A controlled trial of two mind-body interventions for grief in widows and widowers.
Objective: Following bereavement, yearning and grief rumination are repetitive cognitive processes that can lead to disordered grief. Mindfulness training (MT) has been shown to reduce maladaptive repetitive thought. The current quasi-randomized controlled trial examined the feasibility, acceptability, and preliminary efficacy of MT for bereavement-related grief. Method: Ninety-five widow(er)s (Mage = 67.5, 79% women, 98% White) between 6 months to 4 years post-loss were assigned to a 6-week MT intervention or a progressive muscle relaxation (PMR) intervention, or a wait-list condition. Outcome measures were grief severity (Revised Inventory of Complicated Grief), yearning (Yearning in Situations of Loss), rumination (Utrecht Grief Rumination Scale), and decentering (Experiences Questionnaire-Decentering) assessed at baseline, Weeks 2 and 4 of intervention, post-intervention, and 1-month post-intervention. Growth curve analysis examined group differences in rates of improvement in outcomes through follow-up and associations with improvement in grief severity. Results: The MT and PMR groups showed significant rates of decline in grief severity and yearning, though only the PMR group showed a greater rate of decline in grief severity than wait-list. All groups showed significant rates of decline in grief rumination. The PMR and wait-list groups showed significant rates of increase in decentering compared to the MT group. Conclusions: Results support the feasibility and acceptability of MT and PMR for widow(er)s as well as the preliminary efficacy of PMR for improving grief severity in widow(er)s compared to a wait-list control condition. With replication, PMR could be a standalone intervention for non-disordered grief or a component of treatment for disordered grief. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Influence of neutron irradiation on holmium acetylacetonate loaded poly(L-lactic acid) microspheres.
Holmium-loaded microspheres are useful systems in radio-embolization therapy of liver metastases. For administration to a patient, the holmium-loaded microspheres have to be irradiated in a nuclear reactor to become radioactive. In this paper. the influence of neutron irradiation on poly(L-lactic acid) (PLLA) microspheres and films, with or without holmium acetylacetonate (HoAcAc), is investigated, in particular using differential scanning calorimetry (MDSC), scanning electron microscopy, gel permeation chromatography (GPC), infrared spectroscopy, and X-ray diffraction. After irradiation of the microspheres, only minor surface changes were seen using scanning electron microscopy, and the holmium complex remained immobilized in the polymer matrix as reflected by a relatively small release of this complex. GPC and MDSC measurements showed a decrease in molecular weight and crystallinity of the PLLA, respectively, which can be ascribed to radiation induced chain scission. Irradiation of the HoAcAc loaded PLLA matrices resulted in evaporation of the non-coordinated and one coordinated water molecule of the HoAcAc complex, as evidenced by MDSC and X-ray diffraction analysis. Infrared spectroscopy indicated that some degradation of the acetylacetonate anion occurred after irradiation. Although some radiation induced damage of both the PLLA matrix and the embedded HoAcAc-complex occurs, the microspheres retain their favourable properties (no marginal release of Ho, preservation of the microsphere size), which make these systems interesting candidates for the treatment of tumours by radio-embolization.


Assessment and physical treatment of affective disorder.
Over the past decade there has been a tendency to diagnose affective disorder more readily, aided by the development of operational schedules that require few symptoms for diagnosis. This review will cover recent developments in the classification of affective disorder, how depression and mania can be adequately assessed and the treatment of these conditions.


