Plasma Bead Entrapped Liposomes as a Potential Drug Delivery System to Combat Fungal Infections.
Fibrin-based systems offer promises in drug and gene delivery as well as tissue engineering. We established earlier a fibrin-based plasma beads (PB) system as an efficient carrier of drugs and antigens. In the present work, attempts were made to further improve its therapeutic efficacy exploiting innovative ideas, including the use of plasma alginate composite matrices, proteolytic inhibitors, cross linkers, and dual entrapment in various liposomal formulations. In vitro efficacy of the different formulations was examined. Pharmacokinetics of the formulations encapsulating Amphotericin B (AmpB), an antifungal compound, were investigated in Swiss albino mice. While administration of the free AmpB led to its rapid elimination (<72 h), PB/liposome-PB systems were significantly effective in sustaining AmpB release in the circulation (>144 h) and its gradual accumulation in the vital organs, also compared to the liposomal formulations alone. Interestingly, the slow release of AmpB from PB was unusual compared to other small molecules in our earlier findings, suggesting strong interaction with plasma proteins. Molecular interaction studies of bovine serum albumin constituting approximately 60% of plasma with AmpB using isothermal titration calorimetry and in silico docking verify these interactions, explaining the slow release of AmpB entrapped in PB alone. The above findings suggest that PB/liposome-PB could be used as safe and effective delivery systems to combat fungal infections in humans.


A Descriptive Exploratory Study of the Causes and Effects of Hypertension Among Ghanaian Soldiers and Their Families.
The quality of life of any soldier can be affected by a simple diagnosis of Hypertension. Hypertension has not been directly linked to a single cause; however, knowing the associated risks and early diagnosis can help with its management. This study aimed to explore and describe the causes of hypertension among soldiers and its effects on their families. To explore and describe the causes of hypertension and its effects on soldiers and their families. A qualitative technique and an exploratory descriptive design were used in this study. At saturation, a total of 10 soldiers were face-to-face interviewed and gathered data simultaneously transcribed and subjected to a content analytic method of analysis. Participants approved being audio recorded on tape with an audio recording device. Effects of hypertension on personal lives of soldiers, effects of hypertension on family life, and effects of hypertension on social life were identified as the causes and risk factors of hypertension among the soldiers. These themes are further expanded by their subthemes in the areas of decreased physical activity including sex life, decrease interaction with family, and isolation from friends. This study revealed that hypertension does have effects on one's personal life, family life, and social life. Hence, it is recommended that frequent health education on hypertension and its effects should be organized in the various Garrisons by the public health department for all soldiers and their families. Screening programs should be organized for early hypertension detection. Soldiers should be educated on appropriate eating habits, weight and financial management, and reduction in tobacco and alcohol.


Ashkin-Teller model and diverse opinion phase transitions on multiplex networks.
Multiplex networks (MNs) have become a platform of recent research in network sciences because networks in many real-world systems interact and function together. One of the main scientific issues in MNs is how the interdependence changes the emerging patterns or phase transitions. Until now, studies of such an issue have concentrated on cluster-breakdown phenomena, aiming to understand the resilience of the system under random failures of edges. These studies have revealed that various phase transition (PT) types emerge in MNs. However, such studies are rather limited to percolation-related problems, i.e., the limit q→1 of the q-state Potts model. Thus, a systematic study of opinion formation in social networks with the effect of interdependence between different social communities, which may be seen as the study of the emerging pattern of the Ising model on MNs, is needed. Here we study a well-known spin model called the Ashkin-Teller (AT) model in scale-free networks. The AT model can be regarded as a model for interacting systems between two species of Ising spins placed on respective layers in double-layer networks. Our study shows that, depending on the interlayer coupling strength and a network topology, unconventional PT patterns can also emerge in interaction-based phenomena: continuous, discontinuous, successive, and mixed-order PTs and a continuous PT not satisfying the scaling relation. The origins of such rich PT patterns are elucidated in the framework of Landau-Ginzburg theory.


Conflicts over control and use of medical records at the New York hospital before the standardization movement.
Historians of medicine generally credit the hospital standardization movement of the early 20th century with establishing the record as a sign of hospital and staff quality. The medical record's role had already been the subject of intense interest at the New York Hospital several decades before, however. In the 1880s malpractice and insurance concerns caused the administration to attempt to supervise record creation, quality, and access, over the objections of physicians. Contemporary concerns about the uses of the medical record were in play well before 1910.


Innovative solid desiccant dehumidification using distributed microwaves.
Dehumidification is one of the key challenges facing the air conditioning (AC) industry in the treatment of moist air. Over many decades, the dual role of heat exchangers of AC chillers for the sensible and latent cooling of space has hindered the thermal-lift reduction in the refrigeration cycle due to the requirements of water vapor removal at dew-point and heat rejection to the ambient air. These practical constraints of AC chillers have resulted in the leveling of energy efficiency of mechanical vapor compressors (MVC) for many decades. One promising approach to energy efficiency improvement is the decoupling of dehumidification from sensible processes so that innovative but separate processes can be applied. In this paper, an advanced microwave dehumidification method is investigated in the laboratory, where the microwave (2.45 GHz) energy can be irradiated onto the dipole structure of water vapor molecules, desorbing rapidly from the pores of adsorbent. Results show a significant improvement in performance for microwave dehumidification, up to fourfold, as compared to data available in the literature.


Collision tumor: invasive ductal carcinoma in association with mucosa-associated lymphoid tissue (MALT) lymphoma in the same breast.
Synchronous occurrence of multiple neoplastic processes is uncommon and the relationship between breast cancer with lymphoproliferative diseases is unusual as well. Furthermore, breast involvement by malignant lymphoma is a rare event and primary breast mucosa-associated lymphoid tissue (MALT) lymphoma is even rarer. We report a patient with synchronous occurrence of malignant lymphoma of MALT type and ductal carcinoma of the breast, presenting as "collision tumor," invading each other and occurring as a single mass in the breast. Involvement of the sentinel lymph node by MALT lymphoma was demonstrated with no evidence of metastatic carcinoma. Staging bone marrow biopsy did not show involvement by malignant lymphoma or carcinoma. Our patient was treated with chemotherapy for the lymphoma. She also received radiotherapy and aromatase inhibitor as adjuvant therapy for the breast carcinoma.


Morphological ontogeny of Oribatella hungarica (Acari: Oribatida: Oribatellidae).
The morphological ontogeny of Oribatella hungarica Balogh, 1943 is described and illustrated. The nymphs of this species are apopheredermous, i.e. they carry the exuvial scalps of previous instars away from the dorsal integument, using modified setal pair da. The larva has 12 pairs of gastronotal setae, most of them have long barbs, except for c3 with short barbs and minute h3, whereas the nymphs have 13 pairs with short barbs (dm and dp are lacking). In the tritonymph, leg seta d on all femora and genu IV, l" on femora I and II and pair l on genua and tibiae I and II, l' on femur III and genua and tibiae III and IV, and ft on tarsi II-IV are thicker than other setae on these segments. In all juveniles, a humeral organ is present. In the adult, epimeral seta 4c and leg seta l" on genua and tibiae I and II, and l' on genu III and genu and tibia IV are thickened.


Novel structurally altered P(2X1) receptor is preferentially activated by adenosine diphosphate in platelets and megakaryocytic cells.
Experimental and clinical data suggest the presence of multiple types of adenosine diphosphate (ADP) receptors, one coupled to ligand-gated cation channels (P(2X)) and others coupled to G-protein-coupled (P(2Y)) receptors. This report identifies cDNA for a structurally altered P(2X1)-like receptor in megakaryocytic cell lines (Dami and CMK 11-5) and platelets that, when transfected into nonresponsive 1321 cells, confers a specific sensitivity to ADP with the pharmacologic rank order of ADP > > ATP > > > alpha,beta-methylene-ATP as measured by Ca(++) influx. This receptor (P(2X1del)) contains a deletion of 17 amino acids (PALLREAENFTLFIKNS) that includes an NFT consensus sequence for N-linked glycosylation. Glycosylated forms of the P(2X1del) and P(2X1wt) receptors were indistinguishable electrophoretically by Western blot or by immunoprecipitation using available antihuman and antirat antibodies. These results indicate that the expression of the P(2X1del) receptor results in an influx of Ca(++) induced by ADP. Expression of P(2X1del) receptor homomeric subunits is sufficient to express a receptor preferentially activated by ADP and suggests that this altered form, alone or in combination with P(2X1wt) receptors, is a component of an ADP-activated ion channel.


An integrated PCR microfluidic chip incorporating aseptic electrochemical cell lysis and capillary electrophoresis amperometric DNA detection for rapid and quantitative genetic analysis.
A fully integrated microchip for performing cell lysis, polymerase chain reaction (PCR) and quantitative analysis of DNA amplicons in a single step is described herein. The chip was built on glass substrate using an indium-tin-oxide (ITO) microheater and PDMS engraved microchannels, which integrated an electrochemical cell lysis zone, a continuous flow PCR module and capillary electrophoresis amperometric detection (CE-AD) system. The total length of the microchannel was 4625 mm for performing 25 cycles of flow-through PCR and was laid on a handheld form factor of 96 × 96 mm(2) area. The key to the fabrication of such a device lies in the use of a single medium to carry out different kinds of biochemical reactions and hence, a reagentless electrochemical cell lysis protocol was integrated on the microchip which was capable of lysing most cell types, including difficult to lyse gram positive bacteria. The lysate contained genomic DNA from a sample which was proven to be suitable for PCR reactions. Genetic analysis was successfully performed on the microchip with purified lambda phage genomic DNA and various cell types, including non-tumorigenic MCF-10A and tumorigenic MCF-7 human cell lines, gram negative bacteria Escherichia coli O157:H7, and gram positive bacteria Bacillus subtilis, at an optimized flow rate of 5 μl min(-1). For the detection of amplicon DNA, a CE-AD system was used, with semisolid alkaline agarose within the capillary microchannel to minimize interference from cell debris and for efficient resolution of DNA fragments. High signal to noise ratio during amperometric detection and the use of online FFT filtering protocol enhanced the limit of detection of DNA amplicons. Therefore, with a combination of portability, cost-effectiveness and performance, the proposed integrated PCR microchip can be used for one step genetic analysis of most of the cell types and will enable more accessible healthcare.


