[Interleukin-2 based immunotherapy of cancer].
Interleukin-2 (IL-2) is produced by activated T-helper lymphocytes and stimulates both the antigen-specific and the non-specific immune defence. In vitro, IL-2 activated peripheral blood lymphocytes (LAK-cells) can lyse a broad spectrum of both NK-sensitive and NK-resistant tumour cell lines and IL-2 expanded tumour infiltrating lymphocytes (TIL) are, in certain cases, selectively able to lyse autologous tumour cells. In vivo, the mechanism behind the anti-tumour effect of IL-2 is unknown. Recombinant IL-2 has been available since 1984 and world-wide more than 3,000 patients have been treated. IL-2 has most frequently been administered in combination with either in vitro activated autologous effector cells and/or other cytokines or anti-cancer chemotherapeutic agents. The generation of autologous effector cells for patient treatment demands considerable resources and their contribution to the clinical effect is uncertain. The best responding tumour-types have been renal cell carcinoma and malignant melanoma with response rates up to 35% and 24%, respectively. IL-2 therapy is associated with considerable side-effects. The most serious are due to the development of a "capillary leak syndrome" with peripheral vasodilation and increased vascular permeability resulting in hypotension, oedema and organ-dysfunction. The majority of these side-effects are reversible with improvement within hours after terminating the IL-2 administration. It is concluded that IL-2 therapy is still experimental and it should be limited to treatment according to protocols in highly specialized clinical departments in a close cooperation with immunological laboratories.


[Research progress on the effect of chemical environmental pollutant exposure on mitochondrial DNA damage].
People are exposed to a variety of different harmful factors through their daily life, diet, and occupational environment, and exposure to these dangerous factors results in varying degrees of damage to the organism. The damage to mitochondria from exposure to chemical harmful factors in environment is of increasing concern. The integrity of the mitochondrial genome is critical for mitochondrial function and cellular homeostasis, and mitochondria are susceptible to damage and mitochondrial dysfunction when stimulated by various harmful chemical environmental factors. It has been shown that exposure to a variety of chemical pollutants can produce varying degrees of damage to mitochondria, and these pollutants may cause mitochondrial structural and functional disorders by inducing oxidative stress, including impaired electron respiratory chain transmission, alterations in mitochondrial membrane potential, mitochondrial DNA mutations/deletions, and mitochondrial DNA copy number variation. Mitochondrial damage can further lead to abnormal cell function, apoptosis, and death, which induce related diseases. Therefore, this paper provides a review of the role of chemical factor exposure in the environment, such as heavy metals, on mitochondrial damage.


Absence of SARS-CoV-2 in the air and on the surfaces within the school environment.
To the best of our knowledge to date there are no scientific studies specifically investigating whether the SARS-CoV-2 virus is present in the air or on the various surfaces in the school environment. The aim of this study was to determine if SARS-CoV-2 is present on various high touch surfaces and in the air across the elementary, middle and high schools in the Chester County of Pennsylvania, USA. One hundred and fifty surface swab samples and 45 air samples were analysed for the presence of the virus. All the samples tested were negative for the presence of SARS-CoV-2. The results indicate that the spread of the virus through contact and through air in the school buildings across the USA is highly unlikely.


B cells as effectors and regulators of sex-biased arthritis.
B cells have been implicated both with pathogenic as well as protective capabilities in induction and regulation of autoimmune diseases. Rheumatoid arthritis (RA) is an autoimmune disease that occurs more often in women than men. A significant role of B cells as antibody producing and antigen-presenting cells has been demonstrated in RA. Predisposition to RA is associated with the presence of certain HLA class II alleles that share sequences with DRB1*0401. To determine the role of HLA genes and B cells in vivo, we have generated transgenic mice carrying HLA genes, DRB1*0401 and DQ8, known to be associated with susceptibility to RA. Humanized mice can be induced to develop arthritis that mimics human disease in clinical, histopathological and sex bias. Effect of hormones on immune cells and their function has been described in humans and mice and has been suggested to be the major reason for female bias of autoimmune diseases. An immune response to an antigen requires presentation by HLA molecules thus suggesting a critical role of MHC in combination with sex hormones in susceptibility to develop rheumatoid arthritis. Based on our observations, we hypothesize that modulation of B cells by estrogen, presentation of modified antigens by DR4 and production of antigen-specific B cell modulating cytokines leads to autoreactivity in females. These data suggest that considering patient's sex may be crucial in selecting the optimal treatment strategy. Humanized mice expressing RA susceptible and resistant haplotype provide a means to investigate mechanism sex-bias of arthritis and future strategies for therapy.


Historical criteria that distinguish syncope from seizures.
We prospectively sought evidence-based criteria that distinguished between seizures and syncope. Loss of consciousness is usually due to either seizures or syncope. There are no evidence-based historical diagnostic criteria that distinguish them. A total of 671 patients with loss of consciousness completed a 118-item historical questionnaire. Data sets were complete for all subjects. The data set was randomly divided into two equal groups. The contributions of symptoms to diagnoses in one group were estimated with logistic regression and point scores were developed. The accuracy of the decision rule was then assessed using split-half analysis. Analyses were performed with and without inclusion of measures of symptom burden, which were the number of losses of consciousness and the duration of the history. The scores were tested using receiver-operator characteristic analysis. The causes of loss of consciousness were known satisfactorily in 539 patients and included seizures (n = 102; complex partial epilepsy [50 patients] and primary generalized epilepsy [52 patients]) and syncope (n = 437; tilt-positive vasovagal syncope [267 patients], ventricular tachycardia [90 patients] and other diagnoses such as complete heart block and supraventricular tachycardias [80 patients]). The point score based on symptoms alone correctly classified 94% of patients, diagnosing seizures with 94% sensitivity and 94% specificity. Including symptom burden did not significantly improve accuracy, indicating that the symptoms surrounding the loss of consciousness accurately discriminate between seizures and syncope. A simple point score of historical features distinguishes syncope from seizures with very high sensitivity and specificity.


Noticing relevant problem features: activating prior knowledge affects problem solving by guiding encoding.
This study investigated whether activating elements of prior knowledge can influence how problem solvers encode and solve simple mathematical equivalence problems (e.g., 3 + 4 + 5 = 3 + __). Past work has shown that such problems are difficult for elementary school students (McNeil and Alibali, 2000). One possible reason is that children's experiences in math classes may encourage them to think about equations in ways that are ultimately detrimental. Specifically, children learn a set of patterns that are potentially problematic (McNeil and Alibali, 2005a): the perceptual pattern that all equations follow an "operations = answer" format, the conceptual pattern that the equal sign means "calculate the total", and the procedural pattern that the correct way to solve an equation is to perform all of the given operations on all of the given numbers. Upon viewing an equivalence problem, knowledge of these patterns may be reactivated, leading to incorrect problem solving. We hypothesized that these patterns may negatively affect problem solving by influencing what people encode about a problem. To test this hypothesis in children would require strengthening their misconceptions, and this could be detrimental to their mathematical development. Therefore, we tested this hypothesis in undergraduate participants. Participants completed either control tasks or tasks that activated their knowledge of the three patterns, and were then asked to reconstruct and solve a set of equivalence problems. Participants in the knowledge activation condition encoded the problems less well than control participants. They also made more errors in solving the problems, and their errors resembled the errors children make when solving equivalence problems. Moreover, encoding performance mediated the effect of knowledge activation on equivalence problem solving. Thus, one way in which experience may affect equivalence problem solving is by influencing what students encode about the equations.


Treatment and clinical outcomes of elderly idiopathic membranous nephropathy: A multicenter cohort study in Korea.
Idiopathic membranous nephropathy (MN) is the most common glomerulonephritis in elderly patients showing nephrotic syndrome. However, little is known about its treatment options and outcomes in elderly MN patients at long term follow-up. We retrospectively enrolled patients with biopsy-proven MN between April 1990 and December 2015 from eight tertiary hospitals in Korea. Among them, we excluded patients who had secondary causes of MN and subnephrotic-range proteinuria. We evaluated the presenting features and clinical outcomes and analyzed the all-cause mortality, renal outcomes, infection, and remission with respect to age. During the median follow-up at 77.2 months, 198 younger patients (<65 years) and 133 elderly patients (≥65 years) were enrolled. Age was an independent risk factor for all-cause mortality, renal outcome, and infection (for all P < 0.05) except remission. In elderly patients, there was no significant factor associated with mortality rate. The use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) was significantly associated with renal outcome and infection (renal outcome, hazard ration [HR] 0.06, 95% confidence intervals [CI] 0.01-0.36, P = 0.003; infection, HR 0.20, 95% CI 0.04-0.94, P = 0.041). Immunosuppressant therapy significantly increased renal outcome (P = 0.045) and infection (P = 0.029) compared with conservative therapy. In conclusion, old age is one of the clinically important predictors for MN patients. Among the treatment of elderly MN patients, only ACEI or ARB was associated with beneficial effects on renal outcome and infection. Elderly MN patients need a more tailored regimen considering their comorbidities and condition.


Detection of microRNAs in color space.
Deep sequencing provides inexpensive opportunities to characterize the transcriptional diversity of known genomes. The AB SOLiD technology generates millions of short sequencing reads in color-space; that is, the raw data is a sequence of colors, where each color represents 2 nt and each nucleotide is represented by two consecutive colors. This strategy is purported to have several advantages, including increased ability to distinguish sequencing errors from polymorphisms. Several programs have been developed to map short reads to genomes in color space. However, a number of previously unexplored technical issues arise when using SOLiD technology to characterize microRNAs. Here we explore these technical difficulties. First, since the sequenced reads are longer than the biological sequences, every read is expected to contain linker fragments. The color-calling error rate increases toward the 3(') end of the read such that recognizing the linker sequence for removal becomes problematic. Second, mapping in color space may lead to the loss of the first nucleotide of each read. We propose a sequential trimming and mapping approach to map small RNAs. Using our strategy, we reanalyze three published insect small RNA deep sequencing datasets and characterize 22 new microRNAs. A bash shell script to perform the sequential trimming and mapping procedure, called SeqTrimMap, is available at: http://www.mirbase.org/tools/seqtrimmap/ email@example.com Supplementary data are available at Bioinformatics online.