Size and shape dimorphism in great ape mandibles and implications for fossil species recognition.
Sexual dimorphism is an important source of morphological variation, and species differences in dimorphism may be reflected in magnitude, pattern, or both. While the extant great apes are commonly used as a reference sample for distinguishing between sexual dimorphism and intertaxic variation in the fossil record, few studies have evaluated mandibular dimorphism in these taxa. In this study, percentage, degree, and pattern of mandibular dimorphism are evaluated in Pongo, Gorilla, and Pan. Mandibular dimorphism patterns are explored to determine the extent to which such patterns accurately track great ape phylogeny. Pattern stability is assessed to determine whether there are stable patterns of mandibular size and shape dimorphism that may be usefully applied to hominoid or hominid fossil species recognition studies. Finally, the established patterns of dimorphism are used to address recent debates surrounding great ape taxonomy. Results demonstrate that mandibular dimorphism is universally expressed in size, but only Pongo and Gorilla exhibit shape dimorphism. Pattern similarity tends to be greater between subspecies of the same species than between higher-order taxa, suggesting that within the great apes, there is a relationship between dimorphism pattern and phylogeny. However, this relationship is not exact, given that dimorphism patterns are weakly correlated between some closely related taxa, while great ape subspecies may be highly correlated with taxa belonging to other species or genera. Furthermore, dimorphism patterns are not significantly correlated between great ape genera, even between Gorilla and Pan. Dimorphism patterns are more stable in Gorilla and Pongo as compared to Pan, but there is little pattern stability between species or genera. Importantly, few variables differ significantly between taxa that simultaneously show consistently relatively low levels of dimorphism and low levels of variation within taxa. Combined, these findings indicate that mandibular dimorphism patterns can and do vary considerably, even among closely related species, and suggest that it would be difficult to employ great ape mandibular dimorphism patterns for purposes of distinguishing between intra- and interspecies variation in fossil samples. Finally, the degree of pattern similarity in mandibular dimorphism is lower than previously observed by others for craniofacial dimorphism. Thus, the possibility cannot be ruled out that patterns of craniofacial dimorphism in great apes may be associated with a stronger phylogenetic signal than are patterns of mandibular dimorphism.


Chemical surface reactions by click chemistry: coumarin dye modification of 11-bromoundecyltrichlorosilane monolayers.
The functionalization of surfaces and the ability to tailor their properties with desired physico-chemical functions is an important field of research with a broad spectrum of applications. These applications range from the modification of wetting properties, over the alteration of optical properties, to the fabrication of molecular electronic devices. In each of these fields, it is of specific importance to be able to control the quality of the layers with high precision. The present study demonstrates an approach that utilizes the 1,3-dipolar cycloaddition of terminal acetylenes to prepare triazole-terminated monolayers on different substrates. The characterization of the precursor monolayers, the optimization of the chemical surface reactions as well as the clicking of a fluorescent dye molecule on such azide-terminated monolayers was carried out. A coumarin 343 derivative was utilized to discuss the aspects of the functionalization approach. Based on this approach, a number of potential surface reactions, facilitated via the acetylene-substituted functional molecules, for a broad range of applications is at hand, thus leading to numerous possibilities where surface modifications are concerned. These modifications can be applied on non-structured surfaces of silicon or glass or can be used on structured surfaces. Various possibilities are discussed.


Capturing and analysing heterogeneity in residential greywater reuse preferences using a latent class model.
To legally permit greywater reuse as a management strategy, it is necessary to establish allowed uses, as well as guarantee legitimacy, safety and maintain public trust. Cities with previous experience in greywater reuse have reconfigured their regulations according to their own evidence with decentralized water reuse systems. This has allowed them to encourage or restrict certain indoor uses of treated greywater. However, cities starting to use these residential schemes lack the experience to reconfigure their water and sanitation regulation, and thus need "blindly" decide on the type of greywater uses to allow in order to achieve a balance between users' acceptability and avoiding public health problems. In this research, we analyse hypothetical situations of greywater reuse based on real evidence related to decentralized water systems. The main objective of this study is to evaluate the heterogeneity of individuals' preferences regarding residential greywater reuse for six intended indoor uses, using stated choice experiments and a latent class model. Hence, we obtain preliminary evidence about the direction that the regulation or pilot tests should take. We use the context of Santiago (Chile) as a reference, where although allowed, greywater reuse is not taking place widely. Our results show that survey respondents can be classified into four classes (enthusiasts, greywater sceptics, appearance conscious and water expenditure conscious), according to the preferences for the different types of indoor greywater reuse and the appearance of the treated greywater. From a policy perspective, our results show differences across classes as a function of socioeconomic characteristics and previous greywater reuse knowledge, as well as wider household characteristics, including the presence of sensitive individuals (under 15 and over 74 years old), number of residents, number of sanitary devices, and location and type of garden.