Superoxide Production under Soft X-ray Irradiation of Liquid Water.
Soft X-rays behave like particles with high linear energy transfer, as they deposit a large amount of their energy in the nanometric range, triggered by inner-shell ionization. In water, this can lead to the formation of a doubly ionized water molecule (H2O2+) and the emission of two secondary electrons (photoelectron and Auger electron). Our focus lies on detecting and quantifying the superoxide (HO2°) production via the direct pathway, i.e., from the reaction between the dissociation product of H2O2+, i.e., the oxygen atom (∼4 fs), and the °OH radicals present in the secondary electron tracks. The HO2° yield for 1620 eV photons, via this reaction pathway, was found to be 0.005 (±0.0007) μmol/J (formed within the ∼ps range). Experiments were also performed to determine the yield of HO2° production via another (indirect) pathway, involving solvated electrons. The indirect HO2° yield, measured experimentally as a function of photon energy (from 1700 to 350 eV), resulted in a steep decrease at around 1280 eV and a minimum close to zero at 800 eV. This behavior in contradiction with the theoretical prediction reveals the complexity hidden in the intratrack reactions.


Highly sensitive electrochemical detection of proteins using aptamer-coated gold nanoparticles and surface enzyme reactions.
A novel electrochemical detection methodology is described for the femtomolar detection of proteins which utilizes both DNA aptamer-functionalized nanoparticles and a surface enzymatic reaction. Immunoglobulin E (IgE) was used as a model protein biomarker, which possesses two distinct epitopes for antibody (anti-IgE) and DNA aptamer binding. A surface sandwich assay format was utilized involving the specific adsorption of IgE onto a gold electrode surface that was pre-modified with a monolayer of aptamer-nanoparticle conjugates followed by the specific interaction of alkaline phosphatase (ALP) conjugated anti-IgE. To clearly demonstrate the signal enhancement associated with nanoparticle use, anodic current measurements of the ALP catalyzed oxidation of the enzyme substrate 4-aminophenylphosphate (APP) were also compared with electrode surfaces upon which the aptamer was directly attached. The detection of an unlabelled protein at concentrations as low as 5 fM is a significant improvement compared to conventional electrochemical-based immunoassay approaches and provides a foundation for the practical use and incorporation of nanoparticle-enhanced detection into electrochemical biosensing technologies.


Photorelease of incarcerated guests in aqueous solution with phenacyl esters as the trigger.
We report the clean, efficient photorelease of a series of carboxylic acids embedded in octa acid (OA) host and protected by a p-hydroxyphenacyl cage. A key role is played by the cage by providing hydrophobicity for entry into the OA enclosure and yet readily removable as a photoactivated protecting group for release from the host. The rapid photo-Favorskii rearrangement of the departing chromophore does not react with the host OA but diminishes hydrophobicity of the OA contents, leading to their facile release into the solvent.


Content and quality of website information on the treatment of oral ulcers.
To determine the type, accuracy and content of information available on the Internet regarding the treatment of oral ulcers. The search engine Google was used to generate a list of top 100 websites about 'mouth ulcer treatment'. The websites were evaluated using the DISCERN instrument and the JAMA benchmarks. Whether the site displayed the Health on the Net (HON) seal was also recorded. The search yielded 1,460,000 sites on the Google website. Of the top 100 sites a total of 54 sites were suitable for analysis due to duplicate links and non-functioning links. Of the websites analysed, 31.5% achieved all four JAMA benchmarks and 13% achieved only one benchmark. No website receiving the maximum mark on the overall score and six websites received the lowest overall score regarding the DISCERN instrument. The questions with the poorest response score were 'Does it describe how the treatment choices affect overall quality of life?' and 'Does it provide support for shared decision-making?'. Only 7.4% of the websites displayed the HON seal. Diverse information regarding the treatment of oral ulcers is available on the Internet with variable accuracy levels based on both JAMA benchmarks and DISCERN.


Effect of two AMF life strategies on the tripartite symbiosis with Bradyrhizobium japonicum and soybean.
This study is the first in assessing the effect of soil disturbance on the contribution of arbuscular mycorrhizal fungi (AMF) with different life-history strategies to the tripartite symbiosis with soybeans and Bradyrhizobium japonicum (Kirchner) Jordan. We hypothesized that Gigaspora margarita Becker and Hall would be more affected by soil disturbance than Glomus clarum Nicol. and Schenck, and consequently, the tripartite symbiosis would develop more rapidly and lead to greater N(2) fixation in the presence of the latter. Soil pasteurization allowed the establishment of treatments with individual AMF species and soil disturbance enabled the development of contrasting root colonization potentials. In contrast, the colonization potential of B. japonicum was kept the same in all treatments. Soil disturbance significantly reduced root colonization by both AMF, with Gi. margarita being considerably more affected than G. clarum. Furthermore, the tripartite symbiosis progressed faster with G. clarum, and at 10 days after plant emergence, there was 30% more nodules when G. clarum was present compared to that when the bacterial symbiont alone was present. At flowering, the absence of soil disturbance stimulated N(2) fixation by 17% in mycorrhizal plants. However, this response was similar for both AMF.


The expression profile of Gasdermin C-related genes predicts the prognosis and immunotherapy response of pancreatic adenocarcinoma.
Pancreatic adenocarcinoma (PAAD) has a poor prognosis and is relatively unresponsive to immunotherapy. Gasdermin C (GSDMC) induces pyroptosis in cancer cells and inflammation in the tumor microenvironment. However, whether GSDMC expression in PAAD is associated with survival or response to immunotherapy remains unknown. GSDMC expression and the relationship between GSDMC and patient survival or immune infiltration in PAAD were examined using data in the The Cancer Genome Atlas (TCGA), Gene Expression Ominbus (GEO), Genotype-Tissue Expression (GTEx) and Cancer Cell Line Encyclopedia (CCLE) databases. The TCGA PAAD cohort could be divided into two distinct risk groups based on the expression of GSDMC-related genes (GRGs). The TIDE algorithm predicted that the low-risk group was more responsive to immune checkpoint blockade therapy than the high-risk group. A novel 15-gene signature was constructed and could predict the prognosis of PAAD. In addition, the 15-gene signature model predicted the infiltration of immune cells and Immune checkpoint blockade (ICB) treatment response. Immunohistochemical staining assessment of patient-derived human tissue microarray (TMA) from 139 cases of local PAAD patients revealed a positive correlation between GSDMC expression and PD-L1 expression but a negative correlation between GSDMC expression and infiltration of low CD8+ T cells. Moreover, the overexpression of GSDMC was related to poor overall survival (OS). This study suggests that GSDMC is a valuable biomarker for predicting PAAD prognosis and predicts the immunotherapy response of PAAD.


Successful white hair removal with combined coloring and intense pulsed Light (IPL): a randomized clinical trial.
The purpose of this study was to introduce adjunct therapy to intense pulsed light (IPL) and to assess it in terms of safety, expense, feasibility, and efficacy. Currently there is no satisfactory, efficient method for long-term white hair removal. We conducted a randomized clinical trial of hirsute patients with excessive white hair on the chin and cheeks. In addition to IPL, the patients were randomly assigned to have their white hair colored with either black eyeliner or black hair dye as an adjunct to IPL aided for of six sessions (with a 4-week interval between sessions). The primary efficacy outcome, which was defined as the outcome after six sessions of therapy, was scored as poor (<30%), fair (30?60%) or good (>60%) response to white hair removal in predefined areas. The secondary outcome was recurrence 6 months after the final therapy session. In the eyeliner group (n=31), 15 (48.4%) individuals showed a fair response, and 16 (51.6%) individuals showed a good response. In the color-dye group (n=31), 1 (3.2%), 17 (54.8%) and 13 (41.9%) participants scored poor, fair, and good, respectively. There were no differences in clinician judgment of the treatment success between the eyeliner and color-dye groups after the six therapy sessions (p=0.895). Thirty-one patients had 6 months of visits (11 in the hair dye and 20 in the eyeliner group). Three participants in the color-dye group and five participants in the eyeliner group failed to show improvement 6 months after the laser surgery. There was no distinguishable pattern of failure between the two study groups (p=1). This study supports that hair coloring is an efficient and feasible technique that can be combined with IPL to eliminate white facial hair.


Prophylactic bilateral salpingo-oopherectomy in a 17-year-old with Frasier syndrome reveals gonadoblastoma and seminoma: a case report.
Mutations in the Wilms' tumor gene are present in children with Frasier syndrome, Denys-Drash syndrome, WAGR syndrome, and some cases of Wilms' tumor. The Wilms' tumor gene product, WT1, is necessary for normal urogenital development. Frasier syndrome is an association between focal segmental glomerulosclerosis, beginning in the second and third decade, male to female sex reversal, and dysgenetic gonads. We report a case of Frasier syndrome in a 17-year-old adolescent girl with renal failure, kidney transplant, and dysgenetic gonads, with development of gonadoblastoma and dysgerminoma (seminoma). The diagnosis of Frasier syndrome was based on nephrotic syndrome with diffuse mesangial sclerosis leading to chronic renal failure, dysgenetic gonads, 46 XY karyotype in a phenotypic female, and a mutation in the Wilms' tumor gene. Prophylactic laparoscopic bilateral salpingo-oopherectomy revealed gonadoblastoma and seminoma in opposite atrophic ovaries as well as a hypoplastic uterus. Early prophylactic resection of dysgenetic gonads is indicated in children with Frasier syndrome to prevent the development of germ cell malignancy.


Untargeted fecal metabolome analysis in obese dogs after weight loss achieved by feeding a high-fiber-high-protein diet.
In humans and companion animals, obesity is accompanied by metabolic derangements. Studies have revealed differences in the composition of the fecal microbiome between obese dogs and those with an ideal body weight. We have previously reported that the fecal microbiome in obese dogs changes after controlled weight reduction, induced by feeding a diet high in fiber and protein. Despite these findings, it is unclear if taxonomic differences infer differences at the functional level between obese dogs and those with an ideal body weight. Untargeted fecal metabolome analysis was performed on dogs with obesity before and after weight loss achieved by feeding a high-fiber-high-protein diet. Fecal metabolome analysis revealed a total of 13 compounds that changed in concentration in obese dogs after weight loss. Of these compounds, metabolites associated with bacterial metabolism decreased after weight loss including purine, L-(-)-methionine, coumestrol, and the alkaloids 1-methylxanthine and trigonelline. Conversely, the polyphenols (-)-epicatechin and matairesinol and the quinoline derivatives 1,5-isoquinolinediol and 2-hydroxiquinoline increased after weight loss. These results suggest differences in intestinal microbiome at the functional level after weight loss, but further studies are needed to determine the role of these compounds in the etiology of obesity and weight loss.


