The Cellular and Molecular Basis of Translational Immunometabolism.
The immune response requires major changes to metabolic processes, and indeed, energy metabolism and functional activation are fully integrated in immune cells to determine their ability to divide, differentiate, and carry out effector functions. Immune cell metabolism has therefore become an attractive target area for therapeutic purposes. A neglected aspect in the translation of immunometabolism is the critical connection between systemic and cellular metabolism. Here, we discuss the importance of understanding and manipulating the integration of systemic and immune cell metabolism through in-depth analysis of immune cell phenotype and function in human metabolic diseases and, in parallel, of the effects of conventional metabolic drugs on immune cell differentiation and function. We examine how the recent identification of selective metabolic programs operating in distinct immune cell subsets and functions has the potential to deliver tools for cell- and function-specific immunometabolic targeting.


Identification of a Non-Pentapeptide Region Associated with Rapid Mycobacterial Evolution.
A large portion of the coding capacity of Mycobacterium tuberculosis is devoted to the production of proteins containing several copies of the pentapeptide-2 repeat, namely the PE/PPE_MPTR proteins. Protein domain repeats have a variety of binding properties and are involved in protein-protein interactions as well as binding to other ligands such as DNA and RNA. They are not as common in prokaryotes, compared to eukaryotes, but the enrichment of pentapeptide-2 repeats in Mycobacteria constitutes an exception to that rule. The genes encoding the PE/PPE_MPTR proteins have undergone many rearrangements and here we have identified the expansion patterns across the Mycobacteria. We have performed a reclassification of the PE/PPE_MPTR proteins using cohesive regions rather than sparse domain architectures. It is clear that these proteins have undergone large insertions of several pentapeptide-2 domains appearing adjacent to one another in a repetitive pattern. Further, we have identified a non-pentapeptide motif associated with rapid mycobacterial evolution. The sequence composition of this region suggests a different structure compared to pentapeptide-2 repeats. By studying the evolution of the PE/PPE_MPTR proteins, we have distinguished features pertaining to tuberculosis-inducing species. Further studies of the non-pentapeptide region associated with repeat expansions promises to shed light on the pathogenicity of Mycobacterium tuberculosis.


Cell-to-cell influence on growth in large populations.
Recent studies have revealed the importance of outlier cells in complex cellular systems. Quantifying heterogeneity in such systems may lead to a better understanding of organ engineering, microtumor growth, and disease models, as well as more precise drug design. We used the ability of quantitative phase imaging to perform long-term imaging of cell growth to estimate the "influence" of cellular clusters on their neighbors. We validated our approach by analyzing epithelial and fibroblast cultures imaged over the course of several days. Interestingly, we found that there is a significant number of cells characterized by a medium correlation between their growth rate and distance (modulus of the Pearson coefficient between 0.25-.5). Furthermore, we found a small percentage of cells exhibiting strong such correlations, which we label as "influencer" cellular clusters. Our approach might find important applications in studying dynamic phenomena, such as organogenesis and metastasis.


Self-assembly of Janus dendrimers into uniform dendrimersomes and other complex architectures.
Self-assembled nanostructures obtained from natural and synthetic amphiphiles serve as mimics of biological membranes and enable the delivery of drugs, proteins, genes, and imaging agents. Yet the precise molecular arrangements demanded by these functions are difficult to achieve. Libraries of amphiphilic Janus dendrimers, prepared by facile coupling of tailored hydrophilic and hydrophobic branched segments, have been screened by cryogenic transmission electron microscopy, revealing a rich palette of morphologies in water, including vesicles, denoted dendrimersomes, cubosomes, disks, tubular vesicles, and helical ribbons. Dendrimersomes marry the stability and mechanical strength obtainable from polymersomes with the biological function of stabilized phospholipid liposomes, plus superior uniformity of size, ease of formation, and chemical functionalization. This modular synthesis strategy provides access to systematic tuning of molecular structure and of self-assembled architecture.


Interaction of aspartic acid-104 and proline-287 with the active site of m-calpain.
In an ongoing study of the mechanisms of calpain catalysis and Ca(2+)-induced activation, the effects of Asp-104-->Ser and Pro-287-->Ser large subunit mutations on m-calpain activity, the pH-activity profile, Ca(2+)-sensitivity, and autolysis were measured. The importance of these positions was suggested by sequence comparisons between the calpain and papain families of cysteine proteinases. Asp-104 is adjacent to the active-site Cys-105, and Pro-287 is adjacent to the active-site Asn-286 and probably to the active-site His-262; both Asp-104 and Pro-287 are absolutely conserved in the known calpains, but are replaced by highly conserved serine residues in the papains. The single mutants had approx. 10-15% of wild-type activity, due mainly to a decrease in kcat, since Km was only slightly increased. The Pro-287-->Ser mutation appeared to cause a local perturbation of the catalytic Cys-105/His-262 catalytic ion pair, reducing its efficiency without major effect on the conformation and stability of the enzyme. The Asp-104-->Ser mutation caused a marked narrowing of the pH-activity curve, a 9-fold increase in Ca2+ requirement, and an acceleration of autolysis, when compared with the wild-type enzyme. The results indicated that Asp-104 alters the nature of its interaction with the catalytic ion pair during Ca(2+)-induced conformational change in calpain. This interaction may be direct or indirect, but is important in activation of the enzyme.


Gaining ground: Americans' health insurance coverage and access to care after the Affordable Care Act's first open enrollment period.
A new Commonwealth Fund survey finds that in the wake of the Affordable Care Act's first open enrollment period, significantly fewer working-age adults are uninsured than just before the sign-up period began, and many have used their new coverage to obtain needed care. The uninsured rate for people ages 19 to 64 declined from 20 percent in the July-to-September 2013 period to 15 percent in the April-to-June 2014 period. An estimated 9.5 million fewer adults were uninsured. Young men and women drove a large part of the decline: the uninsured rate for 19-to-34-year-olds declined from 28 percent to 18 percent, with an estimated 5.7 million fewer young adults uninsured. By June, 60 percent of adults with new coverage through the marketplaces or Medicaid reported they had visited a doctor or hospital or filled a prescription; of these, 62 percent said they could not have accessed or afforded this care previously.


Shoulder apprehension impacts large-scale functional brain networks.
Shoulder apprehension is defined as anxiety and resistance in patients with a history of anterior glenohumeral instability. It remains unclear whether shoulder apprehension is the result of true recurrent instability or a memorized subjective sensation. We tested whether visual presentation of apprehension videos modifies functional brain networks associated with motor resistance and anxiety. This prospective study includes 15 consecutive right-handed male patients with shoulder apprehension (9 with right shoulder apprehension, 6 with left shoulder apprehension; 27.5 ± 6.4 years) and 10 healthy male right-handed age-matched control participants (29.0 ± 4.7 years). Multimodal MR imaging included 1) functional connectivity tensorial independent component analysis, 2) task-related general linear model analysis during visual stimulation of movies showing typical apprehension movements vs control videos, 3) voxel-based morphometry analysis of GM, and 4) tract-based spatial statistics analysis of WM. Patients with shoulder apprehension had significant (P < .05 corrected) increase in task-correlated functional connectivity, notably in the bilateral primary sensory-motor area and dorsolateral prefrontal cortex and, to a lesser degree, the bilateral dorsomedial prefrontal cortex, anterior insula, and dorsal anterior cingulate cortex (+148% right, +144% left). Anticorrelated functional connectivity decreased in the higher-level visual and parietal areas (-185%). There were no potentially confounding structural changes in GM or WM. Shoulder apprehension induces specific reorganization in apprehension-related functional connectivity of the primary sensory-motor areas (motor resistance), dorsolateral prefrontal cortex (cognitive control of motor behavior), and the dorsal anterior cingulate cortex/dorsomedial prefrontal cortex and anterior insula (anxiety and emotional regulation).


Contemporary incidence, predictors, and outcomes of acute kidney injury in patients undergoing percutaneous coronary interventions: insights from the NCDR Cath-PCI registry.
This study sought to examine the contemporary incidence, predictors and outcomes of acute kidney injury in patients undergoing percutaneous coronary interventions. Acute kidney injury (AKI) is a serious and potentially preventable complication of percutaneous coronary interventions (PCIs) that is associated with adverse outcomes. The contemporary incidence, predictors, and outcomes of AKI are not well defined, and clarifying these can help identify high-risk patients for proactive prevention. A total of 985,737 consecutive patients underwent PCIs at 1,253 sites participating in the National Cardiovascular Data Registry Cath-PCI registry from June 2009 through June 2011. AKI was defined on the basis of changes in serum creatinine level in the hospital according to the Acute Kidney Injury Network (AKIN) criteria. Using multivariable regression analyses with generalized estimating equations, we identified patient characteristics associated with AKI. Overall, 69,658 (7.1%) patients experienced AKI, with 3,005 (0.3%) requiring new dialysis. On multivariable analyses, the factors most strongly associated with development of AKI included ST-segment elevation myocardial infarction (STEMI) presentation (odds ratio [OR]: 2.60; 95% confidence interval [CI]: 2.53 to 2.67), severe chronic kidney disease (OR: 3.59; 95% CI: 3.47 to 3.71), and cardiogenic shock (OR: 2.92; 95% CI: 2.80 to 3.04). The in-hospital mortality rate was 9.7% for patients with AKI and 34% for those requiring dialysis compared with 0.5% for patients without AKI (p < 0.001). After multivariable adjustment, AKI (OR: 7.8; 95% CI: 7.4 to 8.1, p < 0.001) and dialysis (OR: 21.7; 95% CI: 19.6 to 24.1; p < 0.001) remained independent predictors of in-hospital mortality. Approximately 7% of patients undergoing a PCI experience AKI, which is strongly associated with in-hospital mortality. Defining strategies to minimize the risk of AKI in patients undergoing PCI are needed to improve the safety and outcomes of the procedure.