Effect of occupational exposure to rayon manufacturing chemicals on skin barrier to evaporative water loss.
To evaluate the effects of the occupational exposure to rayon manufacturing chemicals (RMC, containing predominantly carbon disulfide (CS(2)) and minor sulfuric acid) in a rayon factory on the basal transepidermal water loss (TEWL), barrier integrity (BI), and sequential increasing TEWL profiles. Six Thais and five Chinese workers in the spinning department of a rayon manufacturing plant and five healthy unexposed controls were recruited as the test subjects. An area of 4.5 x 5.5 cm on the mid-side of the volar forearm on the right hand was stripped by means of moderate pressure with commercially available adhesive tape by the same technician throughout the experiment. The skin was progressively stripped until glistening. TEWL was measured at every three and five tape strips on the right hand. The corresponding site on the left hand was measured parallel as the self-control. We found significant differences in basal TEWL and in BI between Chinese workers and Chinese controls, and between Thai workers and Chinese workers, respectively. Two-stage patterns of progressive TEWL profiles were found in such a chronic and repeated occupational exposure to RMC containing CS(2). The occupational exposure to RMC could result in the perturbation of the skin barrier function. Basal TEWL might be more sensitive to chronic skin irritant exposure. The TEWL profile achieved to the glistening stage might be necessary to avoid erroneous pattern estimation. Due to the lack of Thais control in this study, the racial difference in response to the RMC warrants further study.


Selective inhibition of paraffin deposition under high flow rate as a function of the crude oil paraffin type and content by fluorescence depolarization: polypropylene and high-density polyethylene.
High-density polyethylene (HDPE) and polypropylene (PP) were studied to identify tailor-made materials for walls of pipelines and ducts for crude paraffinic oil that inhibit paraffin depositions. The interfacial interaction was investigated from 50 to 70 degrees C and as a function of the n-C(36)H(74) paraffin concentration added to the paraffinic crude oil. The static and the dynamic interfacial tensions were observed, respectively, by traditional contact angle measurements and by fluorescence depolarization of the natural fluorescent probes of the crude oil, flowing at a high rate. The static interaction showed a low dependence on the n-paraffin content for both surfaces. For PP, it decreased slightly as the n-paraffin concentration increased, evidencing an increase in the liquid-liquid interaction. The dynamic interfacial tension with PP clearly decreased as temperature and n-paraffin concentration increased, the latter effect being attributed to the PP methyl groups hindering the interaction between the n-paraffin and the PP main chain. For the flow on HDPE, the interaction proved to be highly dependent on the n-paraffin concentration and temperature. It increased as n-paraffin was added and temperature decreased. The former effect is attributed to the alignment of the n-paraffin chains within the high rate flowing liquid and the similar molecular geometry of the n-paraffin and the linear polymer surface (almost without branches), which increases the number of sites available for interaction. PP proved to be more suitable for transportation of crude oil rich in paraffins with more than 36 carbon atoms, while HDPE was more suitable for those with smaller paraffinic chains.


Morphological differentiation of eggs of Ancylostoma caninum, Ancylostoma tubaeforme, and Ancylostoma braziliense from dogs and cats in the United States.
The establishment of cat- and dog-derived laboratory strains of Ancylostoma braziliense allowed for a morphological comparison of the eggs of A. braziliense, Ancylostoma caninum, and Ancylostoma tubaeforme. The length, width, and perimeter were determined for images of 10 eggs each of A. braziliense from the feces of a dog infected with a canine isolate and a cat infected with a feline isolate, A. caninum from dog feces, and A. tubaeforme from cat feces. The specific identity of the eggs was verified by polymerase chain reaction and restriction fragment length polymorphism by using HinfI and RsaI restriction digests followed by gel electrophoresis and sequencing. The mean (±SD) length, width, and perimeter and the length-to-width ratio (±SD) (all measurements are in micrometers) for the eggs of each species were as follows: A. braziliense eggs (combined cat and dog source), 53.03 ± 2.33, 36.37 ± 1.35, 140.43 ± 2.56, and 1.46 ± 0.11; A. caninum eggs, 63.92 ± 5.28, 39.21 ± 1.52, 161.99 ± 9.30, and 1.63 ± 0.13; and A. tubaeforme eggs, 61.44 ± 3.05, 39.14 ± 1.40, 157.98 ± 5.81, and 1.57 ± 0.08. The eggs of A. braziliense were significantly (P < 0.001) smaller than the eggs of A. caninum and A. tubaeforme in all dimensions. Thus, the eggs seem to be readily distinguishable using light microscopy, thereby aiding in species identification in fecal samples for a more comprehensive clinical picture and assessment of zoonotic risk.