Development and validation of a method for the determination of buprenorphine and norbuprenorphine in breast milk by gas chromatography-mass spectrometry.
Buprenorphine (BUP) is used for the maintenance of opioid-addicted pregnant women. Because BUP and its main metabolite nor-BUP are excreted into breast milk, a sensitive and specific GC/MS method has been developed, optimized and validated for their determination in breast milk. BUP-d4 was used as internal standard. The sample preparation includes combination of protein precipitation with solid-phase extraction and derivatization (acetylation). The absolute recovery for both analytes was found to be higher than 87.3%. The limits of detection and quantification were 0.07 and 0.20 µg/L, respectively. The calibration curves were linear within the dynamic range 0.20-20.0 µg/L, with a correlation coefficient higher than 0.996. Intra- and inter-day accuracies were ranged from -7.06 to 4.50 and from -5.88 to 7.00%, respectively, while intra- and inter-day precision were less than 5.7 and 6.1%. The analytes were found to be stable in breast milk at 4 °C for one week, at -20 °C for one month, and after three freeze-thaw cycles. The method can be used for the determination of BUP and nor-BUP in breast milk of BUP-maintained mothers, in order to calculate the amount of drug that could pass to the newborn via breast milk and to avoid toxic consequences of breastfeeding.


Synthesis of a Novel Water-Soluble Polymer Complexant Phosphorylated Chitosan for Rare Earth Complexation.
Combining the characteristics of rare earth extractants and water-soluble polymer complexants, a novel complexant phosphorylated chitosan (PCS) was synthesized by Kabachnik-Fields reaction with alkalized chitosan, dimethyl phosphonate, and formaldehyde as raw materials and toluene-4-sulfonic acid monohydrate (TsOH) as catalyst. The complexation properties of PCS and poly (acrylic acid) sodium (PAAS) for lanthanum ions in the solution were compared at the same pH and room temperature. In addition, the frontier molecular orbital energies of polymer-La complexes were calculated by the density functional theory method, which confirmed the complexation properties of the polymers to rare earths. The results indicate that the PCS has better water solubility compared with chitosan and good complex ability to rare earths, which can be used for rare earth separation by the complexation-ultrafiltration process.


Quality, Usability, and Effectiveness of mHealth Apps and the Role of Artificial Intelligence: Current Scenario and Challenges.
The use of artificial intelligence (AI) and big data in medicine has increased in recent years. Indeed, the use of AI in mobile health (mHealth) apps could considerably assist both individuals and health care professionals in the prevention and management of chronic diseases, in a person-centered manner. Nonetheless, there are several challenges that must be overcome to provide high-quality, usable, and effective mHealth apps. Here, we review the rationale and guidelines for the implementation of mHealth apps and the challenges regarding quality, usability, and user engagement and behavior change, with a special focus on the prevention and management of noncommunicable diseases. We suggest that a cocreation-based framework is the best method to address these challenges. Finally, we describe the current and future roles of AI in improving personalized medicine and provide recommendations for developing AI-based mHealth apps. We conclude that the implementation of AI and mHealth apps for routine clinical practice and remote health care will not be feasible until we overcome the main challenges regarding data privacy and security, quality assessment, and the reproducibility and uncertainty of AI results. Moreover, there is a lack of both standardized methods to measure the clinical outcomes of mHealth apps and techniques to encourage user engagement and behavior changes in the long term. We expect that in the near future, these obstacles will be overcome and that the ongoing European project, Watching the risk factors (WARIFA), will provide considerable advances in the implementation of AI-based mHealth apps for disease prevention and health promotion.


Generation of tunable linearly chirped signals with long temporal duration in the photonic time-stretched coherent radar.
Linearly chirped signals with long temporal duration are generated by adding a dispersive loop in the photonic time-stretched coherent radar. The signal-to-noise ratio (SNR) variation of the optical pulse recirculation is analyzed and simulated to evaluate the multiple extension of temporal duration. The achievable temporal duration is confined by the dispersion and the amplified spontaneous emission noise accumulation. The experimental results verify the SNR variation of the optical pulse recirculation. Moreover, tunable linearly chirped signals with temporal duration of 100 ns and a bandwidth of 4 GHz at X or Ku band are generated. With the improvement of the time-bandwidth product, a drone can be successfully observed.


Original Research: Arthritis-Related Functional Limitations and Inadequate Physical Activity Among Female Adult Cancer Survivors.
The American Cancer Society (ACS) Guidelines on Nutrition and Physical Activity for Cancer Prevention recommend an adequate level of physical activity for cancer prevention and survivorship. Many adults have been diagnosed with arthritis, with a significantly higher rate in women. People with arthritis tend to be less physically active than those without arthritis, and are less likely to engage in moderate or vigorous activity. The proportion of adults meeting ACS physical activity guidelines is especially low among those with arthritis. We wanted to explore the extent to which arthritis-related functional limitations are predictive of inadequate physical activity in female adult cancer survivors after accounting for other known predictors. Data included in the analyses were from a sample of 729 adult women diagnosed with cancer who participated in the U.S. National Health and Nutrition Examination Survey between 2011 and 2016. Inadequate physical activity was defined as not meeting ACS physical activity guidelines. Bivariate and multivariate logistic regression analyses were conducted to identify correlates of inadequate physical activity. Being age 65 years or older, having no more than a high school education, being overweight or obese, being clinically depressed, and having arthritis-related functional limitations were found to be significant correlates of inadequate physical activity in the study population. Our results indicate that, in addition to previously identified predictors of inadequate physical activity in cancer survivors, having arthritis-related functional limitations is a significant predictor of inadequate physical activity in female adult cancer survivors. Assessment and management of arthritis-related functional limitations by health care providers are needed to facilitate successful adherence to physical activity guidelines.


Two-photon imaging of neural networks in a mouse model of Alzheimer's disease.
In humans, Alzheimer's disease (AD) develops over many years. It comprises a chain of subtle yet irreversible alterations in brain function, finally leading to impairment of memory and cognition. Presymptomatic and thus invisible in humans, these alterations can be studied in the animal models of AD. Mouse models of the disease expressing AD-related proteins with familial mutations reproduce several pathological hallmarks of AD. Although the models do not recapitulate the abundant neuronal loss seen in humans, they offer a unique opportunity to learn more about synaptic and cellular mechanisms underlying the disease (both in their essence and in their temporal sequence) through in vivo analyses of brain function. This, however, requires in vivo monitoring of brain function in aged living animals at both a single-cell and network level. Tools developed over the last several decades can be used to selectively mark and to visualize in vivo many important elements of the diseased brain parenchyma, such as amyloid plaques, individual neurons, and glial and microglial cells. Here we describe a method in which cell-type-specific labeling of neurons and glia is combined with in vivo two-photon calcium imaging and fluorescent labeling of amyloid plaques to study functional properties of cortical circuits in a mouse model of AD.


Neonatal hypertension: an underdiagnosed condition, a review article.
Advances in neonatology and intensive monitoring has increased our ability to identify and measure blood pressure in sick premature and term infants and this has contributed to an increased awareness of hypertension in the NICU. A few recent studies done by Zubrow and others have offered many new information on blood pressure values over the first month after birth and on other many intrinsic and extrinsic factors that can cause effects on the blood pressure in the neonatal period. There are no definite cut off for labelling hypertension in newborn period and also doubts are there on the pharmacological treatment. This is a field in neonatology which is least studied hence requires further inquiry. This review article will cover several aspects of neonatal hypertension like definition, normotensive data, etiology, clinical characteristics, diagnostic modalities, treatment choices and long term effect of these newborns.


MMPI results: a comparison of trauma victims, psychogenic pain, and patients with organic disease.
Made comparison using MMPI T scores on three private psychiatric sub-populations: Post-trauma patients, patients with organically based illness, and patients with psychogenic pain (complaints functional in origin) (N = 78). The standard 3 validity and 10 clinical scales were used to evaluate possible differences among the groups. Differences were presented among the groups on scales 3 (Hy), 9 (Ma), and (F). Individual profiles also were assessed. In patients with a 1-3/3-1 profile, the psychogenic group had significantly higher elevation over the post-trauma and organic groups. In patients with 8 (Sc) or 9 (Ma) high both with and without 1-3/3-1 high, differences were found; the post-trauma and organic groups showed marked elevation over those in the psychogenic group. Results indicate the MMPI to be a viable aid in distinguishing between patients with post-trauma stress disorder vs. those with functional disorders. The data suggest that MMPI profiles of patients with post-trauma stress disorder more closely resemble the MMPI profiles of patients who have organic disease with pain caused by organic pathology than the profiles of patients with psychogenic pain and/or hypochondriasis.


Design and synthesis of novel isoxazole tethered quinone-amino Acid hybrids.
A new series of isoxazole tethered quinone-amino acid hybrids has been designed and synthesized involving 1,3-dipolar cycloaddition reaction followed by an oxidation reaction using cerium ammonium nitrate (CAN). Using this method, for the first time various isoxazole tethered quinone-phenyl alanine and quinone-alanine hybrids were synthesized from simple commercially available 4-bromobenzyl bromide, propargyl bromide, and 2,5-dimethoxybenzaldehyde in good yield.


Does lithium protect against dementia?
To investigate whether treatment with lithium in patients with mania or bipolar disorder is associated with a decreased rate of subsequent dementia. Linkage of register data on prescribed lithium in all patients discharged from psychiatric health care service with a diagnosis of mania or bipolar disorder and subsequent diagnoses of dementia in Denmark during a period from 1995 to 2005. A total of 4,856 patients with a diagnosis of a manic or mixed episode or bipolar disorder at their first psychiatric contact were included in the study. Among these patients, 2,449 were exposed to lithium (50.4%), 1,781 to anticonvulsants (36.7%), 4,280 to antidepressants (88.1%), and 3,901 to antipsychotics (80.3%) during the study period. A total of 216 patients received a diagnosis of dementia during follow-up (103.6/10,000 person-years). During the period following the second prescription of lithium, the rate of dementia was decreased compared to the period following the first prescription. In contrast, the rates of dementia during multiple prescription periods with anticonvulsants, antidepressants, or antipsychotics, respectively, were not significantly decreased compared to the rate of dementia during the period with one prescription of these drugs. Continued treatment with lithium was associated with a reduced rate of dementia in patients with bipolar disorder in contrast to continued treatment with anticonvulsants, antidepressants, or antipsychotics. Methodological reasons for these findings cannot be excluded due to the nonrandomized nature of the data.