Fructose intake and risk of gout and hyperuricemia: a systematic review and meta-analysis of prospective cohort studies.
The prevalence of hyperuricemia and gout has increased in recent decades. The role of dietary fructose in the development of these conditions remains unclear. To conduct a systematic review and meta-analysis of prospective cohort studies investigating the association fructose consumption with incident gout and hyperuricemia. MEDLINE, EMBASE and the Cochrane Library were searched (through September 2015). We included prospective cohort studies that assessed fructose consumption and incident gout or hyperuricemia. 2 independent reviewers extracted relevant data and assessed study quality using the Newcastle-Ottawa Scale. We pooled natural-log transformed risk ratios (RRs) using the generic inverse variance method. Interstudy heterogeneity was assessed (Cochran Q statistic) and quantified (I2 statistic). The overall quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. 2 studies involving 125 299 participants and 1533 cases of incident gout assessed the association between fructose consumption and incident gout over an average of 17 years of follow-up. No eligible studies assessed incident hyperuricemia as an outcome. Fructose consumption was associated with an increase in the risk of gout (RR=1.62, 95% CI 1.28 to 2.03, p<0.0001) with no evidence of interstudy heterogeneity (I2=0%, p=0.33) when comparing the highest (>11.8% to >11.9% total energy) and lowest (<6.9% to <7.5% total energy) quantiles of consumption. Despite a dose-response gradient, the overall quality of evidence as assessed by GRADE was low, due to indirectness. There were only two prospective cohort studies involving predominantly white health professionals that assessed incident gout, and none assessed hyperuricemia. Fructose consumption was associated with an increased risk of developing gout in predominantly white health professionals. More prospective studies are necessary to understand better the role of fructose and its food sources in the development of gout and hyperuricemia. NCT01608620.


Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.
BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer. In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849. Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths. Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state. FKD Therapies Oy.


From hospice to hospital: short-term follow-up study of hospice patient outcomes in a US acute care hospital surveillance system.
In the USA, there is little systematic evidence about the real-world trajectories of patient medical care after hospice enrolment. The objective of this study was to analyse predictors of the length of stay for hospice patients who were admitted to hospital in a retrospective analysis of the mandatorily reported hospital discharge data. All acute-care hospitals in Florida during 1 January 2010 to 30 June 2012. All patients with source of admission coded as 'hospice' (n=2674). The length of stay and discharge status: (1) died in hospital; (2) discharged back to hospice; (3) discharged to another healthcare facility; and (4) discharged home. Patients were elderly (median age=81) with a high burden of disease. Almost half died (46%), while the majority of survivors were discharged to hospice (80% of survivors, 44% of total). A minority went to a healthcare facility (5.6%) or to home (5.2%). Only 9.2% received any procedure. Respiratory services were received by 29.4% and 16.8% were admitted to the intensive care unit. The median length of stay was 1 day for those who died. In an adjusted survival model, discharge to a healthcare facility resulted in a 74% longer hospital stay compared with discharge to hospice (event time ratio (ETR)=1.74, 95% CI 1.54 to 1.97 p<0.0001), with 61% longer hospital stays among patients discharged home (ETR=1.61, 95% CI 1.39 to 1.86 p<0.0001). Total financial charges for all patients exceeded $25 million; 10% of patients who appeared to exit hospice incurred 32% of the charges. Our results raise significant questions about the ethics and pragmatics of end-of-life medical care, and the intentions and scope of hospices in the USA. Future studies should incorporate prospective linkage of subjective patient-centred data and objective healthcare encounter data.


Antimethicillin-resistant Staphylococcus aureus (MRSA) activity of 'pacific propolis' and isolated prenylflavanones.
The need to discover and develop alternative therapies to treat methicillin-resistant Staphylococcus aureus (MRSA) infections is timely. This study was undertaken to purify and identify some anti-MRSA constituents from propolis, a natural product from the beehive traditionally used in folk medicine for its antimicrobial properties. A crude extract of propolis originating from the Solomon Islands ('Pacific propolis') was screened, using an agar dilution assay, in vitro against 15 MRSA clinical isolates. Results revealed activity worthy of further investigation, and subsequent purification work on this crude extract afforded 23 fractions. Further purification of active fractions led to the isolation of compounds 1-4, characterized upon analysis of their spectroscopic data (1D- and 2D-NMR, MS) and by comparison with the literature, as the prenylflavanones propolin H (1), propolin G (2), propolin D (3), and propolin C (4). This study is the first to report the anti-MRSA activity of 'Pacific propolis' and the presence of prenylflavanones in the propolis sample selected. The anti-MRSA activity of propolin D (3) (MIC 8-16 mg/L) and propolin C (4) (MIC 8-32 mg/L) is reported for the first time.


[Electrochemical analysis of nucleic acids, proteins and polysaccharides in biomedicine].
Electrochemical analysis of nucleic acids, proteins and polysaccharides represents an interesting, although not widely spread alternative to current methods based predominantly on optical detection because it offers a relatively inexpensive, fast and instrumentally simple detection of parallel samples on miniaturized chips, ideal for personalized medicine of the 21st century. Nucleic acid electrochemistry enables, for example, detection of specific DNA sequences (for determination of genes or presence of bacteria and viruses, etc.), DNA damage analysis and interaction with other molecules, DNA methylation or detection of microRNAs as potential cancer bio-markers. In the electrochemistry of proteins, great emphasis is put on construction of immunosensors for capturing specific proteins (antigens) using antibodies, suitable for diagnostics. From a bio-physical point of view, intrinsic electrocatalytic signal of proteins sensitive to conformational changes could be useful in discrimination of mutant proteins (e. g. p53), native and aggregated forms (α-synuclein in Parkinsons disease) or for studies of protein interactions with low molecular weight ligands and DNA. Due to an increased interest of scientists in glycoproteins, new electrochemical papers emerged aiming at detection of oligosaccharides and polysaccharides (i.e. glycans, when part of the protein). These assays employ for instance electroactive labels specific for saccharides or lectin bio-sensors using lectins which strongly bind glycans. Electrochemical analysis thus appears as an interesting tool in current genomics, proteomics and glycomics, as well as for cancer diagnostics.


Effect of exercise training on in vivo insulin-stimulated glucose uptake in intra-abdominal adipose tissue in rats.
Intra-abdominal obesity may be crucial in the pathogenesis of the insulin-resistance syndrome, and training may alleviate this condition. We compared insulin-mediated glucose uptake in vivo in three intra-abdominal adipose tissues (ATs; retroperitoneal, parametrial, and mesenteric) and in subcutaneous AT and also studied the effect of training. Rats were either swim trained (15 wk, n = 9) or sedentary (n = 16). While the rats were under anesthesia, a hyperinsulinemic ( approximately 900 pM), euglycemic clamp was carried out and local glucose uptake was measured by both the 2-deoxy-D-[(3)H]glucose and microdialysis techniques. Blood flow was measured by microspheres. Upon insulin stimulation, blood flow generally decreased in AT. Flow was higher in mesenteric tissue than in other ATs, whereas insulin-mediated glucose uptake did not differ between ATs. Training doubled the glucose infusion rate during hyperinsulinemia, in part, reflecting an effect in muscle. During hyperinsulinemia, interstitial glucose concentrations were lower, glucose uptake per 100 g of tissue was higher in AT in trained compared with sedentary rats, and training influenced glucose uptake identically in all ATs. In conclusion, differences between ATs in insulin sensitivity with respect to glucose uptake do not explain that insulin resistance is associated with intra-abdominal rather than subcutaneous obesity. Furthermore, training may be beneficial by enhancing insulin sensitivity in intra-abdominal fat depots.


SU-E-T-179: MVCB Pelvic Surface Dosimetry.
To compare commonly clinically available methods of estimating skin dose for a Megavoltage Conebeam CT of the pelvis. The clinical 6 MV conebeam uses 15 MU on a Siemens Oncor linac. Film tests using XV-2 film were done on a solid water phantom, as were tests using a parallel plate ion chamber at 2 mm depth. A Rando pelvic phantom was set up for a MVCB CT, and a cylindrically symmetric Isorad 6-12 MV PDM diode was placed at various angles around the phantom and irradiated using a 150 MU 6 MV arc beam with the same geometry as the clinical conebeam, giving higher and more accurate readings than would be obtained with the 15 MU conebeam. A comparison was made with the Pinnacle 8.0m treatment planning system. A strip of Optically Stimulated Luminescence dosimeters provides an accurate check of the surface dose distribution. All methods revealed an expected lateral asymmetry in the dose due to the starting and stopping angles of 270 (-90) and 110 for the conebeam. On the sides of the phantom, the diode dose was comparable to the Pinnacle-calculated dose at a depth of 3-5 mm. Near the anterior portion the diode dose was about 5% higher than the maximum Pinnacle-calculated dose at that angle. This difference is partly due to the increased diode response at shorter SSDs and higher dose rates, and to the geometry with the arc beam radiation being mainly anterior to posterior. The skin dose, corresponding to a depth of about 2 mm, is expected to be somewhat lower. To estimate pelvic skin dose in the MV CB geometry, corrections for measurement depth and geometry can be used to improve the dosimetry for these common clinically available dosimeters.


Testing genetic association by regressing genotype over multiple phenotypes.
Complex disorders are typically characterized by multiple phenotypes. Analyzing these phenotypes jointly is expected to be more powerful than dealing with one of them at a time. A recent approach (O'Reilly et al. 2012) is to regress the genotype at a SNP marker on multiple phenotypes and apply the proportional odds model. In the current research, we introduce an explicit expression for the score test statistic and its non-centrality parameter that determines its power. Same simulation studies as those reported in Galesloot et al. (2014) were conducted to assess its performance. We demonstrate by theoretical arguments and simulation studies that, despite its potential usefulness for multiple phenotypes, the proportional odds model method can be less powerful than regular methods for univariate traits. We also introduce an implementation of the proposed score statistic in an R package named iGasso.


Pre- and post-game body mass changes during an international rugby tournament: a practical perspective.
Pre- and post-game body mass changes were recorded throughout an international rugby union tournament to determine changes in body mass when training and competing on consecutive days. A squad of 28 players with a mean (+/-SD) age of 20.0 yrs (+/-0.6), height of 1.85 m (+/-0.1) and body mass of 94.71 kg (+/-10.71) were selected to play for England and to participate in an international championship in Sydney, Australia. From the squad, 22 players played in 1 or more of 4 games over a 10-day period from the day of the first match to the day of the last match. Data were collected for a total of 84 player appearances across the 4 games. Players had their body masses recorded prior to leaving England, upon arrival in Australia, and pre- and post-game during the tournament. Players were allowed to ingest fluid ad libitum throughout each match. The mean (+/-SD) ambient temperature and relative humidity across all games was 18.5 degrees C (+/-1.63) and 39.5% (+/-17.7), respectively. Pre- and post-game comparisons of body masses for all player appearances were significantly different (p < 0.00), representing a mean loss of 0.94 kg (+/-0.94). However, there was no significant difference between games or player position (forwards vs. backs). The results demonstrate that if appropriate hydration practices are implemented, they may reduce the compound effect of fluid loss when playing multiple games in a short period of time. Strategies include daily monitoring of body mass and fluid intake and educating players about the importance of fluid intake to recovery and subsequent performance when playing and training on consecutive days.