Splenic macrophages in preterm infants: a necropsy study.
To study the frequency and nature of histiocytes in the splenic red pulp of infants who died following complicated immaturity/prematurity. Twenty four preterm/immature infants were investigated. Frozen sections of formalin fixed splenic tissue were stained with Oil Red O. Paraffin wax sections from the same tissue were conventionally stained with haematoxylin and eosin. Immunohistochemistry was carried out for a number of macrophage markers. The administration of Intralipid was compared with the presence and extent of tissue macrophages. The spleens of 10 infants showed varying degrees of Oil Red O positivity ranging from mild to strong. In all these cases varying numbers of macrophages were confirmed in the splenic parenchyma in ordinary sections. The immunomarkers indicated that the histiocytes belonged to the macrophage phagocytic system. Of the 10 cases with splenic macrophages all had received Intralipid. Of those not receiving Intralipid none showed splenic macrophages. Seven had received Intralipid but did not have splenic macrophages; they had either only received small amounts of Intralipid or Intralipid was discontinued before death. Splenic macrophages are common at necropsy in immature/preterm infants. The macrophages are most lucidly demonstrated using Oil Red O staining in frozen sections. There is a strong association between the presence of splenic macrophages and Intralipid administration.


Density functional theory and RRKM calculations of decompositions of the metastable E-2,4-pentadienal molecular ions.
The potential energy profiles for the fragmentations that lead to [C(5)H(5)O](+) and [C(4)H(6)](+*) ions from the molecular ions [C(5)H(6)O](+*) of E-2,4-pentadienal were obtained from calculations at the UB3LYP/6-311G + + (3df,3pd)//UB3LYP/6-31G(d,p) level of theory. Kinetic barriers and harmonic frequencies obtained by the density functional method were then employed in Rice-Ramsperger-Kassel-Marcus calculations of individual rate coefficients for a large number of reaction steps. The pre-equilibrium and rate-controlling step approximations were applied to different regions of the complex potential energy surface, allowing the overall rate of decomposition to be calculated and discriminated between three rival pathways: C-H bond cleavage, decarbonylation and cyclization. These processes should have to compete for an equilibrated mixture of four conformers of the E-2,4-pentadienal ions. The direct dissociation, however, can only become important in the high-energy regime. In contrast, loss of CO and cyclization are observable processes in the metastable kinetic window. The former involves a slow 1,2-hydrogen shift from the carbonyl group that is immediately followed by the formation of an ion-neutral complex which, in turn, decomposes rapidly to the s-trans-1,3-butadiene ion [C(4)H(6)](+*). The predominating metastable channel is the second one, that is, a multi-step ring closure which starts with a rate-limiting cis-trans isomerization. This process yields a mixture of interconverting pyran ions that dissociates to the pyrylium ions [C(5)H(5)O](+). These results can be used to rationalize the CID mass spectrum of E-2,4-pentadienal in a low-energy regime.


Effects of xylazole alone and in combination with ketamine on the metabolic and neurohumoral responses in healthy dogs.
To evaluate the effects of xylazole (an analogue of xylazine), also known as Jingsongling, alone and in combination with ketamine, on metabolic and neurohumoral responses in healthy dogs. Prospective randomized experimental study. Twelve healthy mongrel dogs (7 male, 5 female, aged 13-20 months, weighing 12.8-15.4 kg). Each dog received one of two treatments: xylazole 4 mg kg(-1) (group X n = 6); or xylazole 4 mg kg(-1) plus ketamine 10 mg kg(-1) (group XK; n = 6) intramuscularly. Pulse rate (PR), mean arterial pressure (MAP), respiratory rate (f(R)), and rectal temperature (RT) were recorded before and from 5 to 100 minutes after drug administration. Venous blood samples were taken before and at intervals from 0.5 to 24 hours after drug administration for determination of plasma concentrations of norepinephrine, epinephrine, beta-endorphin, cortisol, insulin, and glucose. Statistical analyses employed anova for repeated measures for changes with time and anova for comparison between treatments. In both treatment groups. PR, f(R) and RT decreased. MAP increased transiently. At some time points PR, MAP and RT were significantly lower in group X than group XK. Plasma norepinephrine, epinephrine, and insulin concentrations decreased, and beta-endorphin and glucose concentrations increased with both treatments. Higher values of plasma norepinephrine, epinephrine, beta-endorphin, and glucose concentrations were observed in the XK group compared with the X group. This study demonstrates that xylazole administered alone or in combination with ketamine in healthy dogs results in physiological, metabolic and neurohumoral responses similar to those seen after xylazine. Compared with xylazole alone, the combination of xylazole and ketamine reduced some of the responses.


Outcome and Complications following Vertical Rectus Abdominis Myocutaneous Flap Surgery to Reconstruct Sacrectomy Defects.
The vertical rectus abdominis myocutaneous flap has been used to reliably reconstruct posterior soft-tissue defects following resection of high sacral tumors, providing skin and soft-tissue bulk. Current literature examining the use of these flaps for high sacral reconstruction is limited. The purpose of this study was to report the authors' institution's outcome on the use of the vertical rectus abdominis myocutaneous flap to reconstruct a high sacral defect following an oncologic resection. Eighty-seven patients (29 female and 58 male) underwent vertical rectus abdominis myocutaneous flap surgery to reconstruct a posterior wound following high sacral tumor resection from 1994 to 2016. The mean age and body mass index were 52 years and 27.8 kg/m(2), respectively. The mean follow-up was 6 years. Sixty-eight patients (79 percent) sustained a complication, most commonly a wound complication [n = 41 (47 percent)]. Twenty patients (23 percent) sustained a donor-site wound complication, most commonly a wound dehiscence (n = 10). Complications resulted in a reoperation in 44 patients (51 percent), with total flap failure occurring in one (1 percent). Preoperative radiotherapy and obesity were found to increase the risk of wound complications (p = 0.004 and p = 0.02, respectively) and deep infection (p = 0.03 and p = 0.02, respectively). Complications were common following vertical rectus abdominis myocutaneous flap surgery; however, total flap loss was not. Patients with obesity and preoperative radiotherapy should be cautioned on their increased risk of complications. Currently, the vertical rectus abdominis myocutaneous flap is the authors' preferred means of soft-tissue reconstruction following high sacral tumor resection. Therapeutic, IV.


Effects of particle size and edge structure on the electronic structure, spectroscopic features, and chemical properties of Au(111)-supported MoS2 nanoparticles.
Materials based on MoS2 are widely used as catalysts and their structure usually consists of single-layered MoS2 nanoparticles whose edges are known to constitute the catalytically active sites. Methods based on density functional theory are used in this work to calculate the electronic structure of representative computational models of MoS2 nanoparticles supported on Au(111). By considering nanoparticles with different edge-terminations, compositions, and sizes, we describe how the electronic structure, Mo3d core-level shifts, and chemical properties (i.e. H adsorption and S vacancy formation) depend on the MoS2 nanoparticle size and structure. In addition, site-specific properties, largely inaccessible when using only slab models of MoS2 edges, are reported, which reveal that the edge sites are not uniform along the nanoparticle and largely depend on the proximity to the corners of the triangular NPs, especially when interacting with a metallic support. Furthermore, a structural motif where H atoms adsorb favourably in a bridging position between two Mo atoms is proposed as an active site for the hydrogen evolution reaction.


Hard Superconducting Gap in InSb Nanowires.
Topological superconductivity is a state of matter that can host Majorana modes, the building blocks of a topological quantum computer. Many experimental platforms predicted to show such a topological state rely on proximity-induced superconductivity. However, accessing the topological properties requires an induced hard superconducting gap, which is challenging to achieve for most material systems. We have systematically studied how the interface between an InSb semiconductor nanowire and a NbTiN superconductor affects the induced superconducting properties. Step by step, we improve the homogeneity of the interface while ensuring a barrier-free electrical contact to the superconductor and obtain a hard gap in the InSb nanowire. The magnetic field stability of NbTiN allows the InSb nanowire to maintain a hard gap and a supercurrent in the presence of magnetic fields (∼0.5 T), a requirement for topological superconductivity in one-dimensional systems. Our study provides a guideline to induce superconductivity in various experimental platforms such as semiconductor nanowires, two-dimensional electron gases, and topological insulators and holds relevance for topological superconductivity and quantum computation.


Mechanical Properties and Failure Behavior of Dry and Water-Saturated Foliated Phyllite under Uniaxial Compression.
Phyllite is widely distributed in nature, and it deserves to be studied considering rock engineering applications. In this study, uniaxial compression tests were conducted on foliated phyllite with different foliation angles under dry and water-saturated conditions. The impacts of water content and foliation angle on the stress-strain curves and basic mechanical properties of the Phyllite were analyzed. The experimental results indicate that the peak stress and peak strain decrease first and then increase with increasing foliation angle as a U-shape or V-shape, and the phyllite specimens are weakened significantly by the presence of water. Moreover, an approach with acoustic emission, digital image correlation, and scanning electron microscopic is employed to observe and analyze the macroscopic and mesoscopic failure process. The results show that tensile microcracks dominate during the progressive failure of phyllite, and their initiation, propagation, and coalescence are the main reasons for the failure of the phyllite specimens. The water acts on biotite and clay minerals that are main components of phyllite, and it contributes to the initiation, propagation, and coalescence of numerous microcracks. Finally, four failure modes are classified as followed: (a) for the specimens with small foliation angles α = 0° or 30° (Saturated), both shear sliding and tensile-split across the foliation planes; (b) for the specimens with low to medium foliation angles α = 30° (Dry) or 45°(Saturated), shear sliding dominates the foliation planes; (c) for the specimens with medium to high foliation angles α = 45° (Dry) or 60°, shear sliding dominates the foliation planes; (d) for the specimens with high foliation angles α = 90°, tensile-split dominates the foliation planes.