Next-Generation Sequencing for the Detection of Microbial Agents in Avian Clinical Samples.
Direct-targeted next-generation sequencing (tNGS), with its undoubtedly superior diagnostic capacity over real-time PCR (RT-PCR), and direct-non-targeted NGS (ntNGS), with its higher capacity to identify and characterize multiple agents, are both likely to become diagnostic methods of choice in the future. tNGS is a rapid and sensitive method for precise characterization of suspected agents. ntNGS, also known as agnostic diagnosis, does not require a hypothesis and has been used to identify unsuspected infections in clinical samples. Implemented in the form of multiplexed total DNA metagenomics or as total RNA sequencing, the approach produces comprehensive and actionable reports that allow semi-quantitative identification of most of the agents present in respiratory, cloacal, and tissue samples. The diagnostic benefits of the use of direct tNGS and ntNGS are high specificity, compatibility with different types of clinical samples (fresh, frozen, FTA cards, and paraffin-embedded), production of nearly complete infection profiles (viruses, bacteria, fungus, and parasites), production of "semi-quantitative" information, direct agent genotyping, and infectious agent mutational information. The achievements of NGS in terms of diagnosing poultry problems are described here, along with future applications. Multiplexing, development of standard operating procedures, robotics, sequencing kits, automated bioinformatics, cloud computing, and artificial intelligence (AI) are disciplines converging toward the use of this technology for active surveillance in poultry farms. Other advances in human and veterinary NGS sequencing are likely to be adaptable to avian species in the future.


Optical fibre-based detection of DNA hybridization.
A dual-peak LPFG (long-period fibre grating), inscribed in an optical fibre, has been employed to sense DNA hybridization in real time, over a 1 h period. One strand of the DNA was immobilized on the fibre, while the other was free in solution. After hybridization, the fibre was stripped and repeated detection of hybridization was achieved, so demonstrating reusability of the device. Neither strand of DNA was fluorescently or otherwise labelled. The present paper will provide an overview of our early-stage experimental data and methodology, examine the potential of fibre gratings for use as biosensors to monitor both nucleic acid and other biomolecular interactions and then give a summary of the theory and fabrication of fibre gratings from a biological standpoint. Finally, the potential of improving signal strength and possible future directions of fibre grating biosensors will be addressed.


Long-term Outcome After Nonoperative Treatment for Rockwood I and II Acromioclavicular Joint Injuries.
Rockwood I and II acromioclavicular joint injuries are generally treated nonoperatively. The long-term outcome is considered to be good but has not yet been properly investigated. To assess the long-term outcome after nonoperative therapy for Rockwood I and II acromioclavicular joint injuries regarding functional and radiologic outcome. Cohort study; Level of evidence, 3. Eligible patients visited the emergency department between January 2003 and December 2015 and were ≥16 years old at the time of presentation. The main study parameters were the Constant score, the Disabilities of the Arm, Shoulder and Hand score, and the Simple Shoulder Test. The Constant score was measured in the injured and contralateral shoulders. Radiologic outcomes in both shoulders included joint displacement, joint space, degenerative changes, osteolysis of the distal clavicle, and ossification of the ligaments. A total of 75 patients were included for follow-up. After a median follow-up of 85 months (interquartile range [IQR], 68.0-100.0), the mean Constant score in the injured shoulder for the total sample was 88.6 (SD, 12.7) as compared with 93.3 (SD, 8.7) in the contralateral shoulder, with a significant difference of 4.7 points between shoulders. The median Disabilities of the Arm, Shoulder and Hand score was 4.2 (IQR, 0.0-10.8), and the median Simple Shoulder Test was 100 (IQR, 91.7-100.0). The median patient satisfaction for the injured shoulder was 83 (IQR, 70.0-95.0). Regarding radiologic outcomes, for the injured shoulder versus the contralateral shoulder, patients had similar rates of degeneration (44% vs 46%) but more frequent osteolysis of the distal clavicle (31% vs 0%), ossification of the ligaments (29% vs 7%), and deformity of the distal clavicle (19% vs 0%). Despite the frequent occurrence of radiographic changes, long-term functional outcome after Rockwood I and II acromioclavicular joint injuries is good, with only clinically nonrelevant functional differences between the injured and contralateral shoulders.