New Names for Old Tumors.
Previous studies described "clear cell" hepatocellular carcinoma (HCC), although definitions have varied. New clear cell subtypes of HCC have been proposed, including chromophobe (C-HCC), steatohepatitic (SH-HCC), and steatotic (S-HCC), and this study assessed the utility and clinical-pathologic profile of these subtypes. Current histologic definitions, including 3 separate proposed definitions for SH-HCC, were applied to tumors previously characterized as clear cell HCC. Histologic and clinical variables were analyzed. Of 66 HCCs, 51 (77%) were classified using modern definitions, including 34 SH-HCCs, 15 S-HCCs, and 2 C-HCCs. Compared with the most permissive SH-HCC definition, the other 2 definitions designated 30 and 25 SH-HCCs (-12% and -26% cases, respectively). Unsurprisingly, S-HCC and SH-HCC were associated with steatotic clear cells (P < .0001). S-HCC was also more typically early type and low grade (P = .0017). The remaining unclassified clear cell HCCs were associated with flocculent (rather than steatotic or optically clear) cytoplasm (P < .0001) but otherwise demonstrated no discrete clinical-pathologic profile. Current definitions could be used to reclassify the majority of "clear cell" HCCs. The subtypes are significantly correlated with a few variables, suggesting valid differences of the subtypes, although additional study is warranted, particularly to standardize the definition of SH-HCC.


Selective N-Arylation of p-Aminophenylalanine in Unprotected Peptides with Organometallic Palladium Reagents.
The selective N-arylation of p-aminophenylalanine in polypeptides with pre-formed palladium oxidative addition complexes is described. The depressed pKa of the aniline NH2 group enables chemoselective C-N bond formation on peptides containing multiple other aliphatic amino groups at lysines or the N-terminus via Curtin-Hammett control under mild conditions. Using palladium complexes derived from electron-poor aryl halides, p-aminophenylalanine is fully arylated in aqueous buffer in as little as one hour at micromolar concentrations. A complementary protocol using the non-nucleophilic, organic base 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), expands the substrate scope to tolerate electron-rich functional groups provides up to 97 % conversion. These procedures enable the chemoselective conjugation of functionally diverse small molecule pharmaceuticals to p-aminophenylalanine containing derivatives of cell-penetrating peptides.


The impact of colour, spatial resolution, and presentation speed on category naming.
Studies of neurological patients with category-specific agnosia have provided important contributions to our understanding of object recognition, although the meaning of such disorders is still hotly debated. One crucial line of research for our understanding of category effects, is through the examination of category biases in healthy normal subjects. This approach has, however, led to contradictory findings with advantages both for natural kinds and for man-made things being documented in healthy subjects. It has been proposed that task conditions may influence the direction of advantage (Gerlach, 2001) and in particular, that sub-optimal viewing conditions underpin natural kinds advantages, while man-made advantages emerge under more optimal viewing conditions. In two experiments with normal subjects, we examined the roles played by spatial resolution (blurring), stimulus type (colour and texture), and speed of presentation in picture naming across category. In both experiments, healthy subjects showed a natural kind advantage for original stimuli and for blurred colour stimuli (at slow and fast presentation speeds), while an advantage for man-made things emerged for line-drawings that were blurred and presented slowly. The implications for category-specific object recognition deficits are discussed.


Ultrafast assembly of swordlike Cu3(1,3,5-benzenetricarboxylate)n metal-organic framework crystals with exposed active metal sites.
Owing to their large surface area and high uptake capacity, metal-organic frameworks (MOFs) have attracted considerable attention as potential materials for gas storage, energy conversion, and electrocatalysis. Various strategies have recently been proposed to manipulate the MOF surface chemistry to facilitate exposure of the embedded metal centers at the crystal surface to allow more effective binding of target molecules to these active sites. Nevertheless, such strategies remain complex, often requiring strict control over the synthesis conditions to avoid blocking pore access, reduction in crystal quality, or even collapse of the entire crystal structure. In this work, we exploit the hydrodynamics and capillary resonance associated with acoustically-driven dynamically spreading and nebulizing thin films as a new method for ultrafast synthesis of swordlike Cu3(1,3,5-benzenetricarboxylate)n (Cu-BTC) MOFs with unique monoclinic crystal structures (P21/n) distinct to that obtained via conventional bulk solvothermal synthesis, with 'swordlike' morphologies whose lengths far exceed their thicknesses. Through pulse modulation and taking advantage of the rapid solvent evaporation associated with the high nebulisation rates, we are also able to control the thicknesses of these large aspect ratio (width and length with respect to the thickness) crystals by arresting their vertical growth, which, in turn, allows exposure of the metal active sites at the crystal surface. An upshot of such active site exposure on the crystal surface is the concomitant enhancement in the conductivity of the MOF, evident from the improvement in its current density by two orders of magnitude.


Disappearance of nutrients and energy in the stomach and small intestine, cecum, and colon of pigs fed corn-soybean meal diets containing distillers dried grains with solubles, wheat middlings, or soybean hulls.
Disappearance of nutrients and energy in the stomach and small intestine, cecum, and colon of pigs fed diets containing distillers dried grains with solubles (DDGS), wheat middlings, or soybean hulls was determined. A second objective was to test the hypothesis that physical characteristics of dietary fiber in diets are correlated with the digestibility of nutrients and energy. Eight barrows (initial BW = 37.3 ± 1.0 kg) with a T-cannula in the distal ileum and another T-cannula in the proximal colon were allotted to a replicated 4 × 4 Latin square design with 4 diets and 4 periods in each square. The basal diet was a corn-soybean meal diet and 3 additional diets were formulated by substituting 30% of the basal diet with DDGS, wheat middlings, or soybean hulls. Following an 8-d adaptation period, fecal samples were collected on d 9 and 10, and samples from the colon and the ileum were collected on d 11 and 12, and d 13 and 14, respectively. Values for apparent ileal digestibility (AID), apparent cecal digestibility (ACD), and apparent total tract digestibility (ATTD) of nutrients and energy were calculated. Results indicated that ACD and ATTD of soluble dietary fiber was not different regardless of diet indicating that the soluble dietary fiber is mostly fermented in the small intestine or in the cecum. Pigs fed the wheat middlings diet had greater ( ≤ 0.05) ACD of insoluble dietary fiber compared with pigs fed diets containing DDGS or soybean hulls indicating that the insoluble fiber in wheat middlings may be more fermentable than insoluble fiber in DDGS or soybean hulls. Insoluble dietary fiber disappearance in the colon of pigs fed the soybean hulls diet was greater ( ≤ 0.05) compared with the DGGS containing diet indicating that insoluble fiber in DDGS are more resistant to fermentation than insoluble fiber in soybean hulls. The ATTD of total dietary fiber in wheat middlings was greater ( ≤ 0.05) than in DDGS and soybean hulls further indicating that fiber in wheat middlings are more fermentable than fiber in DDGS and soybean hulls. Water binding capacity, bulk density, and viscosity of dietary fiber were not correlated with digestibility of nutrients and energy regardless of the diet. In conclusion, soluble dietary fiber is mostly fermented before reaching the colon whereas insoluble dietary fiber is mostly fermented in the colon, but fiber in wheat middlings is more fermentable than fiber in DDGS or soybean hulls.


Centriolar satellite- and hMsd1/SSX2IP-dependent microtubule anchoring is critical for centriole assembly.
Centriolar satellites are numerous electron-dense granules dispersed around the centrosome. Mutations in their components are linked to various human diseases, but their molecular roles remain elusive. In particular, the significance of spatial communication between centriolar satellites and the centrosome is unknown. hMsd1/SSX2IP localizes to both the centrosome and centriolar satellites and is required for tethering microtubules to the centrosome. Here we show that hMsd1/SSX2IP-mediated microtubule anchoring is essential for proper centriole assembly and duplication. On hMsd1/SSX2IP knockdown, the centriolar satellites become stuck at the microtubule minus end near the centrosome. Intriguingly, these satellites contain many proteins that normally localize to the centrosome. Of importance, microtubule structures, albeit not being anchored properly, are still required for the emergence of abnormal satellites, as complete microtubule depolymerization results in the disappearance of these aggregates from the vicinity of the centrosome. We highlighted, using superresolution and electron microscopy, that under these conditions, centriole structures are faulty. Remarkably, these cells are insensitive to Plk4 overproduction-induced ectopic centriole formation, yet they accelerate centrosome reduplication upon hydroxyurea arrest. Finally, the appearance of satellite aggregates is cancer cell specific. Together our findings provide novel insights into the mechanism of centriole assembly and microtubule anchoring.


Detecting singular weak-dissipation limit for flutter onset in reversible systems.
A "flutter machine" is introduced for the investigation of a singular interface between the classical and reversible Hopf bifurcations that is theoretically predicted to be generic in nonconservative reversible systems with vanishing dissipation. In particular, such a singular interface exists for the Pflüger viscoelastic column moving in a resistive medium, which is proven by means of the perturbation theory of multiple eigenvalues with the Jordan block. The laboratory setup, consisting of a cantilevered viscoelastic rod loaded by a positional force with nonzero curl produced by dry friction, demonstrates high sensitivity of the classical Hopf bifurcation onset to the ratio between the weak air drag and Kelvin-Voigt damping in the Pflüger column. Thus, the Whitney umbrella singularity is experimentally confirmed, responsible for discontinuities accompanying dissipation-induced instabilities in a broad range of physical contexts.