Antimicrobial activity of various extracts of Ocimum basilicum L. and observation of the inhibition effect on bacterial cells by use of scanning electron microscopy.
The antimicrobial activities of chloroform, acetone and two different concentrations of methanol extracts of Ocimum basilicum L. were studied. These extracts were tested in vitro against 10 bacteria and 4 yeasts strains by the disc diffusion method. The results indicated that the methanol extracts of O. basilucum exhibited the antimicrobial activity against tested microorganisms. While the chloroform and acetone extracts had no effect, the methanol extracts showed inhibition zones against strains of Pseudomonas aeruginosa, Shigella sp., Listeria monocytogenes, Staphylococcus aureus and two different strains of Escherichia coli. The cells of microorganisms, which were treated and untreated with plant extracts, were observed by using the scanning electron microscope. It was observed that the treated cells were damaged.


Mixed-method study on the association between inclusion to conditional cash transfer program and the multiple faces of malnutrition in children and adolescents aged 3 to 19 years: a school-based evidence from Caraga Region, the Philippines.
This study aimed to investigate the association between inclusion to Pantawid Pamilyang Pilipino Program (4Ps), a CCT program in the Philippines, and malnutrition in children and adolescents and examine the perceptions and experiences of parents and other stakeholders on how 4Ps influenced child nutrition. A concurrent mixed-method study was conducted in the Caraga Region, Philippines. Quantitative data from 5541 children and adolescents aged 3 to 19 were analyzed using multilevel mixed-effect logistic models. To allow in-depth understanding of the programmatic components that support the findings from the quantitative study, eight focused group discussions (FGDs) were concurrently conducted, cumulating 33 participants, including 4Ps parents, school coordinators/teachers, and school nurses. A constructivist grounded theory approach was used for analysis, and joint displays were employed to integrate quantitative and qualitative results. Quantitative findings revealed high rates of malnutrition, with significant rates of stunting (12.0%), wasting/thinness (9.4%), and overweight/obesity (16.4%) among children and adolescents. 4Ps beneficiaries had higher odds of stunting and overweight/obesity compared to non-4Ps beneficiaries (AOR = 1.43, 95%CI: 1.08-1.91; AOR = 1.21, 95%CI: 1.01-1.45, respectively). However, no significant association was observed between inclusion to 4Ps and concurrent stunting and wasting/thinness or overweight/obesity (AOR = 1.05, 95%CI: 0.72-1.55). Geographic variations were observed, with 4Ps children in Agusan del Sur having lower odds of stunting than those in Agusan del Norte (AOR = 0.41, 95%CI: 0.23-0.71). Age and gender also showed significant associations with malnutrition. The qualitative analysis provided insights into the challenges contributing to malnutrition, including child labor, sickness, long distances to school, limited access to healthy food, and larger families. Unintended consequences such as cash card mismanagement, inappropriate cash grant allocation, and falsification of school attendance were identified. However, teachers and parents demonstrated resilience by implementing adaptive approaches to enhance child nutrition. While 4Ps beneficiaries exhibit higher odds of stunting and overweight/obesity, the program's association with malnutrition was significantly influenced by geographic variations. It is crucial for social protection programs to prioritize comprehensive support strategies that effectively counter unintended consequences and challenges faced by beneficiaries and other stakeholders and address malnutrition in children and adolescents.


Food security and nutrition -- the Ethiopian case for action.
To assess the 1999-2000 food security situation and the food relief programmes in Ethiopia, and evaluate the need for a national food and nutrition policy. A systematic search of data sources from the Ethiopian Disaster Prevention and Preparedness Commission (DPPC), the Ethiopian Central Statistical Authority, the World Food Programme (WFP) and United Nations Children's Fund (UNICEF), the bibliographic database Medline and direct contacts with associations, institutions and people concerned with food security in Ethiopia. Consultations to WFP Ethiopia. Food availability was severely restricted due to recurrent disasters such as drought, flood, war and a lack of diversity of food items. Food accessibility was limited due to a weak subsistence-agriculture-based economy, depletion of assets, absence of income diversity and a lack of alternative coping mechanisms. Food intake adequacy was rarely achieved due to food shortages, improper diet and poor sanitary conditions. There was a lack of early warning data to monitor food security indicators. Food aid programmes did not meet the requirements for food quantities and composition, and faced major obstacles in logistics and targeting of the vulnerable population. Improvements in food security and the eradication of famine will require investment in sustainable projects. There is an immediate need for better planning and targeting of food aid and a national food security monitoring system. A national food and nutrition policy is recommended, focusing both on relief efforts and on underlying factors contributing to the famine.


Effects of Cinnamon, Cardamom, Saffron, and Ginger Consumption on Markers of Glycemic Control, Lipid Profile, Oxidative Stress, and Inflammation in Type 2 Diabetes Patients.
Type 2 diabetes (T2D) may be caused by elevated oxidative stress, inflammation, and hyperglycemia. The phytochemicals in several herbal medicines are reported to effectively improve diabetes and to ameliorate diabetic complications. The aim of the present study was to determine the effects of cinnamon, cardamom, saffron, and ginger as supplementary remedies in T2D. This randomized controlled, clinical trial included 204 T2D patients. The participants were randomly assigned to four intervention groups receiving 3 glasses of black tea and either 3 g cardamom, or cinnamon, or ginger, or 1 g saffron and one control group which consumed only 3 tea glasses without any herbal medicine for 8 weeks. Markers of inflammation, oxidative stress, fasting blood sugar, lipid profile, and anthropometric measures were evaluated at baseline and after 8 weeks of intervention. After 8 weeks of intervention, cinnamon, cardamom, ginger, and saffron consumption had significant effects on total cholesterol, LDL, and HDL levels (p < 0.05) compared with controls. However, the herbal products did not have significant effects on measures of glycemic control, anthropometry, inflammation, and oxidative stress. In within-group comparisons only, cinnamon intake significantly decreased fasting blood sugar (FBS). The herbal remedies examined had significantly beneficial effects on cholesterol, but not on measures of glycemic control, oxidative stress, and inflammation. Based on the contradictory results reported in the literature, the effects of herbal medicine in diabetic patients should undergo further detailed investigation.


Reflex and intended responses in motor cortex pyramidal tract neurons of monkey.
1. Monkeys were trained to react to an arm perturbation according to an instruction delivered prior to the perturbation. There were two possible instructions (push or pull), and monkeys learned to respond accordingly regardless of the direction (push or pull) of the triggering perturbation. 2. Pyramidal tract neurons (PTNs) in contralateral motor cortex arm area responded to the triggering perturbation with two dissociable components: 1) a relatively short-latency (20-25 ms) reflex component which depended on the direction of the perturbation, and 2) a longer latency (40-50 ms) intended component which depended on the prior instruction. 3. Intended PTN discharge could occur in arm area with latencies of 50 ms even following arm perturbations whose initial reflex effects on the PTN were inhibitory. 4. Intended PTN responses triggered by perturbations of the appropriate body part occur at shorter latencies than intended PTN responses triggered by auditory or visual stimuli. These short-latency intended PTN responses may play a role in thsshort-latency but volitionally controlled limb movements occurring in response to limb perturbations.


Synthetic small-molecule RNA ligands: future prospects as therapeutic agents.
RNA is one of the most intriguing and promising biological targets for the discovery of innovative drugs in many pathologies and various biologically relevant RNAs that could serve as drug targets have already been identified. Among the most important ones, one can mention prokaryotic ribosomal RNA which is the target of several marketed antibiotics, viral RNAs or oncogenic microRNAs that are tightly involved in the development and progression of various cancers. Oligonucleotides are efficient and specific RNA targeting agents but suffer from poor pharmacodynamic and pharmacokinetic properties. For this reason, a number of synthetic small-molecule ligands have been identified and studied upon screening of chemical libraries or focused design of RNA binders. In this review, we report the most relevant examples of synthetic compounds bearing sufficient selectivity to envisage clinical studies and future therapeutic applications with a particular attention for the main strategies that can be undertaken toward the improvement of selectivity and biological activity.


COVID-19 and time-frequency connectedness between green and conventional financial markets.
Against the backdrop of the exponentially growing trend in green finance investments and the calls for green recovery in the post-COVID world, this study presents the time-frequency connectedness between green and conventional financial markets by using the spillover models of Diebold and Yilmaz (2012) and Baruník and Křehlík (2018). Covering a sample period from January 01, 2008, to July 31, 2020, we aim to explore the dynamics of connectedness between conventional and green investments in fixed income, equity, and energy markets. Additionally, we determine the role of market-wide uncertainty in altering the connectedness structure by performing a subsample analysis for the ongoing COVID-19 pandemic crisis period. Our results show that competing energy investments are not connected, and there is only one-way spillovers from the conventional bonds in the fixed-income investments. Additionally, we observe a low (high) intergroup connectedness for conventional (green) investments. Moreover, the frequency-based analysis shows that connectedness between these competing markets is more pronounced during the short-run. The subsample analysis for the pandemic crisis period shows similar results except for the disconnection between bond markets in the short-run frequency. Our time-varying analysis shows peaks and troughs in the connectedness between climate-friendly and conventional investments that suggest different global events such as the Eurozone Debt Crisis and Shale Oil Revolution drives the association between alternate investments. Similarly, we observe an enhanced connectedness during the recent COVID-19 period, suggesting that financial stability would be a significant factor in determining the smooth transition to green investments.


The role of whole brain radiation therapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline.
Should patients with newly-diagnosed metastatic brain tumors undergo open surgical resection versus whole brain radiation therapy (WBRT) and/or other treatment modalities such as radiosurgery, and in what clinical settings? These recommendations apply to adults with a newly diagnosed single brain metastasis amenable to surgical resection. Surgical resection plus WBRT versus surgical resection alone Level 1 Surgical resection followed by WBRT represents a superior treatment modality, in terms of improving tumor control at the original site of the metastasis and in the brain overall, when compared to surgical resection alone. Surgical resection plus WBRT versus SRS + or - WBRT Level 2 Surgical resection plus WBRT, versus stereotactic radiosurgery (SRS) plus WBRT, both represent effective treatment strategies, resulting in relatively equal survival rates. SRS has not been assessed from an evidence-based standpoint for larger lesions (>3 cm) or for those causing significant mass effect (>1 cm midline shift). Level 3 Underpowered class I evidence along with the preponderance of conflicting class II evidence suggests that SRS alone may provide equivalent functional and survival outcomes compared with resection + WBRT for patients with single brain metastases, so long as ready detection of distant site failure and salvage SRS are possible. Note The following question is fully addressed in the WBRT guideline paper within this series by Gaspar et al. Given that the recommendation resulting from the systematic review of the literature on this topic is also highly relevant to the discussion of the role of surgical resection in the management of brain metastases, this recommendation has been included below.