An updated checklist of the Tenebrionidae sec. Bousquet et al. 2018 of the Algodones Dunes of California, with comments on checklist data practices.
Generating regional checklists for insects is frequently based on combining data sources ranging from literature and expert assertions that merely imply the existence of an occurrence to aggregated, standard-compliant data of uniquely identified specimens. The increasing diversity of data sources also means that checklist authors are faced with new responsibilities, effectively acting as filterers to select and utilize an expert-validated subset of all available data. Authors are also faced with the technical obstacle to bring more occurrences into Darwin Core-based data aggregation, even if the corresponding specimens belong to external institutions. We illustrate these issues based on a partial update of the Kimsey et al. 2017 checklist of darkling beetles - Tenebrionidae sec. Bousquet et al. 2018 - inhabiting the Algodones Dunes of California. Our update entails 54 species-level concepts for this group and region, of which 31 concepts were found to be represented in three specimen-data aggregator portals, based on our interpretations of the aggregators' data. We reassess the distributions and biogeographic affinities of these species, focusing on taxa that are precinctive (highly geographically restricted) to the Lower Colorado River Valley in the context of recent dune formation from the Colorado River. Throughout, we apply taxonomic concept labels (taxonomic name according to source) to contextualize preferred name usages, but also show that the identification data of aggregated occurrences are very rarely well-contextualized or annotated. Doing so is a pre-requisite for publishing open, dynamic checklist versions that finely accredit incremental expert efforts spent to improve the quality of checklists and aggregated occurrence data.


Tyrosine nitration affects thymidylate synthase properties.
Highly purified preparations of thymidylate synthase, isolated from calf thymus, and L1210 parental and FdUrd-resistant cells, were found to be nitrated, as indicated by a specific reaction with anti-nitro-tyrosine antibodies, suggesting this modification to appear endogenously in normal and tumor tissues. Each human, mouse and Ceanorhabditis elegans recombinant TS preparation, incubated in vitro in the presence of NaHCO(3), NaNO(2) and H(2)O(2) at pH 7.5, underwent tyrosine nitration, leading to a V(max)(app) 2-fold lower following nitration of 1 (with human or C. elegans TS) or 2 (with mouse TS) tyrosine residues per monomer. Enzyme interactions with dUMP, meTHF or 5-fluoro-dUMP were not distinctly influenced. Nitration under the same conditions of model tripeptides of a general formula H(2)N-Gly-X-Gly-COOH (X = Phe, Tyr, Trp, Lys, Arg, His, Ser, Thr, Cys, Gly), monitored by NMR spectroscopy, showed formation of nitro-species only for H-Gly-Tyr-Gly-OH and H-Gly-Phe-Gly-OH peptides, the chemical shifts for nitrated H-Gly-Tyr-Gly-OH peptide being in a very good agreement with the strongest peak found in (15)N-(1)H HMBC spectrum of nitrated protein. MS analysis of nitrated human and C. elegans proteins revealed several thymidylate synthase-derived peptides containing nitro-tyrosine (at positions 33, 65, 135, 213, 230, 258 and 301 in the human enzyme) and oxidized cysteine (human protein Cys(210), with catalytically critical Cys(195) remaining apparently unmodified) residues.


Integer lattice gas with a sampling collision operator for the fluctuating diffusion equation.
We developed an integer lattice gas method for the fluctuating diffusion equation. Such a method is unconditionally stable and able to recover the Poisson distribution for the microscopic densities. A key advance for integer lattice gases introduced in this paper is a sampling collision operator that replaces particle collisions with sampling from an equilibrium distribution. This can increase the efficiency of our integer lattice gas by several orders of magnitude.


Patients with pulmonary and cardiac disease show an elevated proportion of immature reticulocytes.
The value of reticulocyte analysis has been largely confined to classification of anaemia. In the present study, we have investigated the value of undertaking automated fluorescent reticulocyte analysis (Abbott Cell-Dyn 4000) in patients with pulmonary or cardiac diseases. A control group of nonanaemic (n = 367) and anaemic patients (n = 57) was established and thereafter compared with a group of patients with pulmonary disease (172 without anaemia, 92 with anaemia) and another group with cardiac disease (520 without anaemia, 254 with anaemia). The Hb level and reticulocyte RNA content (as measured by the immature reticulocyte fraction, IRF) of the study subjects were inversely correlated (r = -0.41). The mean IRF of nonanaemic patients with pulmonary (mean = 0.331, SD=0.124) and cardiac disease (mean = 0.266, SD = 0.079) were both significantly higher (P < 0.05) than in control subjects (mean = 0.220, SD = 0.062). Nonanaemic and anaemic patients with cardiac disease both showed significantly higher (P < 0.05) reticulocyte percentage counts than the equivalent anaemic and nonanaemic controls. Each of these phenomena can all be attributed to hypoxia mediated EPO production. Our observation that 35% of patients with pulmonary disease have elevated levels of IRF, may prove useful in screening for tissue hypoxia in nonanaemic patients. Furthermore, serial monitoring of the IRF may prove valuable in observing the efficacy of therapy in these patients.


Neuropsychological subgroups of adolescents with conduct disorder.
In group-level studies adolescents with conduct disorder (CD) have been found to have deficiencies in verbal and executive functions. Teichner and Golden (2000) addressed the neuropsychological heterogeneity of CD, and hypothesized the existence of six neuropsychologically different subgroups. We used that theoretical basis to identify subgroups among 77 adolescents with CD and 48 controls. Among subjects with CD we identified subjects with no, diffuse, verbal and executive function deficits, but none with specific memory or visuo-spatial deficits. In total, neuropsychological deficits altogether were more common among subjects with CD relative to controls, as were specific verbal deficits. Subgroups did not differ in gender distribution, comorbidity of psychiatric disorders, type or severity of CD, or number of psychosocial risk factors. Among subjects with CD, learning disabilities were common. CD is neuropsychologically a heterogeneous disorder, and neuropsychological deficits should be taken into account in assessing and planning interventions for adolescents with CD.


Legume biofortification is an underexploited strategy for combatting hidden hunger.
Legumes are the world's primary source of dietary protein and are particularly important for those in developing economies. However, the biofortification potential of legumes remains underexploited. Legumes offer a diversity of micronutrients and amino acids, exceeding or complementing the profiles of cereals. As such, the enhancement of legume nutritional composition presents an appealing target for addressing the "hidden hunger" of global micronutrient malnutrition. Affecting ~2 billion people, micronutrient malnutrition causes severe health effects ranging from stunted growth to reduced lifespan. An increased availability of micronutrient-enriched legumes, particularly to those in socio-economically deprived areas, would serve the dual functions of ameliorating hidden hunger and increasing the positive health effects associated with legumes. Here, we give an updated overview of breeding approaches for the nutritional improvement of legumes, and crucially, we highlight the importance of considering nutritional improvement in a wider ecological context. Specifically, we review the potential of the legume microbiome for agronomic trait improvement and highlight the need for increased genetic, biochemical, and environmental data resources. Finally, we state that such resources should be complemented by an international and multidisciplinary initiative that will drive crop improvement and, most importantly, ensure that research outcomes benefit those who need them most.


[Spontaneous pneumomediastinum in asthma].
A pneumomediastinum is characterized by free air within the mediastinum. In most cases it is caused by an injury of the thorax. A spontaneous pneumomediastinum (sPM) occurred without any recognizable cause. By a sudden intraalveolar hypertension (caused by cough or physical exertion) a damage of alveoli is followed by diffusion of air along the bronchovascular sheats to the mediastinal soft tissue. sPM is a rare complication of asthma especially in young men. We demonstrate a young asthmatic patient with sPM first diagnosed as an allergic reaction to draw the attention to this rare but differential diagnostic important entity. sPM is reported in connection with drug inhalation abuse as a more frequent problem within the last years.


Effect of Previous Crops and Soil Physicochemical Properties on the Population of Verticillium dahliae in the Iberian Peninsula.
The soil infestation of Verticillium dahliae has significant Verticillium wilt of olive (VWO) with epidemiological consequences which could limit the expansion of the crop. In this context, there is a misunderstood history of the crops and soil property interactions associated with inoculum density (ID) increases in the soil. In this study, the effect of the combination of both factors was assessed on the ID of V. dahliae in the olive-growing areas of the Iberian Peninsula. Afterwards, the relationship of the ID to the mentioned factors was explored. The detection percentage and ID were higher in Spain than Portugal, even though the fields with a very favourable VWO history had a higher ID than that of the fields with a barely favourable history, regardless of the origin. The soil physicochemical parameters were able to detect the degree to which the ID was increased by the previous cropping history. By using a decision tree classifier, the percentage of clay was the best indicator for the V. dahliae ID regardless of the history of the crops. However, active limestone and the cation exchange capacity were only suitable ID indicators when <2 or 4 host crops of the pathogen were established in the field for five years, respectively. The V. dahliae ID was accurately predicted in this study for the orchard choices in the establishment of the olive.


Transglutaminase 2 facilitates the distant hematogenous metastasis of breast cancer by modulating interleukin-6 in cancer cells.
Inflammation has been implicated in cancer aggressiveness. As transglutaminase 2 (TG2), which has been associated with inflammatory signaling, has been suggested to play a role in tumor behavior, we propose that TG2 may be an important linker inducing interleukin (IL)-6-mediated cancer-cell aggressiveness, including distant hematogenous metastasis. To investigate the role for TG2 and IL-6, TG2-knocked-down and IL-6-knocked-down cancer cells were generated by using shRNA. Human breast cancer cell xenograft model in highly immunocompromised mice and human advanced breast cancer primary tumor tissue microarrays were used in this study. IL-6 production in human breast cancer cells was dependent on their TG2 expression level. In vitro tumor-sphere formation was dependent on TG2 and downstream IL-6 production from cancer cells. Primary tumor growth in the mammary fat pads and distant hematogenous metastasis into the lung was also dependent on TG2 and downstream IL-6 expression levels. The effect of TG2 expression on human breast cancer distant metastasis was investigated by analyzing a tissue microarray of primary tumors from 412 patients with their clinical data after 7 years. TG2 expression in primary tumor tissue was inversely correlated with recurrence-free survival (P = 0.019) and distant metastasis-free survival (DMFS) (P = 0.006) in patients with advanced breast cancer. Furthermore, by using public datasets that included a total of 684 breast cancer patients, we found that the combined high expression of TG2 and IL-6 was associated with shorter DMFS, compared with the high expression of IL-6 only (P = 0.013). We provide evidence that TG2 is an important link in IL-6-mediated tumor aggressiveness, and that TG2 could be an important mediator of distant metastasis, both in a xenograft animal model and in patients with advanced breast cancer.