Diagnostic yield of deep biopsy via endoscopic submucosal dissection for the diagnosis of upper gastrointestinal subepithelial tumors: a systematic review and meta-analysis.
Conventionally, endoscopic ultrasound-guided fine-needle aspiration and biopsy (EUS-FNA)/EUS-FNB) has been used for tissue diagnosis of upper gastrointestinal (GI) subepithelial tumors (SETs). However, deep biopsy (DB) via endoscopic submucosal dissection (ESD) is emerging as an alternative technique, given the inadequate tissue sampling with EUS-FNA/EUS-FNB. Our aim was to conduct a systematic review and meta-analysis to report the overall diagnostic yield of DB via ESD for upper GI SETs. PubMed, Cochrane Library and Web of Science databases were searched to identify studies (from commencement to Oct 2017) that reported the DB via ESD technique for diagnosis of upper GI SETs. The primary outcome of interest was the method's overall diagnostic yield and the secondary outcome was to the occurrence of complications. The meta-analysis was performed using the DerSimonian and Laird random-effects model. A total of 7 studies, comprising 209 patients with a mean age of 57.3 years, were included in the final meta-analysis. The overall pooled diagnostic yield of DB via ESD for upper GI SETs was 95% (95% confidence interval [CI] 84.91-99.98, I2=78.2%). Overall, pooled outcomes of major bleeding and perforation in our meta-analysis was noted in 0.07% (95%CI 0.00-2.32, I2=0%) and 0% (95%CI 0.00-1.70, I2=0%) respectively. Data regarding major bleeding and perforation rates were not reported in 2 studies. Substantial heterogeneity was observed in our meta-analysis. DB via ESD is an effective and safe procedure for diagnosing upper GI SETs. Further multicenter randomized controlled trials are needed to validate these findings.


Chest physiotherapy in primary pneumonia.
One hundred and seventy one patients with primary pneumonia entered a single blind, placebo controlled trial of physiotherapy. Treatment was allocated at random, physiotherapy consisting of postural drainage, external help with breathing, percussion, and vibration and the controls receiving advice on expectoration, deep breathing, and how to exercise to avoid thrombosis. Principles of pharmaceutical management were the same in the two groups. There was no objective evidence that daily physiotherapy helped during the acute phase of the disease. On the contrary, in younger patients, smokers, and patients with interstitial pneumonia physiotherapy appeared to prolong the duration of fever as well as the hospital stay. It is concluded that chest physiotherapy is at best useless in patients with primary infectious pneumonia.


Formation of aggregated nanoparticle spheres through femtosecond laser surface processing.
A detailed structural and chemical analysis of a class of self-organized surface structures, termed aggregated nanoparticle spheres (AN-spheres), created using femtosecond laser surface processing (FLSP) on silicon, silicon carbide, and aluminum is reported in this paper. AN-spheres are spherical microstructures that are 20-100 μm in diameter and are composed entirely of nanoparticles produced during femtosecond laser ablation of material. AN-spheres have an onion-like layered morphology resulting from the build-up of nanoparticle layers over multiple passes of the laser beam. The material properties and chemical composition of the AN-spheres are presented in this paper based on scanning electron microscopy (SEM), focused ion beam (FIB) milling, transmission electron microscopy (TEM), and energy dispersive x-ray spectroscopy (EDX) analysis. There is a distinct difference in the density of nanoparticles between concentric rings of the onion-like morphology of the AN-sphere. Layers of high-density form when the laser sinters nanoparticles together and low-density layers form when nanoparticles redeposit while the laser ablates areas surrounding the AN-sphere. The dynamic nature of femtosecond laser ablation creates a variety of nanoparticles that make-up the AN-spheres including Si/C core-shell, nanoparticles that directly fragmented from the base material, nanoparticles with carbon shells that retarded oxidation, and amorphous, fully oxidized nanoparticles.


Cocaine sensitization increases subthreshold activity in dopamine neurons from the ventral tegmental area.
The progressive escalation of psychomotor responses that results from repeated cocaine administration is termed sensitization. This phenomenon alters the intrinsic properties of dopamine (DA) neurons from the ventral tegmental area (VTA), leading to enhanced dopaminergic transmission in the mesocorticolimbic network. The mechanisms underlying this augmented excitation are nonetheless poorly understood. DA neurons display the hyperpolarization-activated, nonselective cation current, dubbed Ih We recently demonstrated that Ih and membrane capacitance are substantially reduced in VTA DA cells from cocaine-sensitized rats. The present study shows that 7 days of cocaine withdrawal did not normalize Ih and capacitance. In cells from cocaine-sensitized animals, the amplitude of excitatory synaptic potentials, at -70 mV, was ∼39% larger in contrast to controls. Raise and decay phases of the synaptic signal were faster under cocaine, a result associated with a reduced membrane time constant. Synaptic summation was paradoxically elevated by cocaine exposure, as it consisted of a significantly reduced summation indexed but a considerably increased depolarization. These effects are at least a consequence of the reduced capacitance. Ih attenuation is unlikely to explain such observations, since at -70 mV, no statistical differences exist in Ih or input resistance. The neuronal shrinkage associated with a diminished capacitance may help to understand two fundamental elements of drug addiction: incentive sensitization and negative emotional states. A reduced cell size may lead to substantial enhancement of cue-triggered bursting, which underlies drug craving and reward anticipation, whereas it could also result in DA depletion, as smaller neurons might express low levels of tyrosine hydroxylase. This work uses a new approach that directly extracts important biophysical parameters from alpha function-evoked synaptic potentials. Two of these parameters are the cell membrane capacitance (Cm) and rate at any time point of the synaptic waveform. The use of such methodology shows that cocaine sensitization reduces Cm and increases the speed of synaptic signaling. Paradoxically, although synaptic potentials show a faster decay under cocaine their temporal summation is substantially elevated.


Additive antitumour response to the rabbit VX2 hepatoma by combined radio frequency ablation and toll like receptor 9 stimulation.
Radiofrequency ablation (RFA), a palliative therapeutic option for solid hepatic tumours, stimulates localised and systemic antitumour cytotoxic T cells. We studied how far addition of CpG B oligonucleotides, toll like receptor (TLR) 9 agonists, would increase the antitumoural T cell response of RFA in the highly aggressive VX2 hepatoma. Rabbits were randomised to receive RFA, CpG B, their combination or no therapy. The antitumour efficacy of RFA alone or in combination with CpG B was further tested by rechallenging a separate group with intravenously injected VX2 tumour cells after 120 days. Animals were assessed for survival, tumour size and spread, and tumour and immune related histological markers after 120 days. Peripheral blood mononuclear cells were tested for tumour-specific T cell activation and cytotoxicity. Immune modulatory cytokines tumour necrosis factor α, interleukin (IL)-2/IL-8/IL-10/IL-12 and interferon γ, and vascular endothelial growth factor were measured in serum. Mean survival of untreated animals was 36 days, as compared with 97, 78 and 114 days for RFA, CpG and combination therapy, respectively. Compared with untreated controls, antitumour T cell stimulation/cytotoxicity increased 26/16-fold, 32/17-fold and 50/38-fold 2 weeks after RFA, CpG and combination treatments, respectively. The combination inhibited tumour spread to lungs and peritoneum significantly and prohibited new tumour growth in animals receiving a secondary systemic tumour cell injection. RFA alone induced a Th1 cytokine pattern, while IL-8 and IL-10 were only upregulated in CpG treated animals and controls. The combination of TLR9 stimulation with RFA resulted in a potentiated antitumour T cell response and cytotoxicity in the VX2 tumour model. Only this combination prevented subsequent tumour spread and resulted in a significantly improved survival, justifying the need for further exploration of the combination of ablative therapies and TLR9 agonists in liver cancer.


Dietary oxidized frying oil enhances tissue alpha-tocopherol depletion and radioisotope tracer excretion in vitamin E-deficient rats.
Rats fed a diet containing 15% oxidized frying soybean oil (OFO) have been shown to have significantly lower tissue alpha-tocopherol (alpha-T) concentration than rats fed a 15% fresh soybean oil diet. To examine the turnover of alpha-tocopherol, a depletion-repletion experiment and a radioisotope tracer study were conducted. Two groups of male weanling Long-Evans rats were fed vitamin E-deficient diets containing either 15% OFO or 15% vitamin E-stripped fresh soybean oil (control). After 9 wk of depletion, rats fed the OFO diet had significantly higher plasma pyruvate kinase (PK) activity and lower concentrations of alpha-T in RBC, adrenal gland, heart, kidney, liver, spleen, testis and muscle compared with controls (P < 0.05), indicating that the vitamin E-deficient status was aggravated by feeding the OFO diet. After 12 wk, the depleted rats were intraperitoneally injected with a dose of all-rac-alpha-T (2.5 mg/rat, dissolved in Vitamin E-stripped corn oil) every other day. Three doses were administered to each rat during the 1-wk repletion period. Plasma PK activity decreased in both groups (P < 0.05) after repletion but that of the OFO rats was still significantly higher than that of the control group. The repleted OFO gorup also had significantly lower alpha-T concentration in adrenal gland, epididymal fat, liver and spleen than the repleted control group. Two rats from each group that had been vitamin E-depleted for 16 wk were injected intraperitoneally with a single dose of 5-methyl-14C-RRR-alpha-T (740 kBq/kg body weight). During the week after dosing, the radioactivity excreted in urine and feces of the OFO group was 1.3- and 1.7-fold, respectively, that of the control group. Tissue retention of radioactivity was also lower in the OFO rats than in the control rats. The results suggest that more of the alpha-T in the body was catabolized or turned over in rats fed the OFO-containing diet.


Replenishing Peripheral CD4(+) Regulatory T Cells: A Possible Immune-Intervention Strategy in Type 1 Diabetes?
Controlling the diabetogenic activity of peripheral islet antigen-specific T cells is essential to halt the progression of autoimmunity that leads to the development of type 1 diabetes mellitus (T1DM). Over the past years, evidence has been gathered to suggest that the dysfunction of CD4(+)CD25(+) regulatory T (Treg) cells, and the interleukin-10 (IL10) -secreting type 1 regulatory T (Tr1) cells are associated with disease onset in diabetic patients. Although CD4(+)CD25(+) Treg cells develop as a distinct lineage of T cells in the thymus, results from recent studies have shown that they can also arise independently from the peripheral pool of conventional CD4(+) lymphocytes. These observations have led to the development of various methods to convert peripheral CD4(+) T cells into CD4(+)CD25(+) Treg and Tr1 cells in vitro or to induce the development and expansion of Treg cell subsets in vivo. This article reviews the progress made in Treg cell recruitment in vivo that involves the potential for the prevention or even reversal of T1DM.