Locality of interactions in three-strain bacterial competition in E. coli.
The population dynamics that determine the composition and stability of ecosystems ultimately emerge from interactions between individual organisms. One well-studied system is the three-strain E. coli interaction of a heterogeneously toxin-producing C strain that interacts with a toxin-sensitive S and a toxin-resistant R strain. Here, we employ a multi-scale fluorescence microscopy approach, that has been proven useful in identifying previously unknown or underestimated stochastic effects in C-S competition. This approach allows us to investigate the microscopic interaction of the R strain and to quantify the role of stochastic effects in the spatially structured C-R-S interaction. We show that the early colony patterning at 12 h and at small length scales (near single cell level) is characterized by a number of microscopic variables (the number of C and R cell clusters and the area occupied by S) and is subject to random processes in positioning and toxin production. Then, in a second competition phase, mainly deterministic processes such as bacterial growth and global toxin action determine the following population dynamics. Consequently, together with environmental factors, the microscopic variables were predictive of the competition outcome. However, interactions of neighboring R and C clusters could amplify local variations. If R clusters originated near a C cell cluster, R could profit from the toxin produced by C without bearing the cost of production-a mechanism called cheating. By combining information from the micro- and macro-scale dynamics, we can estimate the distance at which the cheating interaction significantly changes to be in the order of 250 µm. In summary, after an initial phase influenced by stochastic patterning, largely deterministic growth dynamics follow, which are additionally affected by local interactions of neighboring clusters. As such, the results underline the importance of stochasticity and local effects in the context of ecological interactions.


Development of occupational hygiene standards in the People's Republic of China.
This article reviews the history and implementation of the development of occupational hygiene standard setting in the People's Republic of China. The author raises questions concerned with standard setting and gives examples of toxicants for which the scientific basis of revision is given. The principles and approaches used to set or revise hygiene standards in China are explained, and suggestions to help speed up the standard setting are also given. As a rule, field and epidemiologic surveys and the utilization of existing toxicologic information are emphasized. Repetitions of animal experimentation should be avoided.


Arm Span and Its Relation to Height in a 2- to 17-Year-Old Reference Population and Heterozygous Carriers of ACAN Variants.
In the clinical assessment of a short or tall child, estimating body disproportion is useful to assess the likelihood of a primary growth disorder, e.g., skeletal dysplasia. Our objectives were (1) to use data from the Maastricht study on healthy children (2-17 years) to calculate relative arm span (AS) for height (H) to serve as age references for clinical purposes; (2) to assess its age and sex dependency; and (3) to investigate relative AS adjustment for age and sex in individuals with ACAN haploinsufficiency. The Maastricht study data (2,595 Caucasian children, 52% boys, 48% girls) were re-analysed to produce reference tables and graphs for age and sex of AS - H and AS/H. Published information on AS/H in Europeans was used as reference data for adults. Relative AS from 33 patients with ACAN haploinsufficiency were plotted against reference data and expressed as standard deviation score (SDS) for age and sex. Mean AS - H from 2 to 17 years increased from -1.2 to +1.5 cm in boys and from -4.8 to +1.6 cm in girls. Mean AS/H increased from 0.9848 to 1.0155 in boys and from 0.9468 to 1.0028 in girls. Mean AS/H in patients with ACAN haploinsufficiency was approximately 1.0, 1.5 and 0.5 SDS in young children, adolescents and 20- to 50-year-olds, respectively, and normal thereafter. These reference charts can be used for 2- to 17-year-old children/adolescents. Carriers of ACAN haploinsufficiency have an elevated mean AS/H in childhood and adolescence and a slightly elevated ratio till 50 years.


Functional group imaging by chemical force microscopy.
Mapping the spatial arrangement of chemical functional groups and their interactions is of significant importance to problems ranging from lubrication and adhesion to recognition in biological systems. A force microscope has been used to measure the adhesive and friction forces between molecularly modified probe tips and organic monolayers terminating in a lithographically defined pattern of distinct functional groups. The adhesive interactions between simple CH(3)/CH(3), CH(3)/COOH, and COOH/COOH functional groups correlate directly with friction images of sample surfaces patterned with these groups. Thus, by monitoring the friction between a specifically functionalized tip and sample, one can produce friction images that display predictable contrast and correspond to the spatial distribution of functional groups on the sample surface. Applications of this chemically sensitive imaging technique are discussed.