Hoveyda-Grubbs catalysts with an N→Ru coordinate bond in a six-membered ring. Synthesis of stable, industrially scalable, highly efficient ruthenium metathesis catalysts and 2-vinylbenzylamine ligands as their precursors.
A novel and efficient approach to the synthesis of 2-vinylbenzylamines is reported. This involves obtaining 2-vinylbenzylamine ligands from tetrahydroisoquinoline by alkylation and reduction followed by the Hofmann cleavage. The resultant 2-vinylbenzylamines allowed us to obtain new Hoveyda-Grubbs catalysts, which were thoroughly characterised by NMR, ESIMS, and X-ray crystallography. The utility of this chemistry is further demonstrated by the tests of the novel catalysts (up to 10-2 mol %) in different metathesis reactions such as cross metathesis (CM), ring-closing metathesis (RCM) and ring-opening cross metathesis (ROCM).


Morphology of gastrointestinal stromal tumors: historical perspectives.
About 2/3 of gastrointestinal stromal tumors occur in the stomach and about 1/5 in the small intestine with few in the rectum, colon, and esophagus. Their cells are related to the interstitial cells of Cajal. They differ by site in terms of cell type and growth pattern. Benign and malignant tumors are separated based on their light microscopic appearances, size as measured by innumerable pathologists and assistants and mitotic counts.


Errors in Converting Principles to Protocols: Where the Bioethics of U.S. Covid-19 Vaccine Allocation Went Wrong.
For much of 2021, allocating the scarce supply of Covid-19 vaccines was the world's most pressing bioethical challenge, and similar challenges may recur for novel therapies and future vaccines. In the United States, the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) identified three fundamental ethical principles to guide the process: maximize benefits, promote justice, and mitigate health inequities. We argue that critical components of the recommended protocol were internally inconsistent with these principles. Specifically, the ACIP violated its principles by recommending overly broad health care worker priority in phase 1a, using being at least seventy-five years of age as the only criterion to identify individuals at high risk of death from Covid-19 during phase 1b, failing to recommend place-based vaccine distribution, and implicitly endorsing first-come, first-served allocation. More rigorous empirical work and the development of a complete ethical framework that recognizes trade-offs between principles may have prevented these mistakes and saved lives.


DNA-directed synthesis of zinc oxide nanowires on carbon nanotube tips.
This paper describes a class of three component hybrid nanowires templated by DNA directed self-assembly. Through the modification of carbon nanotube (CNT) termini with synthetic DNA oligonucleotides, gold nanoparticles are delivered, via DNA hybridization, to CNT tips that then serve as growth sites for zinc oxide (ZnO) nanowires. The structures we have generated using DNA templating represent an advance toward building higher order sequenced one dimensional nanostructures with rational control.


Treating hypertension in active patients: which agents work best with exercise?
Hypertension treatment typically involves drug and nondrug therapies. For patients already exercising and those trying to start, physicians need to be aware of the intricacies of antihypertensive medications, including side effect profiles and whether they are banned by some sports organizations. Although diuretics and beta-blockers have been used in the past by most physicians, in active patients we typically opt for newer agents such as ACE inhibitors, angiotensin-II-receptor blockers, dihydropyridine calcium channel blockers, and alpha-1 blockers. These drugs typically have fewer side effects and impediments to athletic performance. Other drugs may be used in active patients who have other medical problems or when cost is a concern.


Paraoxonase-1 gene haplotypes are associated with metabolic disturbances, atherosclerosis, and immunologic outcome in HIV-infected patients.
Oxidative stress is associated with human immunodeficiency virus (HIV) infection. Paraoxonase-1 (PON1) is an antioxidant enzyme that is bound to high-density lipoproteins (HDLs). We evaluated whether PON1 gene haplotypes influence the metabolic disturbances, presence of subclinical atherosclerosis, and virologic outcome associated with the infection. DNA from blood samples collected from 234 HIV-infected patients and 633 healthy control subjects had single-nucleotide polymorphisms of PON1(192), PON1(55), PON1(-162), PON1(-832), PON1(-909), PON1(-1076), and PON1(-1741) analyzed using the Iplex Gold MassArray method. Subsequently, the influence of these single-nucleotide polymorphisms on measured biochemical and clinical variables was assessed. We observed significant differences in the haplotype distribution between the control subjects and the HIV-infected patients. Haplotype H10 (GTCCGTC) was more prevalent in the HIV-infected patients (6.41% vs 0.64%; P < .001), and haplotype H5 (GACCGTC) was less prevalent in HIV-infected patients (27.7% vs 42.9%; P = .001). In HIV-infected patients, haplotype H7 (AATTCCT) was associated with better CD4(+) cell count recovery, higher levels of HDL cholesterol (P = .048) and apolipoprotein A-I (P = .019), lower levels of triglycerides (P = .004), and lower rates of subclinical arteriosclerosis (P < .001). PON1 haplotypes segregate with HIV infection, HDL metabolism, the presence of subclinical atherosclerosis, and CD4(+) cell recovery after treatment.


Structural basis for CDK7 activation by MAT1 and Cyclin H.
Cyclin-dependent kinase 7 (CDK7), Cyclin H, and the RING-finger protein MAT1 form the heterotrimeric CDK-activating kinase (CAK) complex which is vital for transcription and cell-cycle control. When associated with the general transcription factor II H (TFIIH) it activates RNA polymerase II by hyperphosphorylation of its C-terminal domain (CTD). In the absence of TFIIH the trimeric complex phosphorylates the T-loop of CDKs that control cell-cycle progression. CAK holds a special position among the CDK branch due to this dual activity and the dependence on two proteins for activation. We solved the structure of the CAK complex from the model organism Chaetomium thermophilum at 2.6-Å resolution. Our structure reveals an intricate network of interactions between CDK7 and its two binding partners MAT1 and Cyclin H, providing a structural basis for the mechanism of CDK7 activation and CAK activity regulation. In vitro activity measurements and functional mutagenesis show that CDK7 activation can occur independent of T-loop phosphorylation and is thus exclusively MAT1-dependent by positioning the CDK7 T-loop in its active conformation.


Quantitative phosphoproteomics revealed interplay between Syk and Lyn in the resistance to nilotinib in chronic myeloid leukemia cells.
In this study, we have addressed how Lyn kinase signaling mediates nilotinib-resistance by quantitative phospho-proteomics using Stable Isotope Labeling with Amino acid in Cell culture. We have found an increased tyrosine phosphorylation of 2 additional tyrosine kinases in nilotinib-resistant cells: the spleen tyrosine kinase Syk and the UFO family receptor tyrosine kinase Axl. This increased tyrosine phosphorylation involved an interaction of these tyrosine kinases with Lyn. Inhibition of Syk by the inhibitors R406 or BAY 61-3606 or by RNA interference restored the capacity of nilotinib to inhibit cell proliferation. Conversely, coexpression of Lyn and Syk were required to fully induce resistance to nilotinib in drug-sensitive cells. Surprisingly, the knockdown of Syk also strongly decreased tyrosine phosphorylation of Lyn and Axl, thus uncovering interplay between Syk and Lyn. We have shown the involvement of the adaptor protein CDCP-1 in resistance to nilotinib. Interestingly, the expression of Axl and CDCP1 were found increased both in a nilotinib-resistant cell line and in nilotinib-resistant CML patients. We conclude that an oncogenic signaling mediated by Lyn and Syk can bypass the need of Bcr-Abl in CML cells. Thus, targeting these kinases may be of therapeutic value to override imatinib or nilotinib resistance in CML.


Sodium arsenite and hyperthermia modulate cisplatin-DNA damage responses and enhance platinum accumulation in murine metastatic ovarian cancer xenograft after hyperthermic intraperitoneal chemotherapy (HIPEC).
Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death in the USA. Recurrence rates are high after front-line therapy and most patients eventually die from platinum (Pt) - resistant disease. Cisplatin resistance is associated with increased nucleotide excision repair (NER), decreased mismatch repair (MMR) and decreased platinum uptake. The objective of this study is to investigate how a novel combination of sodium arsenite (NaAsO2) and hyperthermia (43°C) affect mechanisms of cisplatin resistance in ovarian cancer. We established a murine model of metastatic EOC by intraperitoneal injection of A2780/CP70 human ovarian cancer cells into nude mice. We developed a murine hyperthermic intraperitoneal chemotherapy model to treat the mice. Mice with peritoneal metastasis were perfused for 1 h with 3 mg/kg cisplatin ± 26 mg/kg NaAsO2 at 37 or 43°C. Tumors and tissues were collected at 0 and 24 h after treatment. Western blot analysis of p53 and key NER proteins (ERCC1, XPC and XPA) and MMR protein (MSH2) suggested that cisplatin induced p53, XPC and XPA and suppressed MSH2 consistent with resistant phenotype. Hyperthermia suppressed cisplatin-induced XPC and prevented the induction of XPA by cisplatin, but it had no effect on Pt uptake or retention in tumors. NaAsO2 prevented XPC induction by cisplatin; it maintained higher levels of MSH2 in tumors and enhanced initial accumulation of Pt in tumors. Combined NaAsO2 and hyperthermia decreased cisplatin-induced XPC 24 h after perfusion, maintained higher levels of MSH2 in tumors and significantly increased initial accumulation of Pt in tumors. ERCC1 levels were generally low except for NaAsO2 co-treatment with cisplatin. Systemic Pt and arsenic accumulation for all treatment conditions were in the order: kidney > liver = spleen > heart > brain and liver > kidney = spleen > heart > brain respectively. Metal levels generally decreased in systemic tissues within 24 h after treatment. NaAsO2 and/or hyperthermia have the potential to sensitize tumors to cisplatin by inhibiting NER, maintaining functional MMR and enhancing tumor platinum uptake.


Progress in the treatment of Ewing sarcoma: are the rumors of the demise of cytotoxic chemotherapy premature?
In this issue, Bollling et. al. review the development of treatment of Ewing sarcoma as it evolved over the past 30 years of clinical trials in Europe, largely under the leadership of Heribert Jurgens to whom this review is dedicated. The 44 authors were teachers, colleagues, students and co-investigators of Jurgens. The authors attribute the ability to make progress in the treatment of Ewing sarcoma through the establishment of larger and still larger cooperative studies in order to demonstrate statistically significant advances in the treatment of this rare disease.