Veterinary Drug Shops as Main Sources of Supply and Advice on Antimicrobials for Animal Use in the Mekong Delta of Vietnam.
In the Mekong Delta of Vietnam, small-scale poultry farmers use large amounts of antimicrobials to raise their flocks, and veterinary drug shops owners and their staff are a key source of advice to farmers on antimicrobial use (AMU). We described the network of veterinary drug shops (n = 93) in two districts within Dong Thap province (Mekong Delta). We also interviewed a randomly selected sample of chicken farmers (n = 96) and described their linkages with veterinary drug shops. Antimicrobials represented 15.0% [inter quartile range (IQR) 6.0-25.0] of the shops' income. Fifty-seven percent shop owners had been/were affiliated to the veterinary authority, 57% provided diagnostic services. The median number of drug shops supplying antimicrobials to each farm during one production cycle was 2 [IQR 1-2]. Visited shops were located within a median distance of 3.96 km [IQR 1.98-5.85] to farms. Drug shops owned by persons affiliated to the veterinary authority that did not provide diagnostic services had a higher fraction of their income consisting of antimicrobial sales (β = 1.913; p < 0.001). These results suggest that interventions targeting veterinary drug shop owners and their staff aiming at improving their knowledge base on livestock/poultry diseases and their diagnosis may contribute to reducing overall levels of AMU in the area.


Use of arterial blood gas analysis as a superior method for evaluating respiratory function in pet rabbits (Oryctolagus cuniculus).
A retrospective study compared invasive (arterial blood gas analysis) and non-invasive (capnography and pulse oximetry) methods of monitoring respiratory function in conscious rabbits. Arterial samples from 50 healthy dwarf lop rabbits, presenting for routine surgical neutering, were analysed on a point-of-care blood gas analysis machine. Reference intervals were obtained for pH (7.35-7.54), PaCO2 (mm Hg) (25.29-40.37), PaO2 (mm Hg) (50.3-98.2), base excess (mmol/l) (6.7-6.5), HCO3 (mmol/l) (17.96-29.41), TCO2 (mmol/l) (18.9-30.5). SaO2 (per cent) (88.8-98.0), Na (mmol/l) (137.6-145.2), K (mmol/l) (3.28-4.87), iCal (mmol/l) (1.64-1.94), glucose (mmol/l) (6.23-10.53), haematocrit (per cent) (23.3-40.2) and haemoglobin (mg/dl) (7.91-13.63). Pulse oximetry (SPO2) and capnography (ETCO2) readings were taken concurrently. There was no statistically significant relationship between SPO2 and SaO2 with a mean difference between SPO2 and SaO2 of 8.22 per cent. There was a statistically significant relationship between ETCO2 vs PaCO2, but a wide range of ETCO2 values were observed for a given PaCO2. The mean difference between these was 16.16 mm Hg. The study has provided reference intervals for arterial blood gas analysis in rabbits and demonstrated that capnography and pulse oximetry readings should not be relied upon in conscious rabbits as a guide to ventilation and oxygenation.


Part II: A Qualitative Study of Social Risk Screening Acceptability in Patients and Caregivers.
This study aimed to better understand patient and caregiver perspectives on social risk screening across different healthcare settings. As part of a mixed-methods multisite study, the authors conducted semistructured interviews with a subset of adult patients and adult caregivers of pediatric patients who had completed the Center for Medicare and Medicaid Innovation Accountable Health Communities social risk screening tool between July 2018 and February 2019. Interviews, conducted in English or Spanish, asked about reactions to screening, screening acceptability, preferences for administration, prior screening experiences that informed perspectives, and expectations for social assistance. Basic thematic analysis and constant comparative methods were used to code and develop themes. Fifty interviews were conducted across 10 study sites in 9 states, including 6 primary care clinics and 4 emergency departments. There was broad consensus among interviewees across all sites that social risk screening was acceptable. The following 4 main themes emerged: (1) participants believed screening for social risks is important; (2) participants expressed insight into the connections between social risks and overall health; (3) participants emphasized the importance of patient-centered implementation of social risk screening; and (4) participants recognized limits to the healthcare sector's capacity to address or resolve social risks. Despite gaps in the availability of social risk-related interventions in healthcare settings, patient-centered social risk screening, including empathy and attention to privacy, may strengthen relationships between patients and healthcare teams. This article is part of a supplement entitled Identifying and Intervening on Social Needs in Clinical Settings: Evidence and Evidence Gaps, which is sponsored by the Agency for Healthcare Research and Quality of the U.S. Department of Health and Human Services, Kaiser Permanente, and the Robert Wood Johnson Foundation.


Flow cytometric detection of cell-associated interleukin-8 in alveolar macrophages in vivo from patients with hypersensitivity pneumonitis and sarcoidosis.
In comparison with neutrophil-mediated lung diseases, such as acute respiratory distress syndrome, the involvement of IL-8 in lymphocyte-mediated lung diseases has not been fully investigated. Several reports have shown a slight increase in bronchoalveolar lavage fluid (BALF) IL-8 in patients with hypersensitivity pneumonitis (HP) and sarcoidosis (SAR), but the source of the IL-8 has not been clarified. In the present study, the in vivo production of IL-8 by alveolar macrophages (AMs) is examined in these patients by analyzing the cell-associated IL-8, using the flow cytometric method adopted previously. The IL-8 levels in the epithelial lining fluid (ELF) were also assessed. Initially, slight, but significant, increased levels of ELF IL-8 in HP and SAR were confirmed. Using flow cytometric analysis, a significant increase was found in the cell-associated IL-8 of the freshly isolated AMs in HP, but not in SAR, indicating in vivo production of IL-8 by AMs in HP. The cell-associated IL-8 of the AMs cultured with or without lipopolysaccharide was also analyzed. However, in contrast to previous findings in patients with idiopathic pulmonary fibrosis, no differences were found between SAR and HP patients and control subjects. Based on these findings, it is speculated that ELF IL-8 levels are slightly increased in HP and SAR, and they may contribute to the accumulation of neutrophils and possibly lymphocytes. However, the source of IL-8 may be different and AMs are the candidate source of IL-8 in HP, but not in SAR. The flow cytometric method may be useful in assessing cytokines production by AMs.


Chemopreventive effects of wild carrot oil against 7,12-dimethyl benz(a)anthracene-induced squamous cell carcinoma in mice.
Daucus carota L. ssp. carota (Apiacea) is widely distributed throughout the world and has many uses in traditional medicine. The present study investigates the chemopreventive effects of oil extract of D. carota umbels on 7,12-dimethyl benz(a)anthracene (DMBA)-induced skin cancer in mice. D. carota oil extract (DCOE) was prepared by extracting the dried umbels with 50:50 acetone:methanol. Skin papilloma were initiated by DMBA and promoted by 12-O-tetradecanoyl phorobol-13-acetate (TPA). The extract was administered to animals via gavage (0.02 mL of 100% oil), intraperitoneal (0.3 mL of 2% oil), and topical (0.2 mL of 5, 50, and 100% oil) routes for 20 weeks. Tumor appearance, incidence, yield, and volume were compared with those of a non-treated control group. Topical 100% treatment delayed tumor appearance, and inhibited tumor incidence and yield by 40 and 89%, respectively. Topical 50% treatment inhibited tumor incidence and yield by 30 and 83%, respectively, whereas the 5% treatment inhibited tumor yield by 36%. Tumor volume was decreased by 99, 91, and 70% following topical treatments with 100, 50, and 5% oil, respectively. Intraperitoneal treatment inhibited tumor yield by 43%, and decreased tumor volume by 85%, whereas gavage treatment showed minimal effects on both. Intraperitoneal and topical treatment decreased infiltration and hyperplasia with an increase in the level of hyperkeratosis. These findings demonstrate that DCOE has remarkable antitumor activity against DMBA-induced skin cancer compared with non-treated animals paving the ground for further investigations.


External electric field driving the ultra-low thermal conductivity of silicene.
The manipulation of thermal transport is in increasing demand as heat transfer plays a critical role in a wide range of practical applications, such as efficient heat dissipation in nanoelectronics and heat conduction hindering in solid-state thermoelectrics. It is well established that the thermal transport in semiconductors and insulators (phonons) can be effectively modulated by structure engineering or materials processing. However, almost all the existing approaches involve altering the original atomic structure of materials, which would be hindered due to either irreversible structure change or limited tunability of thermal conductivity. Motivated by the inherent relationship between phonon behavior and interatomic electrostatic interaction, we comprehensively investigate the effect of external electric field, a widely used gating technique in modern electronics, on the lattice thermal conductivity (κ). Taking two-dimensional silicon (silicene) as a model, we demonstrate that by applying an electric field (Ez = 0.5 V Å-1) the κ of silicene can be reduced to a record low value of 0.091 W m-1 K-1, which is more than two orders of magnitude lower than that without an electric field (19.21 W m-1 K-1) and is even comparable to that of the best thermal insulation materials. Fundamental insights are gained from observing the electronic structures. With an electric field applied, due to the screened potential resulting from the redistributed charge density, the interactions between silicon atoms are renormalized, leading to phonon renormalization and the modulation of phonon anharmonicity through electron-phonon coupling. Our study paves the way for robustly tuning phonon transport in materials without altering the atomic structure, and would have significant impact on emerging applications, such as thermal management, nanoelectronics and thermoelectrics.


Photocatalytic removal of Escherichia coli from aquatic solutions using synthesized ZnO nanoparticles: a kinetic study.
Development of effective and low-cost disinfection technology is needed to address the problems caused by an outbreak of harmful microorganisms. In this work, an effective photocatalytic removal of Gram-negative bacteria Escherichia coli from aqueous solution was reported by using ZnO nanoparticles under UV light irradiation. The effect of various parameters such as solution pH, ZnO dosage, contact time and initial E. coli concentration were investigated. Maximum photocatalytic disinfection was observed at neutral pH because of the reduced photocatalytic activity of ZnO at low and high pH values originated from either acidic/photochemical corrosion of the catalyst and/or surface passivation with Zn(OH)(2). As the ZnO dosage increased, the photocatalytic disappearance of E. coli was continuously enhanced, but was gradually decreased above 2 g/L of ZnO due to the increased blockage of the incident UV light used. The optimum ZnO dosage was determined as 1 g/L. Photocatalytic removal of E. coli decreased as initial E. coli concentration increased. Three kinetic models (zero-, first- and second-order equations) were used to correlate the experimental data and to determine the kinetic parameters.


