimensional regression problems in prediction of peptide binding affinity.
Identification of robust set of predictive features is one of the most important steps in the construction of clustering, classification and regression models from many thousands of features. Although there have been various attempts to select predictive feature sets from high-dimensional data sets in classification and clustering, there is a limited attempt to study it in regression problems. As semi-supervised and supervised feature selection methods tend to identify noisy features in addition to discriminative variables, unsupervised feature selection methods (USFSMs) are generally regarded as more unbiased approach. Therefore, in this study, along with the entire feature set, four different USFSMs are considered for the quantitative prediction of peptide binding affinities being one of the most challenging post-genome regression problems of very high-dimension comparted to extremely small size of samples. As USFSMs are independent of any predictive method, support vector regression was then utilised to assess the quality of prediction. Given three different peptide binding affinity data sets, the results suggest that the regression performance of USFMs depends generally on the datasets. There is no particular method that yields the best performance compared to their performances in the classification problems. However, a closer investigation of the results appears to suggest that the spectral regression-based approach yields slightly better performance. To the best of our knowledge, this is the first study that presents comprehensive comparison of USFSMs in such high-dimensional regression problems, particularly in biological domain with an application in the prediction of peptide binding affinity, and provides a number of practical suggestions for future practitioners.


Assessing risk screening methods of malnutrition in geriatric patients: Mini Nutritional Assessment (MNA) versus Geriatric Nutritional Risk Index (GNRI).
Elderly subjects are considered a vulnerable group and they have more risk of nutritional problems. The risk of malnutrition increases in hospitalized geriatric patients. To compare the correlation between MNA and GNRI with anthropometric, biochemical and Barthel Index in hospitalized geriatric patients and to test the concordance between MNA and GNRI and between Mini Nutritional Assessment Short Form (MNA-SF) and MNA. It was a cross-sectional study on a sample of 40 hospitalized geriatric patients. For determination nutritional status we used MNA and GNRI; we evaluated the correlation between this both test with biochemical and anthropometric parameters and functional questionnaires. We used Pearson's simple correlation model, oneway ANOVA and multiple logistic regression to evaluate the relationship between MNA and GNRI. According to MNA, 17 patients (42.5%) were malnourished and according to GNRI, 13 patients (32.5%) had high risk of nutritional complications. The concordance of MNA and GNRI was 39% and between MNA-SF and MNA was 81%. The most significant differences were detected in weight, BMI, arm and calf circumference and weight loss parameters. Barthel index was significantly different in both tests. The MNA and GRNI had significant correlations with albumin, total protein, transferring, arm and calf circumference, weight loss and BMI parameters. In conclusion, it would be reasonable to use GRNI in cases where MNA is not applicable, or even use GRNI as a complement to MNA in hospitalized elderly patients. There is no reason why they should be deemed incompatible, and patients could benefit from more effective nutritional intervention.


Potential of conservation agriculture modules for energy conservation and sustainability of rice-based production systems of Indo-Gangetic Plain region.
Rice-based cropping systems are the most energy-intensive production systems in South Asia. Sustainability of the rice-based cropping systems is nowadays questioned with declining natural resource base, soil degradation, environmental pollution, and declining factor productivity. As a consequence, the search for energy and resource conservation agro-techniques is increasing for sustainable and cleaner production. Conservation agriculture (CA) practices have been recommended for resource conservation, soil health restoration and sustaining crop productivity. The present study aimed to assess the different CA modules in rice-based cropping systems for energy conservation, energy productivity, and to define energy-economic relations. A field experiment consisted of four different tillage-based crop establishment practices (puddled-transplanted rice followed by (fb) conventional-till maize/wheat (CTTPR-CT), non-puddled transplanted rice fb zero-till maize/wheat (NPTPR-ZT), zero-till transplanted rice fb zero-till maize/wheat (ZTTPR-ZT), zero-till direct-seeded rice fb zero-till maize/wheat (ZTDSR-ZT)), with two residue management treatments (residue removal, residue retention) in rice-wheat and rice-maize rotations were evaluated for energy budgeting and energy-economic relations. Conservation-tillage treatments (NPTPR-ZT, ZTTPR-ZT, and ZTDSR-ZT) reduced the energy requirements over conventional tillage treatments, with the greater reduction in ZTTPR-ZT and ZTDSR-ZT treatments. Savings of energy in conservation-tillage treatments were attributed to reduced energy use in land preparation (69-100%) and irrigation (23-27%), which consumed a large amount of fuel energy. Conservation-tillage treatments increased grain and straw/stover yields of crops, eventually increased the output energy (6-16%), net energy (14-26%), energy ratio (25-33%), and energy productivity (23-34%) as compared with CTTPR-CT. For these energy parameters, the treatment order was ZTDSR-ZT ≥ ZTTPR-ZT > NPTPR-ZT > CTTPR-CT (p < 0.05). Crop residue retention reduced net energy, energy ratio, and energy productivity when compared with residue removal. Our results of energy-economic relations favored the "conservative hypothesis," which envisages that energy and monetary investments are not essentially the determinants of crop productivity. Thus, zero tillage-based crop establishments (ZTTPR-ZT, ZTDSR-ZT) in rice-based production systems could be the sustainable alternative to conventional tillage-based agriculture (CTTPR-CT) as they conserved non-renewable energy sources, reduced water requirement, and increased crop productivity.