Decision-Making During Percutaneous Coronary Intervention Guided by Optical Coherence Tomography: Insights From the LightLab Initiative.
Use of intracoronary imaging is associated with improved outcomes in patients undergoing percutaneous coronary intervention (PCI). Yet, the impact of intracoronary imaging on real-time physician decision-making during PCI is not fully known. The LightLab Initiative is a multicenter, prospective, observational study designed to characterize the use of a standardized optical coherence tomography (OCT) workflow during PCI. Participating physicians performed pre-PCI and post-PCI OCT in accordance with this workflow and operator assessments of lesion characteristics and treatment plan were recorded for each lesion based on angiography alone and following OCT. Physicians were categorized as having low (n=15), intermediate (n=13), or high (n=14) OCT use in the year preceding participation. Among 925 patients with 1328 lesions undergoing PCI, the prescribed OCT workflow was followed in 773 (84%) of patients with 836 lesions. Operator lesion assessment and decision-making during PCI changed with OCT use in 86% (721/836) of lesions. Pre-PCI OCT use changed operator decision-making in 80% of lesions, including lesion assessment (45%), vessel preparation strategy (27%), stent diameter (37%), and stent length (36%). Post-PCI OCT changed stent optimization decision-making in 31% of lesions. These findings were consistent across strata of physician prior OCT experience. A standardized OCT workflow impacted PCI decision-making in 86% of lesions, with a predominant effect on pre-PCI lesion assessment and planning of treatment strategy. This finding was consistent regardless of operator experience level and provides insight into mechanisms by which intravascular imaging might improve PCI outcomes.


Angiotensin converting enzyme inhibitors for prevention of new-onset type 2 diabetes mellitus: a meta-analysis of 72,128 patients.
Angiotensin converting enzyme inhibitors (ACEIs) have been linked to reduced risk of new-onset diabetes, but the evidence was insufficient. The aim of this study was to evaluate the effect of ACEIs on the development of new-onset type 2 diabetes. Randomized controlled trials (RCTs) about ACEIs and new-onset diabetes were identified by electronic and manual searches. Nine RCTs with 92,404 patients (72,128 non-diabetic patients at baseline) were included in this study. Compared with control group, incidence of new-onset diabetes was significantly reduced in the ACEIs group [OR 0.80, (0.71, 0.91)], irrespective of achieved blood pressure levels at the follow-up. ACEIs therapy was associated with significant reduction in the risk of new-onset diabetes compared with beta-blockers/diuretics [OR 0.78, (0.65, 0.93)], placebo [OR 0.79, (0.64, 0.96)], or calcium channel blockers [OR 0.85, (0.73, 0.99)]. ACEIs treatment was associated with significant reduction in the risk of new-onset diabetes in patients with hypertension [OR 0.80, (0.68, 0.93)], coronary artery disease (CAD) or cardiovascular disease [OR 0.83, (0.68, 1.00)], or heart failure [OR 0.22, (0.10, 0.47)]. Among patients with impaired glucose tolerance or impaired fasting glucose, ramipril did not significantly reduce the incidence of diabetes [OR 0.91, (0.79, 1.05)], but significantly increased regression to normoglycemia. ACEIs have beneficial effects in preventing new-onset diabetes. ACEIs provide additional benefits of lowering the risk of new-onset diabetes in patients with hypertension, CAD or other cardiovascular disease.


Nanoengineering of Crystal and Amorphous Surfaces of Pharmaceutical Particles for Biomedical Applications.
The morphology, size, and surface properties of pharmaceutical particles form an essential role in the therapeutic performance of active pharmaceutical ingredients (APIs) and excipients as constituents in various drug delivery systems and clinical applications. Recent advances in methods for surface modification, however, rely heavily on liquid-phase-based modification processes and afford limited control over the thickness and conformality of the coating. Atomic layer deposition (ALD), on the other hand, enables the formation of conformal nanoscale films on complex structures with thickness control on the molecular level, while maintaining the substrate particle size and morphology. Moreover, this enables nanoengineering of surfaces of pharmaceutical particles also in the dry state. Successful nanoengineeering of crystal and amorphous surfaces of pharmaceutical particles is demonstrated in this study whereby functional properties, such as dissolution and dispersibility, were tailored for drug delivery applications. This expands on our initial work on ALD of alumina on pharmaceutical particles within the lower micro- to higher nanosize ranges to here probe both crystalline and amorphous lactose substrate surfaces (d50 = 3.5 and 21 μm). In addition, both water and ozone coreactants were evaluated, the latter having not been evaluated previously for pharmaceutical particles. The deposition process is carried out at ambient conditions in a fluidized bed reactor for a low number of cycles (i.e., from 4 to 14). Improved dissolution and extended release were achieved by the ALD nanoengineering of both crystalline and amorphous surfaces. This novel concept opens up exciting opportunities to produce more complex materials and structures using temperature- and moisture-sensitive drugs, e.g., targeting and drug delivery opportunities, as well as delivering new functionalities for novel applications in the pharmaceutical, medical, biological, and advanced materials fields. The prospects for advancing inhaled drug delivery are exemplified by the ALD surface nanoengineering concept.


Tunable optical cage array generated by Dammann vector beam.
Optical cages attract considerable attentions recently owing to their potential applications in optical trapping, optical imaging and optical cloaking. However, the generation of tunable optical cage arrays in the transverse plane comes to a great challenge, which restricts the effectiveness of the above applications. In this work, we propose a full polarization-controlled method that optical cage arrays with tunable number and positions in the x-y plane can be generated by a so-called Dammann vector beam (DVB), both under the conditions of high- and low-NA focusing system. By adjusting the polarization state of the DVB with the phase of Dammann grating, the number and positions of optical cages can be adjusted flexibly. This work reveals the relationship between the complex polarization state of an incident vector beam and the output optical cage array in the focal region, and may find valuable applications in optical imaging, optical trapping, etc.


Central nervous system remyelination clinical application of basic neuroscience principles.
Studies in both humans and experimental animals have demonstrated that myelin repair in the CNS is a normal physiological response to myelin damage, similar to tissue injury elsewhere in the body. The unanswered question is why myelin repair is incomplete in multiple sclerosis patients. In this paper we review the morphological characteristics of remyelination, discuss the available animal models of CNS demyelination and their usefulness to identify the molecular, cellular, and morphological events involved in CNS myelin repair, examine the use of immunosuppression, immunoglobulins, protein growth factors, and glial cell transplantation at the primary experimental therapies designed to promote CNS remyelination, and address the potential electrophysiological and clinical benefits of myelin repair in the CNS.


Massive immune response against IVIg interferes with response against other antigens in mice: A new mode of action?
Administration of high dose intravenous immunoglobulin (IVIg) is widely used in the clinic to treat autoimmune and severe inflammatory diseases. However, its mechanisms of action remain poorly understood. We assessed the impact of IVIg on immune cell populations using an in vivo ovalbumin (Ova)-immunization mouse model. High dose IVIg significantly reduced the Ova-specific antibody response. Intriguingly, the results obtained indicate an immediate and massive immune reaction against IVIg, as shown by the activation and expansion of B cells and CD4+ T cells in the spleen and draining lymph nodes and the production of IVIg-specific antibodies. We propose that IVIg competes at the T-cell level with the response against Ova to explain the immunomodulatory properties of IVIg. Two monoclonal antibodies did not succeeded in reproducing the effects of IVIg. This suggests that in addition to the mouse response against human constant domains, the enormous sequence diversity of IVIg may significantly contribute to this massive immune response against IVIg. While correlation of these findings to IVIg-treated patients remains to be explored, our data demonstrate for the first time that IVIg re-directs the immune response towards IVIg and away from a specific antigen response.


Different patterns of illness-related interaction in couples coping with rheumatoid arthritis.
To learn more about the effect of rheumatoid arthritis (RA) on couples' relationships and how couples manage the illness within their dyad. Eight women with RA (ages 31-60 years) and their partners, and 4 men with RA (ages 43-75 years) and their partners were recruited from the rheumatology case load of a hospital in the UK. Interpretative phenomenologic analysis was used for data collection and analysis. During semistructured interviews, couples were asked about the effect of RA on their lives and relationship. This study found clear differences in the way couples managed the illness of one partner and in the nature of their illness-related interactions. Based on these differences, the couples were allocated to 1 of 3 groups: the shared illness management group (SIM), the ill partner in charge group (IPIC), or the conflict over management group (COM). In the SIM group, both partners attended appointments and shared decisions about illness management. In the IPIC group, the ill person claimed and was conceded the right to make autonomous decisions about illness management. In the COM group, the well partner was dissatisfied with the way the ill person was managing the illness, and conflict resulted. Heterogeneity exists in the intradyad management of RA. Identifying each couple's style of illness management could make medical consultations and education programs more responsive to the needs and preferences of patients and their partners. Dissatisfaction of either partner with illness management and resulting conflict could be addressed, with benefits for both partners and possible improvement in disease management.