Relief of hemorrhoid symptoms: pilot study of a new topical ally.
The pathogenesis of hemorrhoids involves vascular congestion, fragmentation of supporting tissues and, in many cases, increased resting anal pressure. A new ointment (Hemolen®) has been devised to control hemorrhoids symptoms acting on all the pathophysiologic mechanisms involved. Pilot study on patients with grade I-III hemorrhoids. The ointment was applied twice daily for 30 days and follow-up visits were scheduled 7 days (T1), 14 days (T2) and 30 days (T3) after recruitment (T0). Signs and symptoms (bleeding, discomfort, itching, edema, thrombosis, congestion, inflammation, pain) were evaluated at each visit using dedicated scores and VAS scale. Resting anal pressure was measured at time T0, 1 hour after the first application and at T1. Use of painkiller was recorded. 48 patients (25 females; mean age 47±15.8 years) were enrolled; 52.1% of them had II degree hemorrhoids and 27.1% had III degree hemorrhoids. The severity scores significantly dropped from T0 to each scheduled visit and a significant reduction of resting anal pressure was observed from T0 to 1 hour after application (z=13.5; p<0.001) and from T0 to T1 (z=6; p<0.001). The comparison of the resting pressure among whole time series showed a significant reduction (Fr=124.4; p=<0.001). Use of pain-killers decreased significantly from T0 to T1 (p<0.001) and from T1 to T2 (p=0.001). The new ointment tested in the present study is safe and effective for the management of hemorrhoid symptoms in the early stages hemorrhoids, during the acute phases and in patients with more severe hemorrhoids awaiting surgery. Prospective, randomized controlled trials are needed to confirm these encouraging results.


3D Printing of Metallic Microstructured Mould Using Selective Laser Melting for Injection Moulding of Plastic Microfluidic Devices.
A new method, a 3D printing technique, in particular, selective laser melting (SLM), has been used to fabricate moulds for the injection moulding of thermoplastic microfluidic chips that are suitable for prototyping and early stage scale-up. The micro metallic patterns are printed on to a pre-finished substrate to form a microstructured mould. The dimensional accuracy, surface morphology, bonding strength between the printed patterns and substrate, as well as the microstructure of micro features were all characterized. A microfluidic mould was successfully printed and used directly for injection moulding of cyclic olefin copolymer (COC) microfluidic chips, which were used subsequently to successfully monitor nitrite concentrations in environmental water. The characterization indicated that this new process can be used for fast fabrication of mould tools for injection moulding/hot embossing microfluidic devices. It is faster, more flexible and less expensive than conventional micro-machining processes, although the accuracy and finish are still needed to improve though process optimization and hybrid SLM and machining processes.


The Role of Technology in Chronic Disease Care.
Chronic disease represents the epidemic of our time, present in half the adult population and responsible for 86% of United States (US) healthcare costs and 70% of deaths. The major chronic diseases are primarily due to health risk behaviors that are widely communicable across populations. As a nation, the US has performed poorly in managing chronic disease, in large part because of a failed delivery model of care. New opportunities exist as a result of recent advances in home-based wireless devices, apps and wearables, enabling health delivery systems to monitor disease metrics in near real time. These technologies provide a framework for patient engagement and a new model of care delivery utilizing integrated practice units, both of which are needed to navigate the healthcare needs of the 21st century.


Peripheral effects of FAAH deficiency on fuel and energy homeostasis: role of dysregulated lysine acetylation.
FAAH (fatty acid amide hydrolase), primarily expressed in the liver, hydrolyzes the endocannabinoids fatty acid ethanolamides (FAA). Human FAAH gene mutations are associated with increased body weight and obesity. In our present study, using targeted metabolite and lipid profiling, and new global acetylome profiling methodologies, we examined the role of the liver on fuel and energy homeostasis in whole body FAAH(-/-) mice. FAAH(-/-) mice exhibit altered energy homeostasis demonstrated by decreased oxygen consumption (Indirect calorimetry). FAAH(-/-) mice are hyperinsulinemic and have adipose, skeletal and hepatic insulin resistance as indicated by stable isotope phenotyping (SIPHEN). Fed state skeletal muscle and liver triglyceride levels was increased 2-3 fold, while glycogen was decreased 42% and 57% respectively. Hepatic cholesterol synthesis was decreased 22% in FAAH(-/-) mice. Dysregulated hepatic FAAH(-/-) lysine acetylation was consistent with their metabolite profiling. Fasted to fed increases in hepatic FAAH(-/-) acetyl-CoA (85%, p<0.01) corresponded to similar increases in citrate levels (45%). Altered FAAH(-/-) mitochondrial malate dehydrogenase (MDH2) acetylation, which can affect the malate aspartate shuttle, was consistent with our observation of a 25% decrease in fed malate and aspartate levels. Decreased fasted but not fed dihydroxyacetone-P and glycerol-3-P levels in FAAH(-/-) mice was consistent with a compensating contribution from decreased acetylation of fed FAAH(-/-) aldolase B. Fed FAAH(-/-) alcohol dehydrogenase (ADH) acetylation was also decreased. Whole body FAAH deletion contributes to a pre-diabetic phenotype by mechanisms resulting in impairment of hepatic glucose and lipid metabolism. FAAH(-/-) mice had altered hepatic lysine acetylation, the pattern sharing similarities with acetylation changes reported with chronic alcohol treatment. Dysregulated hepatic lysine acetylation seen with impaired FAA hydrolysis could support the liver's role in fostering the pre-diabetic state, and may reflect part of the mechanism underlying the hepatic effects of endocannabinoids in alcoholic liver disease mouse models.


Interventions Supporting Mental Health and Positive Behavior in Children Ages Birth-5 Yr: A Systematic Review.
It is critical for providers to use evidence-based interventions to address mental health and behavioral barriers to occupational performance during early childhood. To identify evidence-based interventions within the scope of occupational therapy practice to improve mental health and positive behavior for children ages 0-5 yr and their families. PsycINFO, Cochrane, ERIC, MEDLINE, and OTseeker databases were searched for publications from 2010 through March 2017. This review was completed in accordance with the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines. Risk of bias was assessed for each article using either A Measurement Tool to Assess Systematic Reviews (AMSTAR) or the Cochrane method. Articles meeting inclusion criteria were critically appraised. Forty-six articles met inclusion criteria and were organized into three themes: touch-based interventions (n = 9), parent-child interaction therapy (PCIT; n = 4), and instruction-based interventions (n = 33). Statistically significant findings and overall risk of bias supported the use of touch-based interventions, PCIT, and parent training. The evidence indicates that touch-based interventions can improve infant self-regulation (strong), social behavior, and attachment (moderate) and reduce maternal stress, anxiety, and depression (low). Moderate-strength evidence supports PCIT to improve child behavior. The evidence indicates that parent training can improve parent behavior, maternal-infant attachment (strong), and parent mental health (moderate). Teacher training can improve mental health and behavior (moderate). Group-based parent training and sleep training have insufficient support (low). Occupational therapy professionals working with children younger than age 5 yr can use the results of this systematic review to guide clinical decision making related to mental health and behavioral outcomes.


HIV cure strategies: how good must they be to improve on current antiretroviral therapy?
We examined efficacy, toxicity, relapse, cost, and quality-of-life thresholds of hypothetical HIV cure interventions that would make them cost-effective compared to life-long antiretroviral therapy (ART). We used a computer simulation model to assess three HIV cure strategies: Gene Therapy, Chemotherapy, and Stem Cell Transplantation (SCT), each compared to ART. Efficacy and cost parameters were varied widely in sensitivity analysis. Outcomes included quality-adjusted life expectancy, lifetime cost, and cost-effectiveness in dollars/quality-adjusted life year ($/QALY) gained. Strategies were deemed cost-effective with incremental cost-effectiveness ratios <$100,000/QALY. For patients on ART, discounted quality-adjusted life expectancy was 16.4 years and lifetime costs were $591,400. Gene Therapy was cost-effective with efficacy of 10%, relapse rate 0.5%/month, and cost $54,000. Chemotherapy was cost-effective with efficacy of 88%, relapse rate 0.5%/month, and cost $12,400/month for 24 months. At $150,000/procedure, SCT was cost-effective with efficacy of 79% and relapse rate 0.5%/month. Moderate efficacy increases and cost reductions made Gene Therapy cost-saving, but substantial efficacy/cost changes were needed to make Chemotherapy or SCT cost-saving. Depending on efficacy, relapse rate, and cost, cure strategies could be cost-effective compared to current ART and potentially cost-saving. These results may help provide performance targets for developing cure strategies for HIV.


Heart and liver disease in 32 patients undergoing biopsy of both organs, with implications for heart or liver transplantation.
To determine underlying conditions in patients undergoing both heart and liver biopsies. Our study group consisted of 32 patients at the Mayo Clinic in Rochester, Minn, who underwent both endomyocardial and nonsurgical liver biopsies and who underwent at least one of these procedures between January 1,1981, and December 31,2000. Patients were categorized as having (1) heart disease affecting the liver, (2) liver disease affecting the heart, (3) the same disease affecting both organs, or (4) different diseases affecting each organ independently. Among 32 patients, cardiac dysfunction was present in 28 (19 systolic, 9 diastolic), and hepatic dysfunction was present in 31. In group 1, 3 of 4 patients had cardiac amyloidosis with secondary hepatic congestion. In group 2, all 3 patients had cirrhosis with cirrhotic cardiomyopathy. Group 3 included 5 patients with hemochromatosis, 3 with alcoholism, and 1 with amyloidosis. In group 4, 8 of 16 patients had idiopathic cardiomyopathy, and 8 had hepatitis. Overall, of 8 patients with hemochromatosis, 3 without cardiac iron had improved cardiac function after phlebotomy, and 1 with cardiac iron had no cardiac dysfunction. Among 7 patients with alcoholism, 3 had alcoholic liver and heart disease. Of 5 patients with cardiac amyloidosis, 1 had hepatic amyloid. Ten patients underwent transplantation (6 liver, 3 heart, and 1 heart and liver). In one half of the patients in the study group, heart and liver diseases had independent causes. In patients with hemochromatosis, there was little correlation between cardiac iron and systolic dysfunction. In patients with chronic alcoholism, liver and heart disorders often had nonalcoholic causes. With cardiac amyloidosis, hepatic dysfunction was generally due to congestion. Specific disease in one organ did not necessarily imply similar involvement in the other. Thus, heart or liver biopsy may be useful in patients being evaluated for liver or heart transplantation, respectively.