Toxoplasma-proximal and distal control by GBPs in human macrophages.
Human guanylate binding proteins (GBPs) are key players of interferon-gamma (IFNγ)-induced cell intrinsic defense mechanisms targeting intracellular pathogens. In this study, we combine the well-established Toxoplasmagondii infection model with three in vitro macrophage culture systems to delineate the contribution of individual GBP family members to control this apicomplexan parasite. Use of high-throughput imaging assays and genome engineering allowed us to define a role for GBP1, 2 and 5 in parasite infection control. While GBP1 performs a pathogen-proximal, parasiticidal and growth-restricting function through accumulation at the parasitophorous vacuole of intracellular Toxoplasma, GBP2 and GBP5 perform a pathogen-distal, growth-restricting role. We further find that mutants of the GTPase or isoprenylation site of GBP1/2/5 affect their normal function in Toxoplasma control by leading to mis-localization of the proteins.


Cancer Chemotherapy in Early Life Significantly Alters the Maturation of Pain Processing.
Advances in pediatric cancer treatment have led to a ten year survival rate greater than 75%. Platinum-based chemotherapies (e.g. cisplatin) induce peripheral sensory neuropathy in adult and pediatric cancer patients. The period from birth through to adulthood represents a period of maturation within nociceptive systems. Here we investigated how cisplatin impacts upon postnatal maturation of nociceptive systems. Neonatal Wistar rats (Postnatal day (P) 7) were injected (i.p.) daily with either vehicle (PBS) or cisplatin (1mg/kg) for five consecutive days. Neither group developed mechanical or thermal hypersensitivity immediately during or after treatment. At P22 the cisplatin group developed mechanical (P < 0.05) and thermal (P < 0.0001) hypersensitivity versus vehicle group. Total DRG or dorsal horn neuronal number did not differ at P45, however there was an increase in intraepidermal nerve fiber density in cisplatin-treated animals at this age. The percentage of IB4+ve, CGRP+ve and NF200+ve DRG neurons was not different between groups at P45. There was an increase in TrkA+ve DRG neurons in the cisplatin group at P45, in addition to increased TrkA, NF200 and vGLUT2 immunoreactivity in the lumbar dorsal horn versus controls. These data highlight the impact pediatric cancer chemotherapy has upon the maturation of pain pathways and later life pain experience.


Where Is the Opioid Use Epidemic in Mexico? A Cautionary Tale for Policymakers South of the US-Mexico Border.
In North America, opioid use and its harms have increased in the United States and Canada over the past 2 decades. However, Mexico has yet to document patterns suggesting a higher level of opioid use or attendant harms.Historically, Mexico has been a country with low-level use of opioids, although heroin use has been documented. Low-level opioid use is likely attributable to structural, cultural, and individual factors. However, a range of dynamic factors may be converging to increase the use of opioids: legislative changes to opioid prescribing, national health insurance coverage of opioids, pressure from the pharmaceutical industry, changing demographics and disease burden, forced migration and its trauma, and an increase in the production and trafficking of heroin. In addition, harm-reduction services are scarce.Mexico may transition from a country of low opioid use to high opioid use but has the opportunity to respond effectively through a combination of targeted public health surveillance of high-risk groups, preparation of appropriate infrastructure to support evidence-based treatment, and interventions and policies to avoid a widespread opioid use epidemic.