Nontuberculous mycobacterial cervicofacial lymphadenitis in children from the multicenter, randomized, controlled trial in The Netherlands: relevance of polymorphisms in candidate host immunity genes.
The annual incidence of nontuberculous mycobacterial (NTM) cervicofacial lymphadenitis in otherwise healthy children is unexpectedly high (8 per million). It mostly arises as localized cervicofacial lymphadenitis. Previous research has suggested environmental risk factors for oral exposure to NTM and a temporal association with eruption of teeth. We studied 22 polymorphisms in relevant candidate genes, some related to periodontitis, in children with NTM lymphadenitis. We also tested for the most common mutation in IFNGR1. We analyzed DNA from 81 Dutch children with NTM from a nationwide surveillance study and 215 community controls for 22 polymorphisms in CD209, IL1B, IL8, IL10, IL12B, IL12RB1, IL18, PTX3, TLR4, TNF, VDR and SLC11A1 by MassArray platform (Sequenom) and CONTING. We screened for 818del4 in IFNGR1 by PCR and VspI restriction enzyme cleavage. We found a positive association between NTM lymphadenitis and +3953TT in IL1B (OR 2.9; 95%-CI: 1.2-7.2). Furthermore, our results showed that -592C/A heterozygosity in IL10 is linked to protection from disease (OR 0.54; 95%-CI: 0.3-0.95), but that other polymorphisms were unrelated to localized NTM disease. However, these associations were not robust to Bonferroni's correction for multiple testing. None of the children carried the IFNGR1 818del4 mutation. Dominance of environmental factors over genetic ones and insufficient sample size might explain the fragility of this study's results. Nevertheless, the association between NTM lymphadenitis and 3953C>T, a polymorphism previously linked to periodontitis, supports our hypothesis that oral exposure to mycobacteria during eruption of teeth plays a role in the etiology of cervical NTM lymphadenitis.


Metformin represses drug-induced expression of CYP2B6 by modulating the constitutive androstane receptor signaling.
Metformin is currently the most widely used drug for the treatment of type 2 diabetes. Mechanistically, metformin interacts with many protein kinases and transcription factors that alter the expression of numerous downstream target genes governing lipid metabolism, cell proliferation, and drug metabolism. The constitutive androstane receptor (CAR, NR1i3), a known xenobiotic sensor, has recently been recognized as a novel signaling molecule, in that its activation could be regulated by protein kinases in addition to the traditional ligand binding. We show that metformin could suppress drug-induced expression of CYP2B6 (a typical target gene of CAR) by modulating the phosphorylation status of CAR. In human hepatocytes, metformin robustly suppressed the expression of CYP2B6 induced by both indirect (phenobarbital) and direct CITCO [6-(4-chlorophenyl)imidazo[2,1-b]1,3thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime] activators of human CAR. Mechanistic investigation revealed that metformin specifically enhanced the phosphorylation of threonine-38 of CAR, which blocks CAR nuclear translocation and activation. Moreover, we showed that phosphorylation of CAR by metformin was primarily an AMP-activated protein kinase- and extracellular signal-regulated kinase 1/2-dependent event. Additional two-hybrid and coimmunoprecipitation assays demonstrated that metformin could also disrupt CITCO-mediated interaction between CAR and the steroid receptor coactivator 1 or the glucocorticoid receptor-interacting protein 1. Our results suggest that metformin is a potent repressor of drug-induced CYP2B6 expression through specific inhibition of human CAR activation. Thus, metformin may affect the metabolism and clearance of drugs that are CYP2B6 substrates.


Two-stage surgery for a large cervical dumbbell tumour in neurofibromatosis 1: a case report.
Spinal neurofibromas occur sporadically and typically occur in association with neurofibromatosis 1. Patients afflicted with neurofibromatosis 1 usually present with involvement of several nerve roots. This report describes the case of a 14- year-old child with a large intraspinal, but extradural tumour with paraspinal extension, dumbbell neurofibroma of the cervical region extending from the C2 to C4 vertebrae. The lesions were readily detected by MR imaging and were successfully resected in a two-stage surgery. The time interval between the first and second surgery was one month. We provide a brief review of the literature regarding various surgical approaches, emphasising the utility of anterior and posterior approaches. Neurofibromatosis 1, Dumbbell Neurofibroma, Spinal Tumour, Cervical Spine, Surgical Approach.


Looking at perspective pictures from too far, too close, and just right.
A central problem for psychology is vision's reaction to perspective. In the present studies, observers looked at perspective pictures projected by square tiles on a ground plane. They judged the tile dimensions while positioned at the correct distance, farther or nearer. In some pictures, many tiles appeared too short to be squares, many too long, and many just right. The judgments were strongly affected by viewing from the wrong distance, eye height, and object orientation. The authors propose a 2-factor angles and ratios together (ART) theory, with the following factors: the ratio of the visual angles of the tile's sides and the angle between (a) the direction to the tile from the observer and (b) the perpendicular, from the picture plane to the observer, that passes through the central vanishing point.


Protocol for a Randomised Controlled Trial Investigating Decompression for Leprous Neuropathy (The DELN Protocol).
An expert group of peripheral nerve surgeons, reconstructive surgeons, and immunologists who have extensive experience with Hansen's Disease convened to discuss the status of nerve decompression as a treatment for leprous neuropathy. The expert group recommended an international, multi-center randomised controlled trial (RCT). Subsequently, a study protocol called Decompression for Leprous Neuropathy (DELN) was designed and further refined by multiple investigators worldwide. The DELN RCT seeks to determine the long-term effect of nerve decompression on sensibility, motor function, neuropathic pain, disability, and quality of life. The RCT would enroll patients with clinically diagnosed leprous neuropathy and positive Tinel signs in the upper and lower extremities. Patients would then be randomized to receive nerve decompression or not. Outcomes of interest include sensory function, motor function, pain, disability, and quality of life. The development of ulcers or amputations after surgery and the influence of corticosteroid therapy are also important outcomes that DELN seeks to determine. The study Decompression for Leprous Neuropathy (DELN) is an international, multi-center RCT with the potential to produce high quality data to address whether nerve decompression for leprous neuropathy can conclusively improve patient outcomes. We invite discussion from all those involved in the peripheral nerve and leprosy communities.


[Management of patients with conversion disorder].
The symptoms of conversion disorder are not due to conscious simulation. There should be no doubt that the symptoms of conversion disorder are genuine, even if scans do not reveal any abnormalities. The management of patients with conversion disorder starts with an explanation of the diagnosis. The essence of this explanation is that patients first hear about what the diagnosis actually means and only after this about what they do not have. When explaining the diagnosis it is a good idea to use metaphors. The treatment of patients with conversion disorder is carried out together with a physical therapist. The collaboration of healthcare professionals who are involved in the treatment of a patient with conversion disorder should preferably be coordinated by the patient's general practitioner.


Influence of Electroosmotic Flow on Stochastic Collisions at Ultramicroelectrodes.
The collision events of single Lactococcus lactis bacteria at Pt disk ultramicroelectrodes (UMEs) were characterized using electrochemistry with correlated microscopy. A finite element model was developed which applied coupled simulations of concentration and solution velocity to elucidate the influence of electroosmotic flow on transport of bacteria near the electrode. The model established that, in stochastic collision experiments with steady-state oxidation at disk UMEs in low ionic strength solutions, electroosmotic flow occurring at the glass insulation of the electrode produces significant convection in the vicinity of the electrode disk (velocities >50 μm/s). For L. lactis, the particle velocity due to convection driven by electroosmotic flow exceeded that of electrophoresis at locations radial to the electrode disk, leading to transport away from the electrode. Correlated microscopy of collision experiments of L. lactis using a 5 μm radius Pt disk UME in 2 mM ferrocenemethanol (FcM) with either 0.035 or 0.1 mM KCl confirmed that L. lactis experienced transport by convection due to electroosmotic flow. Velocities of L. lactis extracted from correlated microscopy movies collected at the two KCl concentrations agreed with the finite elements model. Current-time (i-t) curves recorded during the collision experiments showed transients that occurred when colliding L. lactis reduced transport of FcM to the electrode. The current transients had step shapes when L. lactis collided and adsorbed and spike shapes when they collided and then moved away from the electrode. By comparing the microscopy to simulations, we concluded that the driving mechanism for the spike-shaped transients was convection due to electroosmotic flow. Moreover, these findings suggest that electroosmotic flow is significant for particle transport in stochastic collision experiments in solutions of low ionic strength, regardless of the analyte.


Brainstem response audiometry in chronic Lyme borreliosis.
Auditory brainstem responses (ABR) were investigated in 26 patients with acrodermatitis chronic atrophicans, which is a late manifestation of Lyme borreliosis. Nine of the patients showed pathological ABR, four of them unilaterally and five bilaterally. The main pathological findings were: 1) Poor reproducibility of waves IV-V or of wave V; 2) Increased latency of wave V. After antibiotic treatment, ABR was improved in eight of the nine patients, and in three of them it was normal. In the five patients who did not completely recover, the improvement consisted in better reproducibility and a tendency towards normal wave V latencies. The results of this study indicate that the central nervous system may become involved in patients with acrodermatitis chronica atrophicans.


A standalone perfusion platform for drug testing and target validation in micro-vessel networks.
Studying the effects of pharmacological agents on human endothelium includes the routine use of cell monolayers cultivated in multi-well plates. This configuration fails to recapitulate the complex architecture of vascular networks in vivo and does not capture the relationship between shear stress (i.e. flow) experienced by the cells and dose of the applied pharmacological agents. Microfluidic platforms have been applied extensively to create vascular systems in vitro; however, they rely on bulky external hardware to operate, which hinders the wide application of microfluidic chips by non-microfluidic experts. Here, we have developed a standalone perfusion platform where multiple devices were perfused at a time with a single miniaturized peristaltic pump. Using the platform, multiple micro-vessel networks, that contained three levels of branching structures, were created by culturing endothelial cells within circular micro-channel networks mimicking the geometrical configuration of natural blood vessels. To demonstrate the feasibility of our platform for drug testing and validation assays, a drug induced nitric oxide assay was performed on the engineered micro-vessel network using a panel of vaso-active drugs (acetylcholine, phenylephrine, atorvastatin, and sildenafil), showing both flow and drug dose dependent responses. The interactive effects between flow and drug dose for sildenafil could not be captured by a simple straight rectangular channel coated with endothelial cells, but it was captured in a more physiological branching circular network. A monocyte adhesion assay was also demonstrated with and without stimulation by an inflammatory cytokine, tumor necrosis factor-α.