Protective mechanisms of a metalloporphyrinic peroxynitrite decomposition catalyst, WW85, in rat cardiac transplants.
Nitric oxide (NO) derived from inducible NO synthase has been implicated in cardiac rejection. However, little is known about the role of the reactive nitrogen species peroxynitrite. We examined the protective actions of a peroxynitrite decomposition catalyst, WW85, in an experimental model of acute cardiac rejection. Heterotopic, abdominal transplantation of rat donor hearts was performed. Groups included isografts, allografts, or allografts treated with WW85, cyclosporine, or cyclosporine + WW85. We determined graft survival, histological rejection, and graft function (by in situ sonomicrometry). Intragraft biochemical analysis of cytokines and proapoptotic and antiapoptotic gene expression using reverse transcriptase-polymerase chain reaction were determined. Treatment with WW85 or cyclosporine alone prolonged graft survival, improved graft function, and decreased histological rejection. Graft survival was further significantly (P < 0.001) enhanced by combination treatment. A decrease was also shown in nitrotyrosine, poly(ADP-ribose) polymerase (PARP) activation, and lipid peroxide formation by WW85 that was potentiated when given in combination with cyclosporine. Benefits could not be ascribed to changes in intragraft myeloperoxidase activity. Only combination therapy produced significant decreases in inflammatory cytokine gene expression, suggesting that WW85 acted primarily downstream of these stimuli. In general, WW85 had no direct action on expression of the proapoptotic gene, Fas ligand; however, WW85 given alone or with cyclosporine enhanced expression of antiapoptotic genes Bcl-2 and Bcl-xL. Collectively, these findings suggest a protective action of the peroxynitrite decomposition catalyst WW85 on graft rejection that is independent of any action on leukocyte sequestration and cytokine gene expression. Rather, effects seem to be downstream on decreased protein nitration, decreased lipid peroxidation, and decreased PARP activation.


Stat3 orchestrates tumor development and progression: the Achilles' heel of head and neck cancers?
Despite recent advancements in treatment modalities, the overall survival and quality of life of patients with head and neck squamous cell carcinoma (HNSCC) have not improved significantly over the past decade. With the increasing emergency of new biological agents, the development of novel treatment schemes based on cancer cell biology may be promising for this group of patients. We previously introduced the "oncogene addiction" concept as a rationale for molecular targeting in cancer therapy and prevention. In this context, an increasing number of preclinical studies have demonstrated that the Signal Transducers and Activators of transcription 3 (Stat3) transcription factor plays critical roles in the development and progression of a variety of tumors including HNSCC, by regulating cell proliferation, cell cycle progression, apoptosis, angiogenesis, immune evasion, Epithelial-Mesenchymal Transition (EMT) and through effects in cancer stem cells. The purpose of this review is to summarize current experimental and clinical evidence that suggest that HNSCC might be addicted to Stat3 and describe the molecular mechanisms that may explain this phenomenon. In addition, we discuss whether this addiction is an exploitable target for developing approaches for the treatment and prevention of HNSCC.


Beta-catenin expression in relation to genetic instability and prognosis in colorectal cancer.
In the carcinogenesis of colorectal cancer (CRC) genetic instability and dysfunction of the Wnt-signalling pathway play important roles. Most Wnt-signalling dysfunctions lead to the nuclear accumulation of beta-catenin. The aim of the present study was to investigate whether nuclear accumulation of beta-catenin is associated with prognosis and genetic instability. We used immunohistochemistry to study nuclear beta-catenin expression in 67 CRCs. The expression was evaluated in the entire tumour section as mean values and in tumour budding at the invasive margin. We compared the results with chromosomal and microsatellite instability (CIN vs. MSI), p53 accumulation, and clinicopathological variables including survival. The nuclear accumulation of beta-catenin was significantly associated with abnormal p53 expression and aneuploidy, typically for CIN, whereas no tumour with nuclear beta-catenin expression at the invasive margin displayed MSI. The beta-catenin expression pattern did not correlate significantly with CRC patient prognosis when including all stages. However, in the clinically most interesting prognostic group, Dukes' stage B patients, high nuclear accumulation of beta-catenin was associated with a poor prognosis (p=0.01). Our results suggest that nuclear accumulation of beta-catenin in CRC is related to CIN and may be of prognostic importance. However, larger studies are needed to verify these findings.