Comparative Study and Simulation of Capacitive Sensors in Microfluidic Channels for Sensitive Red Blood Cell Detection.
Microfluidics provides an indispensable platform for combining analytical operations such as sample preparation, mixing, separation/enrichment, and detection onto a single compact platform, defined as a lab-on-a-chip (LOC) device with applicability in biomedical and life science applications. Due to its ease of integration, 1D interdigital capacitive (IDC) sensors have been used in microfluidic platforms to detect particles of interest. This paper presents a comparative study on the use of capacitive sensors for microfluidic devices to detect bioparticles, more specifically red blood cells (RBCs). The detection sensitivities of 1D, 2D, and 3D capacitive sensors were determined by simulation using COMSOL Multiphysics® v5.5. A water-filled 25 μm × 25 μm PDMS microfluidic channel was used with different sizes (5-10 μm) of red blood cells passing across the capacitive sensor regions. The conformal mapping was used for translating the 1D IDC sensor dimensions into equivalent 2D/3D parallel plate capacitance (PPC) sensor dimensions, creating similar absolute sensor capacitance. The detection sensitivity of each capacitive sensor is determined, and a new 3D PPC sensor structure was proposed to improve the sensitivity for high-resolution RBC detection in microfluidic channels. Proposed 2D and 3D sensors provide a 3× to 20× improvement in sensitivity compared to the standard 1D IDC structures, achieving a 100 aF capacitance difference when a healthy RBC passes in the structure.


Autosomal Recessive ACTG2-Related Visceral Myopathy in Brothers.
Pediatric intestinal pseudo-obstruction (PIPO) is a heterogeneous condition characterized by impaired gastrointestinal propulsion, a broad clinical spectrum, and variable severity. Several molecular bases underlying primary PIPO have been identified, of which autosomal dominant ACTG2-related visceral myopathy is the most common in both familial or sporadic primary PIPO cases. We present a family with autosomal recessive ACTG2-related disease in which both parents have mild gastrointestinal symptoms and sons have severe PIPO and bladder dysfunction. Clinical genome sequencing was performed on the patients and the mother. Immunohistochemistry was performed on intestinal tissue from the patients to show expression levels of the ACTG2. Genome sequencing identified a 6.8 kb 2p13.1 loss that includes the ACTG2 gene and a maternally inherited missense variant p.Val10Met in the ACTG2 gene. This case demonstrates that monoallelic hypomorphic ACTG2 variants may underly mild primary gastrointestinal symptoms, while biallelic mild variants can cause severe diseases. The Deletions of the noncoding ACTG2 exon can be an under-recognized cause of mild gastrointestinal symptoms unidentifiable by exome sequencing, explaining some instances of interfamilial variability with an apparent autosomal dominant inheritance. Genome sequencing is recommended as a genetic work-up for primary or idiopathic PIPO because of genetic heterogeneity.


A phase II study of a paclitaxel and oxaliplatin combination in platinum-sensitive recurrent advanced ovarian cancer patients.
A multicentric, phase II study to evaluate the efficacy and safety of the combination paclitaxel and oxaliplatin in patients with platinum-sensitive recurrent ovarian cancer. Patients received 175 mg/m(2) paclitaxel (over 3 h) followed by 130 mg/m(2) oxaliplatin (over 2 h) every 21 days for up to nine cycles without hydration or primary granulocyte colony-stimulating factor prophylaxis. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2 and to have received no more than one prior cisplatin- and/or carboplatin-containing chemotherapy regimen with a platinum-progression-free interval > or =6 months. Of the 105 patients enrolled and treated, 98 were eligible. An overall response rate of 81% (79 of 98 patients) (95% confidence interval 71% to 88%) was observed according to RECIST criteria (third party reviewed), and 88% (86 of 98) when this was complemented with CA-125 response. With a median follow up of 43.6 months (range 30.2-64.2) the median progression-free survival was 10.2 months (range 0.3-21.4) and the overall survival 32.4 months. Seven hundred and eight cycles were administered (median seven per patient; range one to nine). A total of 67% of patients experienced National Cancer Institute Common Toxicity Criteria grade 3-4 neutropenia, including 8% with concomitant febrile episode, without treatment-related deaths. Ninety-three per cent of patients experienced neuropathy of grade 1 or more, including 25% with cumulative reversible peripheral neuropathy of grade 3-4. Oxaliplatin doses were reduced in 30 patients due to neurotoxicity. The oxaliplatin/paclitaxel combination can be administered in an outpatient setting every 3 weeks without specific measures. The high level of activity and its duration observed warrants further evaluation of this combination in pretreated platinum-sensitive advanced ovarian cancer patients.


Technical note: improved implementation of Doppler broadening in MCNP5.
Incoherent scattering has a substantial effect on spectroscopic measurements and simulations. Many general-purpose Monte Carlo codes include models that account for the effects of bound electrons on incoherent scattering, including Doppler broadening (DB). This work investigates the DB model used in the Monte Carlo N-particle transport code (MCNP5). Simulations were run with three versions of MCNP5: v1.51, v1.60, and a modified form of v1.60 (v1.60m). All simulations used the MCPLIB04 photon data library, which presents the electron subshell data for incoherent scattering in the form of a probability density function. In v1.60m, the source code was altered to sample the electron subshell from a cumulative density function instead. Each version of the code was tested using an identical set of simulations that investigated DB in a slab of silicon at scattering angles of 15°, 30°, and 45°. For each angle, simulations were run for multiple energies between 200 keV and 800 keV. The spectrum of singly-scattered photons at the exit of the slab was scored. Spectra were analytically calculated for comparison. In v1.51, DB was modeled for incident photon energies below 760 keV, 384 keV, and 260 keV at scattering angles of 15°, 30°, and 45°, respectively. Above these energy thresholds, v1.51 did not model DB. The spectra calculated using v1.60 and v1.60m exhibited DB for all energy-angle combinations; however, v1.60m, exhibited more energy broadening than did v1.60. The spectra calculated with v1.60m agreed with the analytical calculations. MCNP5 v1.51 and v1.60 model partial broadening when used with the MCPLIB04 data library. MCNP5 v1.60m models DB more accurately due to the form of the electron subshell data. In response to these results, Los Alamos National Laboratory has released a new photon data library, MCPLIB84, that presents the electron subshell data in cumulative distribution form. MCNP5 v1.60 should be used with this library when incoherent scattering has a significant impact on simulation results.


Retroviral endostatin gene transfer inhibits human colon cancer cell growth in vivo.
To investigate the therapeutic effect of retroviral endostatin gene transfer on the human colon cancer cell line, LoVo. A retroviral vector pLESSN expressing secretable endostatin was constructed and packaged with a titer of 8.2 x 10(5) CFU/ml. A LoVo cell line was subjected to retrovirus-mediated endostatin gene transfer. The proviral integration of endostatin was analyzed with PCR. The function of endostatin was tested by MTT assay in vitro and a mouse xenograft model in vivo. After transfection and superinfection, amphotropic retrovirus was collected, and transduction with amphotropic retroviruses resulted in endostatin proviral integration. The endostatin secreted by transduced LoVo cells markedly inhibited cell growth up to 67% (P<0.001), compared with the control cells. The gene expression of endostatin in LoVo colon tumor cells significantly inhibited tumor growth in vivo. There was an 86% reduction in tumor size in the endostatin-transduced group, accompanied by a reduction in vessels, compared with the control group (P<0.01). Retroviruses can allow functional expression of the endostatin gene in human colon tumors, showing promise for an antitumor strategy using antiangiogenesis.


Experimental and theoretical study of the rotational reorientation dynamics of 7-aminocoumarin derivatives in polar solvents: hydrogen-bonding effects.
The rotational reorientation dynamics of 7-aminocoumarin derivatives with different alkylation degrees in methanol, dimethylformamide, and dimethyl sulfoxide have been investigated using femtosecond time-resolved stimulated emission pumping fluorescence depletion (FS TR SEP FD) spectroscopy. In addition to a long anisotropy decay time that accounts for the overall rotational relaxation of solutes, a short anisotropy decay time on the order of picoseconds or sub-picoseconds was also observed in hydrogen-bonding systems. Three types of hydrogen bonds involving the nitrogen lone pair, carbonyl group, and amino group of 7-aminocoumarin derivatives were denoted as types A, B, and C, respectively. Density functional theory (DFT) and time-dependent DFT (TDDFT) calculations were carried out to investigate the geometric structures of isolated coumarins and hydrogen-bonded complexes in the ground and excited states, respectively. According to our results and analysis, the rapid anisotropy decays observed here in hydrogen-bonding systems may be associated with the strengthening of hydrogen bonds B or C, or both in the excited state of hydrogen-bonded coumarin-solvent complexes, and are independent of the breaking of hydrogen bond A. The strengthening of hydrogen bond C in the excited state of 7-aminocoumarin-DMF and 7-aminocoumarin-DMSO complexes has been demonstrated theoretically for the first time. Further experimental studies would be crucial to confirm this observation.


Self-reported allergy to latex gloves among health care workers in Jordan.
The objective of this study is to determine the prevalence of natural rubber latex allergy and its associated factors among health care workers in Jordan based on a self-administered questionnaire. In this cross-sectional study, the data were obtained through a self-reported hand-delivered questionnaire that was distributed to 500 health care workers who use natural rubber latex gloves. A total of 420 (84%) health care workers responded by filling the questionnaire. Of the total number of 420 health care workers who filled the questionnaire, 57 (13.6%) reported allergy to latex gloves. The prevalence of allergy to latex gloves was significantly higher for those who had allergy to some foodstuffs (especially avocado, kiwifruits and chestnuts) or with history of eczema and hay fever. However, allergy to latex gloves was independent of gender, age, job, family history, type of gloves, hours of use/day and number of years of use. It is concluded that a high rate of allergy to latex gloves was reported among health care workers in Jordan.


Predicting outcomes in native AV forearm radio-cephalic fistulae; the CAVeA2T2 scoring system.
The aim of this study was to identify significant factors relating to fistula survival and create an easy-to-use scoring system for predicting fistula patency rates. A total of 276 consecutive radio-cephalic forearm fistulae created in a single tertiary vascular unit were identified retrospectively. Numerous patient- and fistula-related demographics were noted. Cox regression analysis was used to identify significant factors predictive of reduced fistula patency rates, and significant variables weighted according to their hazard ratio. Five significant factors were identified: ipsilateral Central venous access, Age >73 years, anastomosed Vein <2.2 mm, previous lower limb Angioplasty and absent intra-operative Thrill (1 point for first three variables, 2 points for the latter two). The CAVeA2T2 score (maximum 7 points) significantly predicted for reduced fistula patency (p = 0.001) and a reduced rate of successful dialysis (p = 0.001). Fistulae with CAVeA2T2 scores ≥2 had 6 week and 1 year patency rates significantly below pooled published rates. Without scoring for thrill, that is in the pre-operative setting, the scoring system remained significant at all stages. The CAVeA2T2 scoring system is a potential scoring system for predicting fistula patency rates and the likelihood of dialysing through a fistula. Further studies and/or external validation is required in the context of methodological limitations. How to manage patients with a high CAVeA2T2 score is unknown.