Recent progress in livestock genomics and potential impact on breeding programs.
Most of the major livestock breeding organizations in the world are actively involved in using the emerging tools for genome analysis to obtain a better understanding of the molecular architecture of their favourite production traits. This is bound to generate a considerable amount of novel biological information that will provide a competitive advantage to those that have access to it. At present, the preferred avenue to exploit this information is via marker-assisted selection (MAS), and several breeding organisations are starting to implement MAS in breeding programs. However, it seems unlikely that the exploitation of genomics information will be limited to MAS in the future. Even though it is difficult to anticipate the ultimate impact of genomics on animal production, it would be very surprising if it were not to revolutionize this industry as it is already revolutionizing the biomedical and plant breeding industries.


Syngeneic transplantation of fetal rat pancreas. II. Effect of insulin treatment on the growth and differentiation of pancreatic implants fifteen days after transplantation.
Eight 18-days-postcoitum fetal pancreases were transplanted to isogenic alloxan-diabetic male rats. Some recipients were treated with insulin for seven days immediately after transplantation. Eight animals in both the insulin-treated group and control group were killed 15days after transplantation for morphologic and hormonal studies of the transplanted tissue. Using the morphometric technique of linear scanning, the insulin, glucagon, and somatostatin immunocytochemically positive, cell masses of the fetal pancreatic implants were quantitated. The beta cell mass of the implants from the control animals increased roughly eightfold from the time of transplant; insulin treatment resulted in a further two- to threefold increase. The insulin content of the implants increased more than did the beta cell mass, resulting in the fivefold increase in insulin per beta cell. The alpha cell and delta cell masses did not change during the transplant site, the mass of functional beta cells, and the cell-to-cell content of the implanted tissue. These results are discussed in relation to previous quantitative studies of pancreatic islet cell growth. The relationships of the transplant site, the mass of functional beta cell, and the cell-to-cell interaction within the islet to the maintenance of glucose homeostasis are also discussed.


Detection, subgroup specificity, and genotype diversity of rotavirus strains in children with acute diarrhea in Paraguay.
Of a total of 220 stool specimens from children with acute diarrhea, mostly under the age of 3 years, collected in Paraguay between January 1999 and March 2000, 70 (31.8%) were found positive for rotaviruses (RV). Positive samples were characterized by electropherotyping and subgrouping. Sixty-one (87.1%) were classified as group A, subgroup II; one (1.4%) was classified as group A, subgroup I; six (8.6%) were group A, non-I non-II; and two (2.9%) were not tested. RV strains were G and P genotyped by reverse transcription-PCR. The following G types were detected: G4 (34.3%), G1 (21.4%), G2 (1.4%), and G9 (5.7%). Mixtures of human and animal genotypes were detected in 15 (21.4%) samples, and 11 samples (15.7%) were nontypeable. The following P types were detected: P[8] (48.6%), P[4] (1.4%), and P[1] (1.4%). A mixed type was found in 10% of samples, and an unexpectedly high percentage (38.6%) of nontypeable samples was found. The common human G- and P-type combinations P[8], G4 (15.7%) and P[8], G1 (14.2%) were detected. Mixed human and animal genotypes were observed as the following combinations: G4 + G5, G4 + G5 + G10, and G1 + G10 for G types and P[8]-P[1] for P types. The emerging G9 genotype was detected in four samples. These results show for the first time the diversity of RV circulating among children in Paraguay and contribute to the knowledge of this pathogen required to devise strategies to prevent diarrheal illness in this country. The finding of mixed genotypes may indicate interspecies transmission of RV between humans and animals.


Periodontal microbiota and carotid intima-media thickness: the Oral Infections and Vascular Disease Epidemiology Study (INVEST).
Chronic infections, including periodontal infections, may predispose to cardiovascular disease. We investigated the relationship between periodontal microbiota and subclinical atherosclerosis. Of 1056 persons (age 69+/-9 years) with no history of stroke or myocardial infarction enrolled in the Oral Infections and Vascular Disease Epidemiology Study (INVEST), we analyzed 657 dentate subjects. Among these subjects, 4561 subgingival plaque samples were collected (average of 7 samples/subject) and quantitatively assessed for 11 known periodontal bacteria by DNA-DNA checkerboard hybridization. Extensive in-person cardiovascular risk factor measurements, a carotid scan with high-resolution B-mode ultrasound, white blood cell count, and C-reactive protein values were obtained. In 3 separate analyses, mean carotid artery intima-media thickness (IMT) was regressed on tertiles of (1) burden of all bacteria assessed, (2) burden of bacteria causative of periodontal disease (etiologic bacterial burden), and (3) the relative predominance of causative/over other bacteria in the subgingival plaque. All analyses were adjusted for age, race/ethnicity, gender, education, body mass index, smoking, diabetes, systolic blood pressure, and LDL and HDL cholesterol. Overall periodontal bacterial burden was related to carotid IMT. This relationship was specific to causative bacterial burden and the dominance of etiologic bacteria in the observed microbiological niche. Adjusted mean IMT values across tertiles of etiologic bacterial dominance were 0.84, 0.85, and 0.88 (P=0.002). Similarly, white blood cell values increased across tertiles of etiologic bacterial burden from 5.57 to 6.09 and 6.03 cells x10(9)/L (P=0.01). C-reactive protein values were unrelated to periodontal microbial status (P=0.82). Our data provide evidence of a direct relationship between periodontal microbiology and subclinical atherosclerosis. This relationship exists independent of C-reactive protein.


Structure and activity of the NAD(P)+-dependent succinate semialdehyde dehydrogenase YneI from Salmonella typhimurium.
Aldehyde dehydrogenases are found in all organisms and play an important role in the metabolic conversion and detoxification of endogenous and exogenous aldehydes. Genomes of many organisms including Escherichia coli and Salmonella typhimurium encode two succinate semialdehyde dehydrogenases with low sequence similarity and different cofactor preference (YneI and GabD). Here, we present the crystal structure and biochemical characterization of the NAD(P)(+)-dependent succinate semialdehyde dehydrogenase YneI from S. typhimurium. This enzyme shows high activity and affinity toward succinate semialdehyde and exhibits substrate inhibition at concentrations of SSA higher than 0.1 mM. YneI can use both NAD(+) and NADP(+) as cofactors, although affinity to NAD(+) is 10 times higher. High resolution crystal structures of YneI were solved in a free state (1.85 Å) and in complex with NAD(+) (1.90 Å) revealing a two domain protein with the active site located in the interdomain interface. The NAD(+) molecule is bound in the long channel with its nicotinamide ring positioned close to the side chain of the catalytic Cys268. Site-directed mutagenesis demonstrated that this residue, as well as the conserved Trp136, Glu365, and Asp426 are important for activity of YneI, and that the conserved Lys160 contributes to the enzyme preference to NAD(+) . Our work has provided further insight into the molecular mechanisms of substrate selectivity and activity of succinate semialdehyde dehydrogenases.


Clinical features of right-sided infective endocarditis occurring in non-drug users.
Right-sided infective endocarditis (RIE) occurs predominantly in intravenous drug users in western countries, and it has a relatively good prognosis. Clinical features and prognosis of RIE occurring in non-drug users are not well known. We investigated the clinical findings of RIE in non-drug users. We retrospectively reviewed 345 cases diagnosed with IE. Cases with RIE or left-sided infective endocarditis (LIE) defined by the vegetation site were included and cases having no vegetation or both-side vegetation were excluded. Clinical findings and in-hospital outcome of RIE were compared to those of LIE. Among the 245 cases, 39 (16%) cases had RIE and 206 (84%) cases had LIE. RIE patients were younger (40 ± 19 yr vs 50 ± 18 yr, P=0.004), and had a higher incidence of congenital heart disease (CHD) (36% vs 13%, P<0.001) and central venous catheter (CVC) (21% vs 4%, P=0.001) compared to LIE patients. A large vegetation was more common in RIE (33% vs 9%, P<0.001). Staphylococcus aureus was the most common cause of RIE, while Streptococcus viridans were the most common cause of LIE. In-hospital mortality and cardiac surgery were not different between the two groups. CHD and use of CVC were common in non-drug users with RIE. The short-term clinical outcome of RIE is not different from that of LIE.


Early life malaria exposure and academic performance.
Malaria is a major cause of morbidity and mortality in sub-Saharan Africa. It is also a dynamic contributor to poverty through its effects on children's cognitive development. This paper examines the degree to which malaria in early childhood impacts on educational achievement in later childhood. The substantial decline in malaria in the region over recent years allows an assessment of its impact to be made. Focusing on Tanzania, we combine data from the Malaria Atlas Project and the 2010-2014 Uwezo household surveys (N = 246,325). We relate the district-level risk of malaria in a child's year of birth to his/her performance in tests of acquired cognitive skills (literacy and numeracy). For causal identification, we rely on differences across districts in the pace of decline in malaria prevalence occurring over the last 15 years. We control for time-invariant district level, age, birth cohort and survey year effects, as well as district-level trends and individual and household-specific factors. In addition, we use sibling variation in birth-year exposure to malaria to strengthen our identification. A ten percentage-point decrease in malaria prevalence in birth year is associated with a 0.06 standard deviation (p = 0.000) increase in English literacy achievement. This estimate is comparable in magnitude to education intervention programs with very large effects. Our results are robust to a large number of sensitivity analyses. We find no statistically significant effects of birth-year malaria exposure on attainments in numeracy and Kiswahili, and we argue that this is probably attributable to strong ceiling effects in these test scores. We conclude that in Tanzania malaria is an important factor in geographical variation in English literacy. This indicates that malaria is a significant public health challenge to educational achievement in this country, and probably in other regions with malaria.


Single-shot measurement of the full spatio-temporal field of ultrashort pulses with multi-spectral digital holography.
We present a remarkably simple technique for measuring the full spatio-temporal electric field of a single ultrashort laser pulse. It involves capturing a large digital hologram containing multiple smaller holograms, each of which characterizes the spatial intensity and phase distributions of an individual frequency component of the pulse. From that single camera frame, we numerically reconstruct the complete electric field, E(x,y,t), using a direct algorithm. While holography requires a well-characterized reference pulse, this pulse can easily be generated from the pulse itself in most cases, so the technique is self-referencing. We experimentally demonstrate this technique using femtosecond pulses from a mode-locked Ti:Sapphire oscillator.