Evolution of diverse antiviral CD8+ T cell populations after murine cytomegalovirus infection.
Cytomegalovirus (CMV) is a major human pathogen normally controlled by cellular immune responses. The infection can be modeled in the mouse using murine CMV (MCMV). During the latent phase of infection, two different patterns of CD8(+) T cell responses have been observed: some specificities show increasing frequencies over time ("memory inflation"), while others, which are present acutely, are barely detectable at later time points. This distinction is independent of initial immunodominance. We analyzed the extent to which such responses differ functionally and tracked both their population distribution and their evolution over time. We observed two clear patterns of memory development that diverged early after infection. Acutely, CD8(+) T cells directed against all epitopes showed similar activation, phenotype and distribution. Thereafter, one set of responses ("inflationary") increased in frequency over time, was found in high numbers in non-lymphoid organs and was associated with an activated (CD28(low) CD27(low)CD122(low)) phenotype. In contrast, CD8(+) T cells responses specific for other MCMV epitopes ("non-inflationary") showed a slow reversion to a classical "central" memory phenotype without enrichment in non-lymphoid organs. A simple model to describe the equilibrium state in MCMV is presented, which may point to previously unexplored antiviral populations present after human CMV infection.


Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline CDH1 sequence variants.
The variant curation guidelines published in 2015 by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) provided the genetics community with a framework to assess variant pathogenicity; however, these rules are not gene specific. Germline pathogenic variants in the CDH1 gene cause hereditary diffuse gastric cancer and lobular breast cancer, a clinically challenging cancer predisposition syndrome that often requires a multidisciplinary team of experts to be properly managed. Given this challenge, the Clinical Genome Resource (ClinGen) Hereditary Cancer Domain prioritized the development of the CDH1 variant curation expert panel (VCEP) to develop and implement rules for CDH1 variant classifications. Here, we describe the CDH1 specifications of the ACMG/AMP guidelines, which were developed and validated after a systematic evaluation of variants obtained from a cohort of clinical laboratory data encompassing ∼827,000 CDH1 sequenced alleles. Comparing previously reported germline variants that were classified using the 2015 ACMG/AMP guidelines to the CDH1 VCEP recommendations resulted in reduced variants of uncertain significance and facilitated resolution of variants with conflicted assertions in ClinVar. The ClinGen CDH1 VCEP recommends the use of these CDH1-specific guidelines for the assessment and classification of variants identified in this clinically actionable gene.


Mary Broadfoot Walker: 83 years since a historical discovery.
Mary Broadfoot Walker was a Scottish physician who, in 1935, described in great detail the effect of an anticholinesterase drug (physostigmine) on the signs and symptoms of myasthenia gravis. An original five-minutes movie is available online and the skepticism of her contemporary British medical doctors is understandable when the drastic effect of the treatment is shown in this movie. What Mary Walker taught us, more than eight decades ago, about myasthenia gravis continues to be the basis of a pharmacological diagnostic test and treatment of this disease.