PPP2R2B hypermethylation causes acquired apoptosis deficiency in systemic autoimmune diseases.
Chronic inflammation causes target organ damage in patients with systemic autoimmune diseases. The factors that allow this protracted response are poorly understood. We analyzed the transcriptional regulation of PPP2R2B (B55ß), a molecule necessary for the termination of the immune response, in patients with autoimmune diseases. Altered expression of B55ß conditioned resistance to cytokine withdrawal-induced death (CWID) in patients with autoimmune diseases. The impaired upregulation of B55ß was caused by inflammation-driven hypermethylation of specific cytosines located within a regulatory element of PPP2R2B preventing CTCF binding. This phenotype could be induced in healthy T cells by exposure to TNF-α. Our results reveal a gene whose expression is affected by an acquired defect, through an epigenetic mechanism, in the setting of systemic autoimmunity. Because failure to remove activated T cells through CWID could contribute to autoimmune pathology, this mechanism illustrates a vicious cycle through which autoimmune inflammation contributes to its own perpetuation.


[Assessment of correction effect in relation to fulcrum bending flexibility in adult idiopathic scoliosis patients].
To study the relationship between the fulcrum bending flexibility (FBF) and correction rate (CR) of adult idiopathic scoliosis, and to explore the ability of FBF to assess the correction effect in relation to fulcrum bending flexibility. 69 patients with adult idiopathic scoliosis with structural curves at thoracic or lumbarthoracic segments, 16 males and 53 females, aged 26.5 (19 - 53) were treated by pedicle screws instrumentation. Pre-operative standing and fulcrum bending films and postoperative standing X-ray film were taken. Cobb angle was measured. The data underwent regression analysis with the software SPSS 10.0. A regression formula was established: CR = 0.213 + 0.768 x FBF with P < 0.01. A definite linear relation exists between the FBF and CR of adult idiopathic scoliosis. By using the formula in proper samples, the effects of new instrumentation or correction technique can be objectively assessed.


Diurnal variation in the therapeutic efficacy of 5-fluorouracil against murine colon cancer.
Mice bearing the murine colon carcinomas Colon 38 or Colon 26 were treated with 5-fluorouracil (5 FU) (60 or 100 mg/kg, respectively) weekly for 4 weeks at 08.30 hr or at 18.30 hr. The antitumor effect of treatment at 08.30 hr was significantly better for both types of tumors, but most pronounced for Colon 38. Toxicity was evaluated after administration of 60 mg 5 FU/kg. No thrombocytopenia was observed. Leucopenia was observed after treatment at 18.30 hr. It is concluded that the therapeutic efficacy of 5 FU against murine colon cancer is higher when 5 FU is administered at 08.30 hr.


Necroptosis and Prostate Cancer: Molecular Mechanisms and Therapeutic Potential.
Necroptosis is a programmed form of necrosis characterized by mitochondrial alterations and plasma membrane permeabilization resulting in the release of cytoplasmic content into extracellular space, and leading to inflammatory reactions. Besides its critical role in viral defense mechanisms and inflammatory diseases, necroptosis plays pivotal functions in the drug response of tumors, including prostate cancer. Necroptosis is mainly governed by kinase enzymes, including RIP1, RIP3, and MLKL, and conversely to apoptosis, is a caspase-independent mechanism of cell death. Numerous compounds induce necroptosis in prostate cancer models, including (i) compounds of natural origin, (ii) synthetic and semisynthetic small molecules, and (iii) selenium and selenium-based nanoparticles. Here, we overview the molecular mechanisms underlying necroptosis and discuss the possible implications of drugs inducing necroptosis for prostate cancer therapy.


Trauma and fibromyalgia: is there an association and what does it mean?
The primary objective is to review current research with respect to the role of trauma in fibromyalgia (FM). A secondary objective is to hypothesize which steps need to be taken, first to determine whether such an association truly exists, and second to clarify what such an association might mean. An extensive literature review was undertaken, including Medline from 1979 to the present. The strongest evidence supporting an association between trauma and FM is a recently published Israeli study in which adults with neck injuries had greater than a 10-fold increased risk of developing FM within 1 year of their injury, compared with adults with lower extremity fractures (P= .001). Several other studies provide a hypothetical construct for such an association. These include studies on (1) postinjury sleep abnormalities; (2) local injury sites as a source of chronic distant regional pain; and (3) the concept of neuroplasticity. There are, however, several primary arguments against such an association: (1) FM may not be a distinct clinical entity; (2) FM may be a psychological, rather than physical, disease; (3) the evidence supporting any association is limited and not definitive; (4) the Israeli study, itself, has some methodological limitations; and (5) other factors may be more important than the injurious event in determining chronic symptoms after an acute injury. Although there is some evidence supporting an association between trauma and FM, the evidence is not definitive. Further prospective studies are needed to confirm this association and to identify whether trauma has a causal role.


Implementation of TMD pain screening questionnaire in peruvian dental students.
The aim of this study was to screen for painful TMD conditions by implementing the validated Axis I screening instrument from the Diagnostic Criteria for Temporomandibular Disorders. Using the screener as a surrogate, the prevalence of the conditions was estimated among a convenience sample of dental students in Peru. A total 2,562 dental students, 63.7% women, aged 18 to 62 completed the instrument. Prevalence was estimated using both the short and long versions. The prevalence of painful TMD conditions was 19.4% with the short and 16.1% with the long version. The distribution of the conditions according to gender differed significantly between groups (p<.001). Prevalence estimates of painful TMD conditions using the screening instrument seems to be logistically adequate in a field assessment involving multiple geographic and cultural regions in Peru. These estimates seem to be consistent with internationally reported values.


Enhancing the Production of the Phenolic Extracts of Asparagus Using an Advanced Green Process.
Asparagus officinalis L. is a common vegetable widely consumed due to its high consumer acceptance. In addition to its flavor, green asparagus contains a high amount of bioactive compounds with health-promoting effects. In this sense, the growing concern of the public health system to promote a diet with a higher consumption of vegetables makes research on phytochemicals from this food of interest. In order to study the content of bioactive compounds from plant matrices, the combination of advanced extraction and analytical techniques within the context of green chemistry is an indispensable working model in today's research. In the present experimental work, the composition of the phytochemicals of green asparagus from the Protected Geographical Indication (PGI) located in Huétor Tájar, Granada (Spain), was evaluated by environmentally friendly extraction techniques. In order to carry out this work, the recovery of bioactive compounds was evaluated by pressurized liquid extraction (PLE) using GRAS (Generally Recognized As Safe) solvents (mixtures of water and ethanol). The extraction was optimized using a Response Surface Methodology (RSM) based on a 24 factorial Central Composite Design (CCD). The experimental model was followed by high-performance liquid chromatography coupled to electrospray ionization time-of-flight mass spectrometry (HPLC-ESI-TOF-MS) analytical methodology for a comprehensive characterization. The optimized methodology was compared with conventional solid-liquid extraction protocols using ethanol and water. The results highlighted the potential of advanced PLE techniques compared to conventional systems for the recovery of green asparagus phytochemicals. Moreover, the analytical characterization allowed the identification and quantitation of major phenolic compounds belonging to phenolic acids and flavonoids families. Therefore, an easy, fast, and novel methodology to optimize the extraction of bioactive compounds from green asparagus has been optimized, using Green and GRAS methodology, which enables a better understanding of the bioactive composition of this widely consumed food.


Influence of pressure on the boson peak: stronger than elastic medium transformation.
We study the changes in the low-frequency vibrational dynamics of poly(isobutylene) under pressure up to 1.4 GPa, corresponding to a density change of 20%. Combining inelastic neutron, x-ray, and Brillouin light scattering, we analyze the variations in the boson peak, transverse and longitudinal sound velocities, and the Debye level under pressure. We find that the boson peak variation under pressure cannot be explained by the elastic continuum transformation only. Surprisingly, the shape of the boson peak remains unchanged even at such high compression.


[Difficult airway management in paediatric patients].
A difficult airway in childhood is very uncommon. Therefore, it will always be an unfamiliar and menacing situation for most anaesthetists. Knowledge of the individual pathology, associated anaesthesiological problems and possible solutions provide the basis for successful airway management. Endoscopical techniques are essential for the process. The following article shows how a difficult airway in childhood can be recognized and which anaesthesiological options exist to handle such a situation.


Autoradiography of nadolol and propranolol in the rat.
Whole-body autoradiography of rats dosed with [14C]propranolol or [14C]nadolol have confirmed physicochemical predictions that nadolol, in contrast to propranolol, penetrates the CNS only to a slight extent, if at all. Differences between the CNS penetration of different beta-blockers have implications for the mechanism of the hypotensive action and the prevalence of side-effects associated with disturbance of the CNS.


Short communication: Cultivation of Lentinus edodes mycelia using whey permeate as an alternative growth substrate.
The major objective of this research was to use whey permeate as an alternative growth medium for the cultivation of mycelia of the edible mushroom Lentinus edodes and to find an optimum condition for solid-state cultivation. Response surface analysis was applied to determine the combination of substrate concentration (40 to 60 g of lactose/L), temperature (20 to 30 degrees C), and pH (4 to 6) resulting in a maximal mycelial growth rate. The radial extension rates, estimated by measuring the diameters of growing colonies on the Petri dishes, were used as the growth rate of the mycelia at different conditions. The conditions predicted to maximize the mycelial growth of 6.41 +/- 0.47 mm/d were determined to be 40 g of lactose/L, temperature 23.6 degrees C, and pH 5.0. It was concluded that a partial cubic equation could accurately model the response surface of, and predict optimal growth conditions for, L. edodes mycelia using whey permeate because the model prediction agreed with the experimental growth rate, 6.39 +/- 0.22 mm/d. The results suggest that whey permeate could be utilized as a growth substrate for the cultivation of mycelia from the edible mushroom L. edodes, enhancing the use of this by-product by the cheese manufacturing industry.