Computer simulation of coronary flow waveforms during caval occlusion.
Mathematical modeling of the cardiovascular system is a powerful tool to extract physiologically relevant information from multi-parametric experiments. The purpose of the present work was to reproduce by means of a computer simulator, systemic and coronary measurements obtained by in vivo experiments in the pig. We monitored in anesthetized open-chest pig the phasic blood flow of the left descending coronary artery, aortic pressure, left ventricular pressure and volume. Data were acquired before, during, and after caval occlusion. Inside the software simulator (CARDIOSIM) of the cardiovascular system, coronary circulation was modeled in three parallel branching sections. Both systemic and pulmonary circulations were simulated using a lumped parameter mathematical model. Variable elastance model reproduced Starling's law of the heart. Different left ventricular pressure-volume loops during experimental caval occlusion and simulated cardiac loops are presented. The sequence of coronary flow-aortic pressure loops obtained in vivo during caval occlusion together with the simulated loops reproduced by the software simulator are reported. Finally experimental and simulated instantaneous coronary blood flow waveforms are shown. The lumped parameter model of the coronary circulation, together with the cardiovascular system model, is capable of reproducing the changes during caval occlusion, with the profound shape deformation of the flow signal observed during the in vivo experiment. In perspectives, the results of the present model could offer new tool for studying the role of the different determinants of myocardial perfusion, by using the coronary loop shape as a "sensor" of ventricular mechanics in various physiological and pathophysiological conditions.


The role of liposomal amphotericin B in the treatment of systemic fungal infections.
Amphotericin B remains the treatment of choice for systemic fungal infections, but amphotericin B is toxic and is often not effective in treating disseminated infections. Liposome intercalation of amphotericin B reduces the toxicity associated with amphotericin B and targets reticuloendothelial tissues most heavily involved in fungal infections. The targeted delivery and reduced toxicity of liposomal amphotericin B improves the therapeutic index of amphotericin B. Although liposomes have been shown to effectively treat a variety of experimental and human fungal infections, the optimal composition of liposomal amphotericin has not been established. Vesicle type, lipid content, size, and conditions of storage markedly affect toxicity, therapeutic efficacy, and tissue distribution. In vitro studies have been poor predictors of in vivo efficacy and toxicity. Animal models can be used to evaluate in vivo the optimal liposome preparation. Liposomal amphotericin B appears to be an improved means of amphotericin B delivery and may improve the treatment of patients with systemic fungal infections.


Stimulation of host immune defenses by a small molecule protects C. elegans from bacterial infection.
The nematode Caenorhabditis elegans offers currently untapped potential for carrying out high-throughput, live-animal screens of low molecular weight compound libraries to identify molecules that target a variety of cellular processes. We previously used a bacterial infection assay in C. elegans to identify 119 compounds that affect host-microbe interactions among 37,214 tested. Here we show that one of these small molecules, RPW-24, protects C. elegans from bacterial infection by stimulating the host immune response of the nematode. Using transcriptome profiling, epistasis pathway analyses with C. elegans mutants, and an RNAi screen, we show that RPW-24 promotes resistance to Pseudomonas aeruginosa infection by inducing the transcription of a remarkably small number of C. elegans genes (∼1.3% of all genes) in a manner that partially depends on the evolutionarily-conserved p38 MAP kinase pathway and the transcription factor ATF-7. These data show that the immunostimulatory activity of RPW-24 is required for its efficacy and define a novel C. elegans-based strategy to identify compounds with activity against antibiotic-resistant bacterial pathogens.


Aspergillus Test Profiles and Mortality in Critically Ill COVID-19 Patients.
The literature regarding COVID-19-associated pulmonary aspergillosis (CAPA) has shown conflicting observations, including survival of CAPA patients not receiving antifungal therapy and discrepancy between CAPA diagnosis and autopsy findings. To gain insight into the pathophysiology of CAPA, we performed a case-control study in which we compared Aspergillus test profiles in CAPA patients and controls in relation to intensive care unit (ICU) mortality. This was a multinational case-control study in which Aspergillus test results, use of antifungal therapy, and mortality were collected from critically ill COVID-19 patients. Patients were classified using the 2020 European Confederation for Medical Mycology and the International Society for Human and Animal Mycology (ECMM/ISHAM) consensus case definitions. We analyzed 219 critically ill COVID-19 cases, including 1 proven, 38 probable, 19 possible CAPA cases, 21 Aspergillus-colonized patients, 7 patients only positive for serum (1,3)-β-d-glucan (BDG), and 133 cases with no evidence of CAPA. Mortality was 53.8% in CAPA patients compared to 24.1% in patients without CAPA (P = 0.001). Positive serum galactomannan (GM) and BDG were associated with increased mortality compared to serum biomarker-negative CAPA patients (87.5% versus 41.7%, P = 0.046; 90.0% versus 42.1%, P = 0.029, respectively). For each point increase in GM or 10-point BDG serum concentration, the odds of death increased (GM, odds ratio [OR] 10.208, 95% confidence interval [CI], 1.621 to 64.291, P = 0.013; BDG, OR, 1.247, 95% CI, 1.029 to 1.511, P = 0.024). CAPA is a complex disease, probably involving a continuum of respiratory colonization, tissue invasion, and angioinvasion. Serum biomarkers are useful for staging CAPA disease progression and, if positive, indicate angioinvasion and a high probability of mortality. There is need for a biomarker that distinguishes between respiratory tract colonization and tissue-invasive CAPA disease.