The light of life: evidence that the sun modulates human lifespan.
This paper describes the effects of radiation, probably ultraviolet radiation (UVR), on the human genome at peaks of solar cycles. This phenomenon was not previously reported because peak cycle lifespan had not been separated from non-peak lifespan. This paper reinforces the findings of others regarding the seasonality of various diseases and that there are factors occurring early in utero that increase susceptibility to diseases later in life. The authors use the vital statistics of 320,247 Maine citizens over a 29-year period to show that those born in 3-year peaks of 11-year solar cycles live an average of 1.5 years (CL 1.3-1.7) less than those born in non-peak years. Males are more sensitive than females to this phenomenon, which is statistically demonstrable well into adult life, showing the effect of probable UVR on the early human embryo despite superimposed adult lifetime hazards. The authors also show that changes in seasonal light modulate lifespan differently in males and females and that genome and environment must be tightly interactive early after conception. Published literature supports the hypothesis that UVR suppresses the maternal immune system by producing cytokines in circulating lymphocytes that probably affect the fetal genome. The intermittent and incompletely predictable solar cycles periodically stress the genomes of all life producing genetic changes which may be harmful or adaptive. The evidence presented in this study indicates that solar cycles, particularly the most irradiant which have occurred over the past 65 years, are fundamental engines of evolution, even underlying natural selection, and we bear their marks even to the end of our lives. Future researchers must further define the pathogenesis of solar radiation on early embryonic development to possibly minimize a predisposition to diseases at their origin. This study explores the relationship of season of birth and human lifespan particularly in reference to the intensity of solar radiation that occurs in 11-year cycles. The birth years were obtained and lifespan calculated for 320,247 Maine citizens over a 29-year period. Those who were born at 3-year peaks of 11-year solar cycles were separated from those born in non-peak years. Using SAS statistical tools, a randomization technique was used to compare the lifespan between peak and non-peak years to eliminate selection bias, cohort effects, and confounding variables. Those born in peaks of solar cycles lived an average of 1.5 years (CL 1.3-1.7) less than those born in non-peak years. Males were more sensitive to this phenomenon than females. A similar analysis was performed for month of birth and the pattern of peak to non-peak lifespan difference was nearly identical to the pattern of seasonal variation in light. Lifespan variation appears to be modulated by seasonal light confirming that genome and environment are closely linked very early after conception. Although the precise pathogenesis is still unknown, the phenomenon must involve radiant energy, probably ultraviolet light, possibly affecting the maternal immune system through the dermis. This study also supports the reliability theory of aging which suggests that events affecting the genome early after conception are important in the expression of adult diseases.


Monkey and human face perception: inversion effects for human faces but not for monkey faces or scenes.
Three rhesus monkeys and two groups of 10 human subjects judged upright or inverted pictures as same or different. The pictures were black and white pairs of human faces, monkey faces, or scenes. The monkeys were trained with sets of 50 pictures and were tested with other sets of 36 pictures from each category. The groups of 10 human subjects were tested with the same pictures used to test monkeys. Both monkeys and humans showed large performance decrements to inverted human faces relative to upright human faces but neither species showed inversion effects for monkey faces or scenes. A second test with both monkeys and humans showed the same pattern of results with a different set of human-face pictures that varied more in sex (female as well as male), facial hair, eyeglasses, haircut, view angle, and background than those of the first test. The results indicate similar face-processing mechanisms in monkeys and humans despite experiential and evolutionary differences.


Learning loss due to school closures during the COVID-19 pandemic.
Suspension of face-to-face instruction in schools during the COVID-19 pandemic has led to concerns about consequences for students' learning. So far, data to study this question have been limited. Here we evaluate the effect of school closures on primary school performance using exceptionally rich data from The Netherlands (n ≈ 350,000). We use the fact that national examinations took place before and after lockdown and compare progress during this period to the same period in the 3 previous years. The Netherlands underwent only a relatively short lockdown (8 wk) and features an equitable system of school funding and the world's highest rate of broadband access. Still, our results reveal a learning loss of about 3 percentile points or 0.08 standard deviations. The effect is equivalent to one-fifth of a school year, the same period that schools remained closed. Losses are up to 60% larger among students from less-educated homes, confirming worries about the uneven toll of the pandemic on children and families. Investigating mechanisms, we find that most of the effect reflects the cumulative impact of knowledge learned rather than transitory influences on the day of testing. Results remain robust when balancing on the estimated propensity of treatment and using maximum-entropy weights or with fixed-effects specifications that compare students within the same school and family. The findings imply that students made little or no progress while learning from home and suggest losses even larger in countries with weaker infrastructure or longer school closures.