Rates of DNA change and phylogeny from the DNA sequences of the alcohol dehydrogenase gene for five closely related species of Hawaiian Drosophila.
The sequence of 1.6 kb of DNA surrounding the alcohol dehydrogenase (Adh) gene from five species of the Planitibia subgroup of the Hawaiian picture-winged Drosophila, with estimated divergence times of 0.4-5.1 Myr, has been determined. The gene trees which were found by using the sequence divergence from different regions of the sequences are generally in accord with the phylogeny proposed for these species when chromosomal inversions and island of origin are used. One of the species (D. picticornis) appears to be more distant from the other species in this group than they are from a member of the Grimshawi group (D. affinidisjuncta) which is chromosomally more distant. Two of the species (D. differens and D. plantibia) show heterogeneity in the nucleotide changes in the Adh coding region, heterogeneity which is interpreted to be due to a gene conversion or recombination after hybridization between the two species. The minimal rate of nucleotide substitution of synonymous nucleotides and of nontranscribed nucleotides downstream from the coding region is estimated as 1.5 x 10(-8) and 1.1 x 10(-8) substitutions/nucleotide/year, respectively. This rate is two to three times the maximal rate estimated for mammalian synonymous substitutions.


Virtual Healthcare in Rural and Remote Settings: A Qualitative Study of Canadian Rural Family Physicians' Experiences during the COVID-19 Pandemic.
This paper aims to explore the experiences of rural family physicians using virtual healthcare in their clinical practice during the COVID-19 pandemic in Canada. A community-based participatory approach. Rural and remote communities in Canada. Thirteen rural family physicians with at least one year of clinical experience. The data illustrate significant issues associated with virtual healthcare in rural healthcare. The adoption of virtual healthcare has been expressed to pose a harsh polarity; the benefit conferred to rural family physicians with the opportunity to have flexible working hours and work at home while interacting with family members is starkly contrasted with the struggles of insufficient financial support to facilitate setting up virtual healthcare for rural physicians, unreliable technological infrastructure, and inadequate technological resources, which are all exacerbated by the lack of adequate health literacy in rural communities. Results were compiled into five major categories underpinning the lived experiences of rural family physicians: 1-potential trade-off between convenience and quality of care; 2-work-family boundaries; 3-patient-doctor communication; 4-technology as barrier or enabler; 5-increased call duration. The differing trends assessed in the findings illustrate the complications faced in providing virtual healthcare, which resonates with the experiences and views of rural physicians. The findings of this study may guide the development of tailored technologies that adjust for the complexity of administering virtual healthcare in rural communities.


The route of administration influences the therapeutic index of an anti-proNGF neutralizing mAb for experimental treatment of Diabetic Retinopathy.
Many neurodegenerative retinal diseases are treated with monoclonal antibodies (mAb) delivered by invasive intravitreal injection (IVT). In Diabetic Retinopathy there is a scarcity of effective agents that can be delivered using non-invasive methods, and there are significant challenges in the validation of novel therapeutic targets. ProNGF represents a potential novel target, and IVT administration of a function-blocking anti-proNGF mAb is therapeutic in a mouse model of DR. We therefore compared invasive IVT to less invasive systemic intravenous (IV) and local subconjunctival (SCJ) administration, for therapy of Diabetic Retinopathy. The IV and SCJ routes are safe, afford sustained pharmacokinetics and tissue penetration of anti-proNGF mAb, and result in long-term therapeutic efficacy that blocks retinal inflammation, edema, and neuronal death. SCJ may be a more convenient and less-invasive approach for ophthalmic use and may enable reduced frequency of intervention for the treatment of retinal pathologies.


From proteomics to systems biology of bacterial pathogens: approaches, tools, and applications.
The hallmark of a systems biology approach is the integration of computational tools with experimental data encompassing multiple classes of biomolecules across different functional levels. Equally important as the availability of reasonably comprehensive information at the gene, protein, and metabolite levels is the development of adequate analysis and visualization tools to reduce the inherent complexity to interpretable dimensions. In this paper, we describe the integration of a 2-D gel-based proteome map of Staphylococcus aureus Mu50 with genomic and transcriptomic information through a customized data integration and user interface built on the Ensembl genome browser. We illustrate its application and potential through the analysis of a defined system perturbation caused by a mutation in the formyltransferase gene. We envision that this software package, which we called Insieme, can support the development of novel antibiotics by allowing a systems-based view of the bacterial response pathways.


Indirect costs and public finance consequences of heart failure in Poland, 2012-2015.
As a consequence of unfavourable epidemiological trends and the development of disease management, the economic aspects of heart failure (HF) have become more and more important. The costs of treatment (direct costs) appear to be the most frequently addressed topic in the economic research on HF; however, less is known about productivity losses (indirect costs) and the public finance burden attributable to the disease. Therefore, the aim of this study was to estimate the indirect costs and public finance consequences of HF in Poland in the period 2012-2015. The study uses a societal perspective and a prevalence-based top-down approach to estimate the following components of HF indirect costs: absenteeism of the sick and their caregivers, presenteeism of the sick, disability, and premature mortality. The human capital method has been chosen to identify the value of productivity losses attributable to HF and the public finance consequences of the disease. Deterministic sensitivity analysis was performed to assess the robustness of the results. The total indirect costs of HF in Poland were €871.9 million in 2012, and they increased to €945.3 million in 2015. In the period investigated, these costs accounted for 0.212-0.224% of GDP, an equivalent of 22.63€-24.59€ per capita. Mortality proved to be the main driver of productivity losses, with 59.3-63.4% of the total costs depending on year, followed by presenteeism (21.1-22.5%), disability (11.1-14.2%) and the sick's absenteeism (3.3-4.0%). The cost of caregivers' absenteeism was unimportant. The social insurance expenditure for benefits associated with HF accounted for €40.7 million in 2012 and €45.6 million in 2015 (0.56-0.59% expenditure for all diseases). The potential public revenue losses associated with HF were €262.7-€287.9 million. Sensitivity analysis showed that the costs varied by - 12.1% to + 28.8% depending on the model parameter values. HF is a substantial burden on the economy and public finance in Poland. By confronting the disease more effectively, the length and quality of life for those affected by HF could be improved, but society as a whole could also benefit from the increased economic output.


Do fluoride toothpastes have similar preventive effect in permanent and primary teeth against erosive tooth wear?
Little is known about fluoride toothpastes effect on primary teeth submitted to erosive tooth wear. To evaluate the preventive effect of different toothpastes on surface loss (SL) after severe erosion/abrasion model and to compare this effect between permanent (PT) and primary teeth (pt). Enamel samples were randomly divided according toothpastes groups (n = 17). G1: placebo; G2: NaF; G3: AmF-NaF-SnCl2 anti-erosion; G4: SnF2 ; and G5: NaF anti-erosion for children. Samples were incubated in artificial saliva (1 hour), submitted to erosive challenge (3 minutes; 1% citric acid; pH3.6; at 25°C) and to toothbrush abrasion (2 minutes slurry immersion; 50 strokes; 200 g) during 30 cycles. Surface loss (μm; mean ± SD) was quantified by contactless profilometry. The effects of the two covariables "tooth" and "toothpaste" were analysed by non-parametric ANOVA, variables with significant effects were tested by Wilcoxon tests. pt showed significantly higher surface loss than PT in all groups (P < 0.001). The mean values of SL of each group were: G1 PT 18.18(±3.98), pt 25.65(±9.21); G2 PT 14.76(±2.82), pt 18.11(±3.92); G3 PT 12.62(±5.29), pt 15.61(±6.70); G4 PT 17.12(±2.24), pt 23.41(±7.9); G5 PT 13.24(±1.29), pt 18.28(±8.96). In permanent teeth, G3 showed the best preventive effect. In primary teeth, G1, G3, and G5 showed similar effect.


Nutritional Status at Diagnosis as Predictor of Survival from Childhood Cancer: A Review of the Literature.
Few studies so far have examined the impact of nutritional status on the survival of children with cancer, with the majority of them focusing on hematological malignancies. We summarized published evidence reporting the association of nutritional status at diagnosis with overall survival (OS), event-free survival (EFS), relapse, and treatment-related toxicity (TRT) in children with cancer. Published studies on children with leukemia, lymphoma, and other solid tumors have shown that both under-nourished and over-nourished children at cancer diagnosis had worse OS and EFS. Particularly, the risk of death and relapse increased by 30-50% among children with leukemia with increased body mass index at diagnosis. Likewise, the risk of TRT was higher among malnourished children with osteosarcoma and Ewing sarcoma. Nutritional status seems to play a crucial role in clinical outcomes of children with cancer, thus providing a significant modifiable prognostic tool in childhood cancer management. Future studies with adequate power and longitudinal design are needed to further evaluate the association of nutritional status with childhood cancer outcomes using a more standardized definition to measure nutritional status in this population. The use of new technologies is expected to shed further light on this understudied area and give room to person-targeted intervention strategies.


Effects of trotting speed on muscle activity and kinematics in saddlehorses.
A thorough knowledge of the horse's back and limb movements at different speeds is important in the design of training programmes and the prevention of speed-related injuries. The objective of this study was to investigate changes in muscle activity and kinematics of the trot with increased speed. To evaluate these effects, 4 Saddlehorses were recorded while trotting on a horizontal treadmill at speeds ranging from 3.5-6.0 m/s. The 3-D trajectories of skin markers on the left side of the horse and the dorsal midline of the trunk were established. Electrical activity was obtained simultaneously from 6 muscles using surface electrodes. Ten consecutive strides were analysed for each horse at each of the 5 velocity steps. The increase in speed resulted in a decrease in stride and stance phase duration, increased muscle activity and range of motion of the limbs, but a decrease in back movements. During the stance phase, the limbs appeared more loaded, which resulted in more flexion of the joints and higher excentric muscle activity. During the swing phase, the higher concentric activity of the muscles was responsible for an increased shortening of the limbs. Understanding the effects of speed on equine locomotion is a prerequisite for the development of training programmes.


Note on the computation of critical effective population sizes.
This work extends the work of Whitlock in examining the critical effective population sizes from the fixation of both deleterious and beneficial mutations under drift and selection to prevent mutation breakdown of the population. The validity of approximations for the probability of fixation depends on the nature of the assumed distribution for the fitness effect of both types of mutations. Using no approximation for the probability of fixation and assuming a heavy tailed fitness effect distribution, the current model indicates that the coefficients of variation for the fitness effect distributions of both types of mutations and the fitness effect distribution mean for the beneficial mutations are important predictors of the critical effective population size. The current model further predicts that very small populations can be sustained if the fitness effect variances for both types of mutations and the mean for beneficial mutations are large.