Robust and low cost uniform (15)N-labeling of proteins expressed in Drosophila S2 cells and Spodoptera frugiperda Sf9 cells for NMR applications.
Nuclear magnetic resonance spectroscopy is a powerful tool to study structural and functional properties of proteins, provided that they can be enriched in stable isotopes such as (15)N, (13)C and (2)H. This is usually easy and inexpensive when the proteins are expressed in Escherichiacoli, but many eukaryotic (human in particular) proteins cannot be produced this way. An alternative is to express them in insect cells. Labeled insect cell growth media are commercially available but at prohibitive prices, limiting the NMR studies to only a subset of biologically important proteins. Non-commercial solutions from academic institutions have been proposed, but none of them is really satisfying. We have developed a (15)N-labeling procedure based on the use of a commercial medium depleted of all amino acids and supplemented with a (15)N-labeled yeast autolysate for a total cost about five times lower than that of the currently available solutions. We have applied our procedure to the production of a non-polymerizable mutant of actin in Sf9 cells and of fragments of eukaryotic and viral membrane fusion proteins in S2 cells, which typically cannot be produced in E. coli, with production yields comparable to those obtained with standard commercial media. Our results support, in particular, the putative limits of a self-folding domain within a viral glycoprotein of unknown structure.


Progressively Growing Arteriovenous Malformation.
Retinal arteriovenous malformation (AVM) is a rare unilateral developmental disease that is stable over time in most cases. The authors present a case of a man who was diagnosed with an asymptomatic juxtapapillary AVM of the left eye at the age of 25 years. Visual acuity was 20/20. Fundus pictures realized during an 11-year follow-up disclosed a slowly progressive enlargement of the lesion with vascular loops increasing in number and size. Vision remained stable. No complication was observed. This case demonstrates that retinal AVMs may progressively grow and remain asymptomatic and uncomplicated for a long period of time. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e284-e286.].


K9 water searches: scent and scent transport considerations.
Increased use of water search dogs for detecting submerged bodies has created the need for a better understanding of scent emanating from the bodies and how it transits the water to the dog's nose. A review of recent literature identifies likely scent sources, potential scent transport processes, and research needs. Scent sources include gases in bubbles or dissolved in the water, liquids as buoyant plumes and droplets or dissolved in the water, and solids consisting of buoyant particulates with secretions, bacteria, and body fluids. Potential transport processes through the water include buoyancy, entrainment, and turbulence. Transport processes from the water surface into the air include volatilization and evaporation enhanced by bubble bursting, breaking waves, splashing, and wind spray. Implications for the use of water search dogs are examined. Observations of submerged, decomposing bodies are needed to quantify the physical and chemical characteristics of the scent and scent transport processes.


Inhaled latex allergen (Hev b 1).
IgE-mediated responses to natural rubber latex allergens have become a major health problem among recognized risk groups. The purpose of this investigation was to measure the amounts of Hevea brasiliensis latex allergen (Hev b 1) inhaled and deposited on surfaces when latex or vinyl gloves were worn and compare the results with the conventional measures (breathing zone samplers) of occupational exposure. Hev b 1 exposure was measured by nasal sampling and breathing zone sampling. Latex allergen exposure was generated by having each subject don a pair of powdered latex examination gloves and continuing his or her normal daily activity for 30 minutes. By means of adhesive tape, surface dust samples were collected from the surfaces of gloves, the subject's hands, and work areas. Sampling was performed with subjects wearing no gloves, subjects wearing powdered vinyl gloves, subjects wearing powdered latex gloves, and nearby colleagues wearing latex gloves. All samples were assayed through use of the HALOgen assay (Inhalix, Sydney, Australia) with a Hev b 1-specific mAb. Particles transporting latex allergen were identified by a surrounding immunostain halo, and these were quantified and reported as total numbers of particles inhaled, airborne, or found on surface areas evaluated. Study subjects inhaled 26 times more allergen when powdered latex gloves were worn than under the "no glove" and powdered vinyl glove conditions. During the same period, Hev b 1 particle levels measured in the ambient air through use of the breathing zone sampler increased by 24-fold. The median numbers of particles carrying Hev b 1 allergen per square centimeter on the surface of the hands after the wearing of latex and vinyl gloves were 1964 and 5, respectively. Latex allergen was physically associated both with cornstarch granules and with larger dust particles having a darker, more irregular appearance. In a laboratory where gloves are worn for protection, the use of latex gloves resulted in a 26-fold increase in inhaled latex allergen over background levels measured while vinyl gloves were worn as controls. Low levels of latex exposure also occurred when vinyl gloves or no gloves were worn; the reasons for this are under investigation.


Zyflamend sensitizes tumor cells to TRAIL-induced apoptosis through up-regulation of death receptors and down-regulation of survival proteins: role of ROS-dependent CCAAT/enhancer-binding protein-homologous protein pathway.
TNF (tumor necrosis factor)-related apoptosis-inducing ligand (TRAIL), is a selective killer of tumor cells, although its potential is limited by the development of resistance. In this article, we investigated whether the polyherbal preparation Zyflamend(®) can sensitize tumor cells to TRAIL. We found that Zyflamend potentiated TRAIL-induced apoptosis in human cancer cells. Zyflamend manifested its effects through several mechanisms. First, it down-regulated the expression of cell survival proteins known to be linked to resistance to TRAIL. Second, Zyflamend up-regulated the expression of pro-apoptotic protein, Bax. Third, Zyflamend up-regulated the expression of death receptors (DRs) for TRAIL. Up-regulation of DRs was critical as gene-silencing of these receptors significantly reduced the effect of Zyflamend on TRAIL-induced apoptosis. The up-regulation of DRs was dependent on CCAAT/enhancer-binding protein-homologous protein (CHOP), as Zyflamend induced CHOP, its gene-silencing abolished the induction of receptors, and mutation of the CHOP binding site on DR5 promoter abolished Zyflamend-mediated DR5 transactivation. Zyflamend mediated its effects through reactive oxygen species (ROS), as ROS quenching reduced its effect. Further, Zyflamend induced DR5 and CHOP and down-regulated the expression of cell survival proteins in nude mice bearing human pancreatic cancer cells. Zyflamend can sensitize tumor cells to TRAIL through modulation of multiple cell signaling mechanisms that are linked to ROS. Zyflamend potentiates TRAIL-induced apoptosis through the ROS-CHOP-mediated up-regulation of DRs, increase in pro-apoptotic protein and down-regulation of cell survival proteins.


Analyses of Epstein-Barr virus latent membrane protein-1 in Malaysian nasopharyngeal carcinoma: high prevalence of 30-bp deletion, Xho1 polymorphism and evidence of dual infections.
Nasopharyngeal carcinoma, a malignancy associated closely with Epstein-Barr virus (EBV), is prevalent among Chinese of Southern China origin. Epidemiological studies indicate a high prevalence of EBV in Asia with viral isolates having typical characteristics of the putative viral oncogene, latent membrane protein 1 (LMP-1), such as the loss of the Xho1 restriction site in Exon 1 and the 30-bp deletion in Exon 3. The EBV LMP-1 gene from throat washings of 120 nasopharyngeal carcinoma patients and 14 healthy individuals were analyzed. Similar analyses were also carried out on 30 and 12 postnasal space biopsies from nasopharyngeal carcinoma patients and healthy individuals, respectively. The 30-bp deletion was detected in 20% of nasopharyngeal carcinoma throat washes and in 100% of nasopharyngeal carcinoma postnasal space biopsies. Interestingly, 16% of the nasopharyngeal carcinoma biopsies possessed both the deleted and the undeleted variants, suggestive of dual infections. The notion of dual infections in nasopharyngeal carcinoma was further supported by the coexistence of both "F" and "f" (BamH1F region) EBV variants in 11% of the nasopharyngeal carcinoma biopsies. All of the throat washes and biopsies from the healthy controls showed the undeleted variant. The loss of the Xho1 restriction site was found with higher frequency both in throat washes and biopsies from patients with nasopharyngeal carcinoma. The discrepancy in the frequency of the 30-bp deletion between throat washes (20%) and postnasal space biopsies (100%) was an indication that this deletion is specific for viral isolates from primary tumour sites.


Interactions between plants and primates shape community diversity in a rainforest in Madagascar.
Models of ecological community assembly predict how communities of interacting organisms may be shaped by abiotic and biotic factors. Competition and environmental filtering are the predominant factors hypothesized to explain community assembly. This study tested the effects of habitat, phylogenetic and phenotypic trait predictors on species co-occurrence patterns and abundances, with the endemic primates of Madagascar as an empirical system. The abundance of 11 primate species was estimated along gradients of elevation, food resource abundance and anthropogenic habitat disturbance at local scales in south-east Madagascar. Community composition was compared to null models to test for phylogenetic and functional structure, and the effects of phylogenetic relatedness of co-occurring species, their trait similarity and environmental variables on species' abundances were tested using mixed models and quantile regressions. Resource abundance was the strongest predictor of community structure. Where food tree abundance was high, closely related species with similar traits dominated communities. High-elevation communities with lower food tree abundance consisted of species that were distantly related and had divergent traits. Closely related species had dissimilar abundances where they co-occurred, partially driven by trait dissimilarity, indicating character displacement. By integrating local-scale variation in primate community composition, evolutionary relatedness and functional diversity, this study found strong evidence that community assembly in this system can be explained by competition and character displacement along ecological gradients.


Managing Budd-Chiari syndrome: a retrospective review of percutaneous hepatic vein angioplasty and surgical shunting.
The role of percutaneous hepatic vein angioplasty in the management of Budd-Chiari syndrome has not been well defined. Over a 10 year period at our unit, we have often used this technique in cases of short length hepatic vein stenosis or occlusion, reserving surgical mesocaval shunting for cases of diffuse hepatic vein occlusion or failed angioplasty. To review the outcome of angioplasty and surgical shunting to define their respective roles. All patients treated by angioplasty or surgical shunting for non-malignant hepatic vein obstruction over a ten year period from 1987 to 1996. A case note review of pretreatment features and clinical outcome. Angioplasty was attempted in 21 patients with patent hepatic vein branches and was successful in 18; in three patients treatment was unsuccessful and these patients had surgical shunts. Fifteen patients were treated by surgical shunting only. Mortality according to definitive treatment was 3/18 following angioplasty and 8/18 following surgery; in most cases this reflected high risk status prior to treatment. Venous or shunt reocclusion rates were similar for both groups and were associated with subtherapeutic warfarin in half of these cases. Most surviving patients in both groups are asymptomatic although one surgical patient has chronic hepatic encephalopathy. With appropriate case selection, many patients with Budd-Chiari syndrome caused by short length hepatic vein stenosis or occlusion may be managed successfully by angioplasty alone. Medium term outcome is good following this procedure provided that anticoagulation is maintained. Further follow up is required to assess for definitive benefits but we suggest that this should be included as a valid initial approach in the algorithm for management of Budd-Chiari syndrome.