Comparing results from vestibular caloric stimulation and vHIT from a specialised outpatient clinic.
Until recently, vestibular caloric stimulation was the only objective diagnostic method for isolating the function of the lateral semi-circular canals responsible for maintaining balance. Since 2014, the Video Head Impulse Test (vHIT) has been applied in the Czech Republic to investigate the function of all semi-circular canals. Studies conducted so far have shown that the results of these two methods do not often agree. The aim of this study was to compare the results of vestibular caloric stimulation and vHIT in a cohort of patients with peripheral vestibular syndrome at a specialized outpatient clinic. The study lasted from July 2016 to August 2017 and included patients with unilateral peripheral vestibular syndrome (n=32; 24 females and 8 males, mean age 49.4 years) and a positive result with either vestibular caloric stimulation or vHIT. 90% of the patients had a positive vestibular caloric stimulation result, while the vHIT was positive only in 50% of the patients. Both methods were positive in 13 subjects, vestibular caloric stimulation was positive and vHIT was negative in 16 subjects and in 3 cases vestibular caloric stimulation was negative and vHIT was positive. Based on these numbers, both methods concur in 45% of the cases. In 13 patients, apart from lateral canal disorders, vHIT revealed disorders in one of the vertical canals - the front right in 4, the rear right in 2, the front left in 3 and the rear left in 4. When sorted into subgroups of the "TiTrATE" diagnostic algorithm based on the time course and triggering factor, vHIT was found to be positive for acute spontaneous vertigo in 62.5% of cases. vHIT was negative for 70% of chronic and spontaneous episodic complaints. The diagnosis of peripheral vestibular disorders should take the pathophysiological basis of the disease into account, as this can differ in peripheral disorders. This could then explain the discrepancy between the results of the two methods. The time course of the disease can be a predictor of the vHIT outcome. Localizing the impaired function of particular semi-circular canals using vHIT can inform selective vestibular rehabilitation.


Development of motor speed and associated movements from 5 to 18 years.
To study the development of motor speed and associated movements in participants aged 5 to 18 years for age, sex, and laterality. Ten motor tasks of the Zurich Neuromotor Assessment (repetitive and alternating movements of hands and feet, repetitive and sequential finger movements, the pegboard, static and dynamic balance, diadochokinesis) were administered to 593 right-handed participants (286 males, 307 females). A strong improvement with age was observed in motor speed from age 5 to 10, followed by a levelling-off between 12 and 18 years. Simple tasks and the pegboard matured early and complex tasks later. Simple tasks showed no associated movements beyond early childhood; in complex tasks associated movements persisted until early adulthood. The two sexes differed only marginally in speed, but markedly in associated movements. A significant laterality (p<0.001) in speed was found for all tasks except for static balance; the pegboard was most lateralized, and sequential finger movements least. Associated movements were lateralized only for a few complex tasks. We also noted a substantial interindividual variability. Motor speed and associated movements improve strongly in childhood, weakly in adolescence, and are both of developmental relevance. Because they correlate weakly, they provide complementary information.


Production and Comprehension of Pantomimes Used to Depict Objects.
Pantomime, gesture in absence of speech, has no conventional meaning. Nevertheless, individuals seem to be able to produce pantomimes and derive meaning from pantomimes. A number of studies has addressed the use of co-speech gesture, but little is known on pantomime. Therefore, the question of how people construct and understand pantomimes arises in gesture research. To determine how people use pantomimes, we asked participants to depict a set of objects using pantomimes only. We annotated what representation techniques people produced. Furthermore, using judgment tasks, we assessed the pantomimes' comprehensibility. Analyses showed that similar techniques were used to depict objects across individuals. Objects with a default depiction method were better comprehended than objects for which there was no such default. More specifically, tools and objects depicted using a handling technique were better understood. The open-answer experiment showed low interpretation accuracy. Conversely, the forced-choice experiment showed ceiling effects. These results suggest that across individuals, similar strategies are deployed to produce pantomime, with the handling technique as the apparent preference. This might indicate that the production of pantomimes is based on mental representations which are intrinsically similar. Furthermore, pantomime conveys semantically rich, but ambiguous, information, and its interpretation is much dependent on context. This pantomime database is available online: https://dataverse.nl/dataset.xhtml?persistentId=hdl:10411/QZHO6M. This can be used as a baseline with which we can compare clinical groups.


The effects of proteasome inhibitors on bone remodeling in multiple myeloma.
Bone disease is a characteristic feature of multiple myeloma, a malignant plasma cell dyscrasia. In patients with multiple myeloma, the normal process of bone remodeling is dysregulated by aberrant bone marrow plasma cells, resulting in increased bone resorption, prevention of new bone formation, and consequent bone destruction. The ubiquitin-proteasome system, which is hyperactive in patients with multiple myeloma, controls the catabolism of several proteins that regulate bone remodeling. Clinical studies have reported that treatment with the first-in-class proteasome inhibitor bortezomib reduces bone resorption and increases bone formation and bone mineral density in patients with multiple myeloma. Since the introduction of bortezomib in 2003, several next-generation proteasome inhibitors have also been used clinically, including carfilzomib, oprozomib, ixazomib, and delanzomib. This review summarizes the available preclinical and clinical evidence regarding the effect of proteasome inhibitors on bone remodeling in multiple myeloma.