High-efficiency high performance liquid chromatographic analysis of red wine anthocyanins.
The analysis of anthocyanins in natural products is of significant relevance in recent times due to the recognised health benefits associated with their consumption. In red grapes and wines in particular, anthocyanins are known to contribute important properties to the sensory (colour and taste), anti-oxidant- and ageing characteristics. However, the detailed investigation of the alteration of these compounds during wine ageing is hampered by the challenges associated with the separation of grape-derived anthocyanins and their derived products. High performance liquid chromatography (HPLC) is primarily used for this purpose, often in combination with mass spectrometric (MS) detection, although conventional HPLC methods provide incomplete resolution. We have previously demonstrated how on-column inter-conversion reactions are responsible for poor chromatographic efficiency in the HPLC analysis of anthocyanins, and how an increase in temperature and decrease in particle size may improve the chromatographic performance. In the current contribution an experimental configuration for the high efficiency analysis of anthocyanins is derived using the kinetic plot method (KPM). Further, it is shown how analysis under optimal conditions, in combination with MS detection, delivers much improved separation and identification of red wine anthocyanins and their derived products. This improved analytical performance holds promise for the in-depth investigation of these influential compounds in wine during ageing.


Shedding light on fish otolith biomineralization using a bioenergetic approach.
Otoliths are biocalcified bodies connected to the sensory system in the inner ears of fish. Their layered, biorhythm-following formation provides individual records of the age, the individual history and the natural environment of extinct and living fish species. Such data are critical for ecosystem and fisheries monitoring. They however often lack validation and the poor understanding of biomineralization mechanisms has led to striking examples of misinterpretations and subsequent erroneous conclusions in fish ecology and fisheries management. Here we develop and validate a numerical model of otolith biomineralization. Based on a general bioenergetic theory, it disentangles the complex interplay between metabolic and temperature effects on biomineralization. This model resolves controversial issues and explains poorly understood observations of otolith formation. It represents a unique simulation tool to improve otolith interpretation and applications, and, beyond, to address the effects of both climate change and ocean acidification on other biomineralizing organisms such as corals and bivalves.


Assessing the impact of global versus local ancestry in association studies.
To account for population stratification in association studies, principal-components analysis is often performed on single-nucleotide polymorphisms (SNPs) across the genome. Here, we use Framingham Heart Study (FHS) Genetic Analysis Workshop 16 data to compare the performance of local ancestry adjustment for population stratification based on principal components (PCs) estimated from SNPs in a local chromosomal region with global ancestry adjustment based on PCs estimated from genome-wide SNPs. Standardized height residuals from unrelated adults from the FHS Offspring Cohort were averaged from longitudinal data. PCs of SNP genotype data were calculated to represent individual's ancestry either 1) globally using all SNPs across the genome or 2) locally using SNPs in adjacent 20-Mbp regions within each chromosome. We assessed the extent to which there were differences in association studies of height depending on whether PCs for global, local, or both global and local ancestry were included as covariates. The correlations between local and global PCs were low (r < 0.12), suggesting variability between local and global ancestry estimates. Genome-wide association tests without any ancestry adjustment demonstrated an inflated type I error rate that decreased with adjustment for local ancestry, global ancestry, or both. A known spurious association was replicated for SNPs within the lactase gene, and this false-positive association was abolished by adjustment with local or global ancestry PCs. Population stratification is a potential source of bias in this seemingly homogenous FHS population. However, local and global PCs derived from SNPs appear to provide adequate information about ancestry.


Skin and soft-tissue infections caused by Aeromonas species.
This study investigated the clinical characteristics of patients with skin and soft-tissue infections (SSTIs) due to Aeromonas species. Patients with SSTIs caused by Aeromonas species during the period from January 2009 to December 2011 were identified from a computerized database of a regional hospital in southern Taiwan. The medical records of these patients were retrospectively reviewed. A total of 129 patients with SSTIs due to Aeromonas species were identified. A. hydrophila (n = 77, 59.7 %) was the most common pathogen, followed by A. veronii biovar sobria (n = 22, 17.1 %), A. veronii biovar veronii (n = 20, 15.5 %), A. caviae (n = 9, 7.0 %), and A. schubertii (n = 1, 0.8 %). The most common isolates obtained from patients with polymicrobial infections were Klebsiella species (n = 33), followed by Enterococcus spp. (n = 24), Enterobacter spp. (n = 21), Escherichia coli (n = 17), Staphylococcus spp. (n = 17), Streptococcus spp. (n = 17), and Acinetobacter spp. (n = 15). Liver cirrhosis and concomitant bacteremia were more common among patients with monomicrobial Aeromonas SSTIs than among patients with polymicrobial SSTIs. Nine (7 %) patients required limb amputations. The in-hospital mortality rate was 1.6 %. In conclusion, Aeromonas species should be considered as important causative pathogens of SSTIs, and most infections are polymicrobial. In addition, the clinical presentation differs markedly between patients with monomicrobial and those with polymicrobial Aeromonas SSTIs.


Despite a massive increase in cortisol secretion in women during parturition, there is an equally massive increase in prostaglandin synthesis. A paradox?
In this investigation, we sought to resolve the apparent paradox that is posed by the fact that there is a simultaneous increase in the production of prostaglandin and cortisol in women during labor. A paradox obtains, since in most tissues, cortisol acts to inhibit prostaglandin formation. Using previously characterized model systems for the in vitro study of arachidonic acid metabolism in amnion, decidua, and myometrium, we found that prostaglandin production by amnion and endometrial stromal cells in monolayer culture was not decreased by glucocorticosteroid treatment. On the other hand, prostaglandin production by myometrial smooth muscle cells in culture was inhibited by greater than 90% in response to dexamethasone (10(-7) M) treatment. Importantly, the major prostaglandin produced by myometrium, as well as myometrial smooth muscle cells in culture, is prostacyclin, a prostaglandin that acts to cause uterine quiescence. We suggest that the immunity of amnion and decidua to the action of glucocorticosteroids may allow for the accelerated production of prostaglandins E2 and F2 alpha, which act to cause myometrial contractions; simultaneously, glucocorticosteroid produced in large quantities in women in labor may lead to decreased production of prostacyclin by myometrium, thereby reducing uterine quiescence. In this coordinated manner, the uterine contractions that culminate in delivery of the fetus may proceed uninterrupted in the face of increased cortisol production.


Exploring the Interaction of Motor and Social Skills With Autism Severity Using the SFARI Dataset.
Social communicative deficits and stereotyped or repetitive interests or behaviors are the defining features of autism spectrum disorder (ASD). A growing body of research suggests that gross motor deficits are also present in most children with ASD. This study sought to understand how pediatric ASD severity is related to motor skills and social skills. A multivariate analysis of variance analysis of 483 children with autism ( N = 444) and ASD ( N = 39) revealed a nonsignificant difference between groups. Results suggest little difference between severity groups on gross motor and social skills within the limited age range of the participants (about 5.6 years of age).


Plasticity of transposed rhombomeres: Hox gene induction is correlated with phenotypic modifications.
In this study we have analysed the expression of Hoxb-4, Hoxb-1, Hoxa-3, Hoxb-3, Hoxa-4 and Hoxd-4 in the neural tube of chick and quail embryos after rhombomere (r) heterotopic transplantations within the rhombencephalic area. Grafting experiments were carried out at the 5-somite stage, i.e. before rhombomere boundaries are visible. They were preceeded by the establishment of the precise fate map of the rhombencephalon in order to determine the presumptive territory corresponding to each rhombomere. When a rhombomere is transplanted from a caudal to a more rostral position it expresses the same set of Hox genes as in situ. By contrast in many cases, if rhombomeres are transplanted from rostral to caudal their Hox gene expression pattern is modified. They express genes normally activated at the new location of the explant, as evidenced by unilateral grafting. This induction occurs whether transplantation is carried out before or after rhombomere boundary formation. Moreover, the fate of the cells of caudally transplanted rhombomeres is modified: the rhombencephalic nuclei in the graft develop according to the new location as shown for an r5/6 to r8 transplantation. Transplantation of 5 consecutive rhombomeres (i.e. r2 to r6), to the r8 level leads to the induction of Hoxb-4 in the two posteriormost rhombomeres but not in r2,3,4. Transplantations to more caudal regions (posterior to somite 3) result in some cases in the induction of Hoxb-4 in the whole transplant. Neither the mesoderm lateral to the graft nor the notochord is responsible for the induction. Thus, the inductive signal emanates from the neural tube itself, suggesting that planar signalling and predominance of posterior properties are involved in the patterning of the neural primordium.


Mood-congruent true and false memory: effects of depression.
The Deese/Roediger-McDermott paradigm was used to investigate the effect of depression on true and false recognition. In this experiment true and false recognition was examined across positive, neutral, negative, and depression-relevant lists for individuals with and without a diagnosis of major depressive disorder. Results showed that participants with major depressive disorder falsely recognised significantly more depression-relevant words than non-depressed controls. These findings also parallel recent research using recall instead of recognition and show that there are clear mood congruence effects for depression on false memory performance.