Ancient divergence of Indian and Tibetan wolves revealed by recombination-aware phylogenomics.
The grey wolf (Canis lupus) expanded its range across Holarctic regions during the late Pleistocene. Consequently, most grey wolves share recent (<100,000 years ago) maternal origins corresponding to a widespread Holarctic clade. However, two deeply divergent (200,000-700,000 years ago) mitochondrial clades are restricted, respectively, to the Indian subcontinent and the Tibetan Plateau, where remaining wolves are endangered. No genome-wide analysis had previously included wolves corresponding to the mitochondrial Indian clade or attempted to parse gene flow and phylogeny. We sequenced four Indian and two Tibetan wolves and included 31 additional canid genomes to resolve the phylogenomic history of grey wolves. Genomic analyses revealed Indian and Tibetan wolves to be distinct from each other and from broadly distributed wolf populations corresponding to the mitochondrial Holarctic clade. Despite gene flow, which was reflected disproportionately in high-recombination regions of the genome, analyses revealed Indian and Tibetan wolves to be basal to Holarctic grey wolves, in agreement with the mitochondrial phylogeny. In contrast to mitochondrial DNA, however, genomic findings suggest the possibility that the Indian wolf could be basal to the Tibetan wolf, a discordance potentially reflecting selection on the mitochondrial genome. Together, these findings imply that southern regions of Asia have been important centers for grey wolf evolution and that Indian and Tibetan wolves represent evolutionary significant units (ESUs). Further study is needed to assess whether these ESUs warrant recognition as distinct species. This question is especially urgent regarding the Indian wolf, which represents one of the world's most endangered wolf populations.


Role of valsartan, amlodipine and hydrochlorothiazide fixed combination in blood pressure control: an update.
The treatment of moderate or severe hypertension in most cases requires the contemporaneous use of multiple antihypertensive agents. The most available two-drug combinations have an agent that addresses renin secretion and another one that is statistically more effective in renin-independent hypertension. The practice of combining agents that counteract different mechanisms is the most likely explanation for the fact that most available two-drug combinations have an agent that addresses renin secretion (beta-blocker, angiotensin converting enzyme inhibitor, angiotensin II receptor blocker or direct renin inhibitor) and another one that is more effective in renin-independent hypertension (diuretic, dihydropyridine or non-dihydropyridine calcium channel blocker). Based on these considerations, addition of hydrochlorothiazide to the combination of an antagonist of the renin-angiotensin system with a calcium channel blocker would constitute a logical approach. Inclusion of a diuretic in the triple combination is based on the evidence that these agents are effective and cheap, enhance the effect of other antihypertensive agents, and add a specific effect to individuals with salt-sensitivity of blood pressure. The benefit of triple combination therapy with amlodipine, valsartan and hydrochlorothiazide over its dual component therapies has been demonstrated, and the use of a single pill will simplify therapy resulting in better blood pressure control.


Photoelectron angular distributions of pyridinide: a benchmark application of the mixed s-p model to a truly polyatomic anion.
We report a photoelectron imaging study of the pyridinide anion, C5H4N(-), obtained by deprotonation of pyridine at the C4 position. The photoelectron angular distributions are used to test the theoretical formalism for photodetachment from mixed-character s-p states, demonstrating its first application to a truly polyatomic system. The mixed s-p model describes the initial state of the anion in terms of a superposition of one s orbital and one p orbital centered on the deprotonated carbon. Using the model parameter values determined from ab initio calculations, without any fits to the experimental data, the theory yields good quantitative agreement to the experiment. The agreement is demonstrated using either the canonical Hartree-Fock highest-occupied molecular orbital of the anion or the corresponding Dyson orbital. The results confirm the predictive power of the mixed s-p model and suggest that despite its approximate nature it captures the essential physics of the photoemission process.


Multimodality assessment of cardiac involvement in Churg-Strauss syndrome patients in clinical remission.
Cardiac involvement in Churg-Strauss syndrome (CSS) is not uncommon, but its frequency varies widely and may depend on the activity of the disease. Therefore, the cardiac involvement in CSS patients in clinical remission was assessed in the present study. In 20 CSS patients in remission and 20 sex- and age-matched healthy controls, an ECG stress test, echocardiography, and 24-h ECG Holter monitoring were performed, together with cardiac magnetic resonance imaging (cMRI). Cardiac involvement was present in 90% (18/20) of CSS patients. Left ventricular ejection fraction (LVEF) was on average lower in the CSS group than in controls (P<0.05), with 7 patients showing systolic heart failure (LVEF <50%). cMRI changes included late gadolinium enhancement lesions in the LV in 89% of patients (17/19), present in all layers of the myocardium. Signs of ongoing inflammation (early gadolinium enhancement) and edema (T2-weighted imaging) were present in 6/19 patients. Holter monitoring revealed both supraventricular and ventricular arrhythmias more frequently in CSS patients when compared with controls (P<0.05). Absolute eosinophil count before the initiation of treatment was higher in rhythm disturbances (P<0.05), and inversely correlated with LV systolic function (rho -0.65). Heart involvement in CSS patients who are in clinical remission is very common. It is characterized not only by fibrosis, but also by an active inflammatory process. The latter finding might influence therapeutic decisions in CSS patients in full clinical remission.


Changing air mass frequencies in Canada: potential links and implications for human health.
Many individual variables have been studied to understand climate change, yet an overall weather situation involves the consideration of many meteorological variables simultaneously at various times diurnally, seasonally, and yearly. The current study identifies a full weather situation as an air mass type using synoptic scale classification, in 30 population centres throughout Canada. Investigative analysis of long-term air mass frequency trends was completed, drawing comparisons between seasons and climate zones. We find that the changing air mass trends are highly dependent on the season and climate zone being studied, with an overall increase of moderate ('warm') air masses and decrease of polar ('cold') air masses. In the summertime, general increased moisture content is present throughout Canada, consistent with the warming air masses. The moist tropical air mass, containing the most hot and humid air, is found to increase in a statistically significant fashion in the summertime in 46% of the areas studied, which encompass six of Canada's ten largest population centres. This emphasises the need for heat adaptation and acclimatisation for a large proportion of the Canadian population. In addition, strong and significant decreases of transition/frontal passage days were found throughout Canada. This result is one of the most remarkable transition frequency results published to date due to its consistency in identifying declining trends, coinciding with research completed in the United States (US). We discuss relative results and implications to similar US air mass trend analyses, and draw upon research studies involving large-scale upper-level air flow and vortex connections to air mass changes, to small-scale meteorological and air pollution interactions. Further research is warranted to better understand such connections, and how these air masses relate to the overall and city-specific health of Canadians.


Binning enables efficient host genome reconstruction in cnidarian holobionts.
Many cnidarians, including stony corals, engage in complex symbiotic associations, comprising the eukaryotic host, photosynthetic algae, and highly diverse microbial communities-together referred to as holobiont. This taxonomic complexity makes sequencing and assembling coral host genomes extremely challenging. Therefore, previous cnidarian genomic projects were based on symbiont-free tissue samples. However, this approach may not be applicable to the majority of cnidarian species for ecological reasons. We therefore evaluated the performance of an alternative method based on sequence binning for reconstructing the genome of the stony coral Porites rus from a hologenomic sample and compared it to traditional approaches. Our results demonstrate that binning performs well for hologenomic data, producing sufficient reads for assembling the draft genome of P. rus. An assembly evaluation based on operational criteria showed results that were comparable to symbiont-free approaches in terms of completeness and usefulness, despite a high degree of fragmentation in our assembly. In addition, we found that binning provides sufficient data for exploratory k-mer estimation of genomic features, such as genome size and heterozygosity. Binning constitutes a powerful approach for disentangling taxonomically complex coral hologenomes. Considering the recent decline of coral reefs on the one hand and previous limitations to coral genome sequencing on the other hand, binning may facilitate rapid and reliable genome assembly. This study also provides an important milestone in advancing binning from the metagenomic to the hologenomic and from the prokaryotic to the eukaryotic level.


Trends in Perceived Access to Marijuana Among Adolescents in the United States: 2002-2015.
There is concern that changes in marijuana-related policy and public opinion may lead to increased access to marijuana among young people in the United States. However, little research has been conducted on changes in youth's perceptions of marijuana access, and studies have yet to systematically examine trends in perceived access across key sociodemographic and externalizing behavioral subgroups. Using population-based data collected between 2002 and 2015 as part of the National Survey on Drug Use and Health, we examined trends in perceived marijuana access among non-Hispanic White, African American, and Hispanic adolescents (ages 12-17, n = 221,412). Following the trend analysis method outlined by the Centers for Disease Control and Prevention, we conducted logistic regression analyses to test for secular trends. Between 2002 and 2015, we observed a 27% overall reduction in the relative proportion of adolescents ages 12-17-and a 42% reduction among those ages 12-14-reporting that it would be "very easy" to obtain marijuana. This pattern was uniformly observed among youth in all sociodemographic subgroups (i.e., across age, gender, race/ethnicity, household income) and among youth reporting involvement/no involvement in most measures of substance use (alcohol, marijuana) and delinquency (handgun carrying, attacks). However, perceived very easy access remained stable among youth reporting tobacco use and criminal justice system involvement. Despite the legalization of recreational and medical marijuana in some states, our findings suggest that, with the notable exception of adolescent tobacco users and juvenile offenders, perceptions that marijuana would be very easy to obtain are on the decline among American youth.