Genome duplications of early vertebrates as a possible chronicle of the evolutionary history of the neural crest.
It is now accepted that ancestral vertebrates underwent two rounds of genome duplication. Here we test the possible utility of these genome duplication events as a reference time for the evolutionary history of vertebrates, by tracing the molecular evolutionary history of the genes involved in vertebrate neural crest development. For most transcription factors that are involved in neural crest specification, more than two paralogs are involved in that process. These were likely involved in the specification of the neural crest before the genome duplications occurred in ancestral vertebrates, although FoxD3 may have acquired that role after the genome duplications. By contrast, the epithelial-mesenchymal transition of neural crest cells is controlled by genes that evolved after the genome duplications, such as cadherin6, cadherin7, cadherin11, and rhoB. This suggests that primitive neural crest cells control their delamination by using a small or distinct set of cell adhesion molecules. Alternatively, these observations suggest that delamination of the neural crest evolved after the genome duplications. In that case, the neural crest might have evolved in sequential steps; the specification of the neural crest occurred before the genome duplications, and the neural crest acquired a new cell migration property after the genome duplications.


A Molecular Survey of Ulva (Chlorophyta) in Temperate Australia Reveals Enhanced Levels of Cosmopolitanism.
The green algal genus Ulva includes a speciose group of marine macroalgae inhabiting shallow seas worldwide. Although algal blooms in Asia highlight the opportunistic nature of several "nuisance" species, recent research clearly reveals important positive benefits of Ulva. Applied research requires accurate, reliable, and rapid identification, however, identification of Ulva spp. has met with con-siderable difficulty. Consequently, many have turned to molecular markers to aid in taxonomy. Previous studies of plants and algae have relied heavily on ITS and rbcL. Recently, tufA has been presented as a suitable barcoding gene to facilitate species-level identification of green macroalgae and it is used here to explore the diversity of Ulva spp. in temperate Australia. Ninety Ulva specimens collected from 38 sites across five states were sequenced for this gene region with exemplars from each genetic group also sequenced for rbcL to test for congruence. Collections of Australian Ulva spp. were compared to samples from Asia and North America and exhibited trends consistent with recent studies in terms of species relationships. Results support an overwhelmingly cosmopolitan flora in temperate Australia that contrasts with other Australasian surveys of Ulva that report a greater number of endemics and new species. Four new records, as well as numerous range extensions for taxa already known from the country, are documented. Evidence for three nonindigenous Ulva species in temperate Australia is discussed.


Kangfuxin promotes apoptosis of gastric cancer cells through activating ER‑stress and autophagy.
Gastric cancer is a leading cause of cancer‑associated mortality worldwide. In studies on the mechanisms of antigastric cancer drugs, autophagy and endoplasmic reticulum (ER) stress have been demonstrated to serve an active role in gastric cancer. The organic extract of Periplaneta americana (also termed American Cockroach), which is named Kangfuxin (KFX) in China, has been used clinically as a traditional Chinese medicine against disorders, including stomach bleeding, gastric ulcers, tuberculosis, burns and trauma. However, the role of KFX and its mechanism in gastric cancer remains to be elucidated. The present study aimed to determine the effects of KFX in vitro against cultured the human carcinoma SGC‑7901 cell line, and to explore the potential mechanism of the anticancer effects of KFX in gastric cancer. SGC‑7901 cells were treated with different concentrations of KFX for varying amounts of time. As a result, KFX treatment decreased the ratio of apoptosis regulators Bcl‑2/Bax, activated ER stress and induced significant apoptosis in SGC‑7901 cells. Furthermore, KFX was able to restore the ER stress activation blocked by 4‑phenylbutyrate. In addition, KFX activated autophagy in SGC‑7901 cells. These results demonstrated that ER stress, autophagy and the apoptosis‑inducing effects of KFX in SGC‑7901 cells may achieve promising anticancer effects in numerous other types of cancer. In particular, ER stress may serve an essential role in KFX‑induced anticancer effects on gastric carcinoma and a secondary role in autophagy.