Application of Ethics for Providing Telemedicine Services and Information Technology.
Advanced technology has increased the use of telemedicine and Information Technology (IT) in treating or rehabilitating diseases. An increased use of technology increases the importance of the ethical issues involved. The need for keeping patients' information confidential and secure, controlling a number of therapists' inefficiency as well as raising the quality of healthcare services necessitates adequate heed to ethical issues in telemedicine provision. The goal of this review is gathering all articles that are published through 5 years until now (2012-2017) for detecting ethical issues for providing telemedicine services and Information technology. The reason of this time is improvement of telemedicine and technology through these years. This article is important for clinical practice and also to world, because of knowing ethical issues in telemedicine and technology are always important factors for physician and health providers. the required data in this research were derived from published electronic sources and credible academic articles published in such databases as PubMed, Scopus and Science Direct. The following key words were searched for in separation and combination: tele-health, telemedicine, ethical issues in telemedicine. A total of 503 articles were found. After excluding the duplicates (n= 93), the titles and abstracts of 410 articles were skimmed according to the inclusion criteria. Finally, 64 articles remained. They were reviewed in full text and 36 articles were excluded. At the end, 28 articles were chosen which met our eligibility criteria and were included in this study. Ethics has been of a great significance in IT and telemedicine especially the Internet since there are more chances provided for accessing information. It is, however, accompanied by a threat to patients' personal information. Therefore, suggestions are made to investigate ethics in technology, to offer standards and guidelines to therapists. Due to the advancement in technology, access to information has become simpler than the past. This has prompted hackers to seize the opportunity. This research shows that the ethical issues in telemedicine can be investigated from several aspects like technology, doctor-patient relationship, data confidentiality and security, informed consent, patient's and family's satisfaction with telemedicine services. Following ethical issues in telemedicine is a primary aspect of high quality services. In other words, if therapists abide by ethical rules, they can provide better services for patients. Attention to ethical issues in telemedicine guarantees a safer use of the services.


A study of IMRT planning parameters on planning efficiency, delivery efficiency, and plan quality.
To improve planning and delivery efficiency of head and neck IMRT without compromising planning quality through the evaluation of inverse planning parameters. Eleven head and neck patients with pre-existing IMRT treatment plans were selected for this retrospective study. The Pinnacle treatment planning system (TPS) was used to compute new treatment plans for each patient by varying the individual or the combined parameters of dose∕fluence grid resolution, minimum MU per segment, and minimum segment area. Forty-five plans per patient were generated with the following variations: 4 dose∕fluence grid resolution plans, 12 minimum segment area plans, 9 minimum MU plans, and 20 combined minimum segment area∕minimum MU plans. Each plan was evaluated and compared to others based on dose volume histograms (DVHs) (i.e., plan quality), planning time, and delivery time. To evaluate delivery efficiency, a model was developed that estimated the delivery time of a treatment plan, and validated through measurements on an Elekta Synergy linear accelerator. The uncertainty (i.e., variation) of the dose-volume index due to dose calculation grid variation was as high as 8.2% (5.5 Gy in absolute dose) for planning target volumes (PTVs) and 13.3% (2.1 Gy in absolute dose) for planning at risk volumes (PRVs). Comparison results of dose distributions indicated that smaller volumes were more susceptible to uncertainties. The grid resolution of a 4 mm dose grid with a 2 mm fluence grid was recommended, since it can reduce the final dose calculation time by 63% compared to the accepted standard (2 mm dose grid with a 2 mm fluence grid resolution) while maintaining a similar level of dose-volume index variation. Threshold values that maintained adequate plan quality (DVH results of the PTVs and PRVs remained satisfied for their dose objectives) were 5 cm(2) for minimum segment area and 5 MU for minimum MU. As the minimum MU parameter was increased, the number of segments and delivery time were decreased. Increasing the minimum segment area parameter decreased the plan MU, but had less of an effect on the number of segments and delivery time. Our delivery time model predicted delivery time to within 1.8%. Increasing the dose grid while maintaining a small fluence grid allows for improved planning efficiency without compromising plan quality. Delivery efficiency can be improved by increasing the minimum MU, but not the minimum segment area. However, increasing the respective minimum MU and∕or the minimum segment area to any value greater than 5 MU and 5 cm(2) is not recommended because it degrades plan quality.


Endoscopic physiologic approach to allergy-associated chronic rhinosinusitis: a preliminary study.
Patients with allergy-associated chronic rhinosinusitis respond poorly to functional endoscopic sinus surgery (FESS), probably because of the altered nasosinus ventilatory physiology and the increased contamination of the nasosinus mucosa by the offending allergens. With this in mind, we describe the concept and technique of functional endoscopic nasosinus surgery (FENS) in such cases. The advantages of this technique are that it preserves the uncinate process, it limits ethmoidal exenteration via a transbullar approach, and it simultaneously corrects both septal and lateral wall pathologies. The aim of our randomized prospective study was to subjectively and objectively compare the efficacy of FESS and FENS in 64 patients with allergy-associated chronic rhinosinusitis. Subjective assessment was ascertained by visual analog scores, and objective assessment was made by nasal endoscopy. In this preliminary study, we found that FENS was superior to FESS in treating chronic sinusitis associated with nasal allergy.


Glycosylation status of the membrane protein CD9P-1.
The membrane protein CD9P-1 is a major component of the tetraspanin web, a network of molecular interactions in the plasma membrane, in which it specifically associates with tetraspanins CD9 and CD81. The various functional effects of CD9 and CD81 may be related to their partners. Thus, we have addressed the characterization of the CD9P-1 glycosylation using stably transfected HEK-293 cells. After immunoprecipitation, CD9P-1 was subjected to enzymatic PNGase F cleavage of N-glycans, resulting in Asn to Asp conversion and increase in 1 mass unit. Thus, following protease digestion, deglycosylated peptides were selectively identified by high mass accuracy FTICR-MS, using this conversion as a signature. This has demonstrated that all nine potential N-glycosylation sites were actually engaged. On the other hand, the N-glycan structures were determined combining chemical derivatization and exoglycosidase digestions followed by MALDI-TOF MS, ESI-MS/MS, and GC-MS analysis. CD9P-1 was shown to exhibit more than 40 different N-glycans, essentially composed of complex and high mannose-type structures. Finally, 2-D PAGE and lectino-blot analyses have revealed the presence of at least 17 glycosylated isoforms of CD9P-1 at cell surface. All CD9P-1 isoforms associate with CD9 leading to additional level of complexity of this primary complex in the tetraspanin web.


Use of calcium hydroxylapatite in the upper third of the face: Retrospective analysis of techniques, dilutions and adverse events.
Calcium hydroxylapatite (CaHA) is a commonly used soft tissue filler for aesthetic facial improvement, in particular for the lower and mid-face. The golden standard for upper facial filler indications is hyaluronic acid (HA) injection. In this report we investigate the safety, efficacy and complication rates after injections of CaHA to the upper third of the face using a variety of different techniques. This was a retrospective analysis performed on patients who had received CaHA in 2016 and 2017 at various dilutions in the upper third of the face (frontal area, eyebrows and temporal hollows) using a number of injection techniques and both blunt-tipped cannulas as well as sharp needles. Records of adverse events and side effects were studied. Seventy patients had been injected with CaHA in the upper third of the face. There were 36 treatments to the frontal area, most with a cannula in the subgaleal space with standard dilution of CaHA (16.7% lidocaine containing epinephrine). There were 13 treatments to the brow, mostly with a cannula and multilevel technique, and 66 treatments to the temporal hollows, mostly with a cannula in the interfascial space with standard CaHA dilution. No serious complications were recorded. CaHA was effective and well-tolerated for a range of upper-face indications. More (prospective) research is required to further determine the value of CaHA treatments in these areas.


Bee venom inhibits the proliferation and migration of cervical-cancer cells in an HPV E6/E7-dependent manner.
Bee venom (BV), secreted from the venom gland of the honey bee, contains several biological active compounds. BV has been widely used as a traditional medicine for treating human disease, including cancer. In this study, we have shown the molecular mechanism underlying the therapeutic effect of BV on cancer. Treatment with BV reduced the proliferation of cervical-cancer cells in a dose- and time-dependent manner. Interestingly, the killing effect of BV was specific to HPVpositive cervical-cancer cell lines, such as Caski and HeLa cells, and not to HPV-negative cervical-cancer cells (C33A). BV reduced the expression of HPV E6 and E7 at RNA and protein levels, leading to an increase in the expression of p53 and Rb in Caski and HeLa cells. Further, BV decreased the levels of cell-cycle proteins, such as cyclin A and B, and increased the levels of cell-cycle inhibitors, such as p21 and p27. BV significantly induced apoptosis and inhibited wound healing and migration of cervical-cancer cells. It also upregulated the expression of pro-apoptotic BAX and downregulated the expression of anti-apoptotic Bcl-2 and Bcl-XL. Cleavage of caspase-3, caspase-9, and PARP were also induced by BV treatment, whereas the phosphorylation of mitogenic signalingrelated proteins, such as AKT, JNK, p38, and ERK, were downregulated. Our results indicate that BV has a therapeutic selectivity for HPV-positive malignant cells, so further clinical studies are needed to assess its clinical application. [BMB Reports 2020; 53(8): 419-424].


Strength indices of the proximal femur and shaft in prepubertal female gymnasts.
The role of impact loading activity on bone mass is well established; however, there are little data on the effects of exercise on bone geometry and indices of bone strength. The primary purpose of this study was to compare indices of bone strength at the proximal femur (PF) between elite premenarcheal gymnasts (N= 30) and age-matched controls (N= 30). Structural properties of the proximal femur were derived from the hip analyses program and included measurement of subperiosteal width, endosteal diameter, cross-sectional area, bone mineral density, cross-section moment of inertia (CSMI), and section modulus (Z). These parameters were measured for two regions of the PF: the narrow neck (NN), and the shaft (S). In addition, a strength index (S-SI) was calculated at the shaft by dividing the Z at the shaft by the femur length. A secondary purpose was to compare bone mineral content (BMC) values at the total body, lumbar spine, and three sites at the PF (neck, trochanter, and total) between the groups. All dependent values were compared adjusting for height and weight using an ANCOVA procedure and for relative lean body mass. RESULTS The gymnasts had significantly greater size-adjusted strength indices (CSMI, Z, and SI) at the NN and S. Gymnasts also had significantly greater size-adjusted BMC at all sites investigated. However, these differences disappeared when adjusted for relative lean body mass. When adjusted for body size, gymnasts had significantly greater indices of both axial strength and bending strength at the NN region of the PF and S, as well as a greater bone SI at the femoral shaft. These differences may be related to greater relative lean body mass attained in gymnastics training.