Technical Note: Validation of TG 233 phantom methodology to characterize noise and dose in patient CT data.
Phantoms are useful tools in diagnostic CT, but practical limitations reduce phantoms to being only a limited patient surrogate. Furthermore, a phantom with a single cross sectional area cannot be used to evaluate scanner performance in modern CT scanners that use dose reduction techniques such as automated tube current modulation (ATCM) and iterative reconstruction (IR) algorithms to adapt x-ray flux to patient size, reduce radiation dose, and achieve uniform image noise. A new multisized phantom (Mercury Phantom, MP) has been introduced, representing multiple diameters. This work aimed to ascertain if measurements from MP can predict radiation dose and image noise in clinical CT images to prospectively inform protocol design. The adult MP design included four different physical diameters (18.5, 23.0, 30.0, and 37.0 cm) representing a range of patient sizes. The study included 1457 examinations performed on two scanner models from two vendors, and two clinical protocols (abdominopelvic with and chest without contrast). Attenuating diameter, radiation dose, and noise magnitude (average pixel standard deviation in uniform image) was automatically estimated in patients and in the MP using a previously validated algorithm. An exponential fit of CTDIvol and noise as a function of size was applied to patients and MP data. Lastly, the fit equations from the phantom data were used to fit the patient data. In each patient distribution fit, the normalized root mean square error (nRMSE) values were calculated in the residuals' plots as a metric to indicate how well the phantom data can predict dose and noise in clinical operations as a function of size. For dose across patient size distributions, the difference between nRMSE from patient fit and MP model data prediction ranged between 0.6% and 2.0% (mean 1.2%). For noise across patient size distributions, the nRMSE difference ranged between 0.1% and 4.7% (mean 1.4%). The Mercury Phantom provided a close prediction of radiation dose and image noise in clinical patient images. By assessing dose and image quality in a phantom with multiple sizes, protocol parameters can be designed and optimized per patient size in a highly constrained setup to predict clinical scanner and ATCM system performance.


Deprescribing benzodiazepine receptor agonists: Evidence-based clinical practice guideline.
To develop an evidence-based guideline to help clinicians make decisions about when and how to safely taper and stop benzodiazepine receptor agonists (BZRAs); to focus on the highest level of evidence available and seek input from primary care professionals in the guideline development, review, and endorsement processes. The overall team comprised 8 clinicians (1 family physician, 2 psychiatrists, 1 clinical psychologist, 1 clinical pharmacologist, 2 clinical pharmacists, and 1 geriatrician) and a methodologist; members disclosed conflicts of interest. For guideline development, a systematic process was used, including the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Evidence was generated by conducting a systematic review of BZRA deprescribing trials for insomnia, as well as performing a review of reviews of the harms of continued BZRA use and narrative syntheses of patient preferences and resource implications. This evidence and GRADE quality of evidence ratings were used to generate recommendations. The team refined guideline content and recommendations through consensus and synthesized clinical considerations to address front-line clinician questions. The draft guideline was reviewed by clinicians and stakeholders. We recommend that deprescribing (tapering slowly) of BZRAs be offered to elderly adults (≥ 65 years) who take BZRAs, regardless of duration of use, and suggest that deprescribing (tapering slowly) be offered to adults aged 18 to 64 who have used BZRAs for more than 4 weeks. These recommendations apply to patients who use BZRAs to treat insomnia on its own (primary insomnia) or comorbid insomnia where potential underlying comorbidities are effectively managed. This guideline does not apply to those with other sleep disorders or untreated anxiety, depression, or other physical or mental health conditions that might be causing or aggravating insomnia. Benzodiazepine receptor agonists are associated with harms, and therapeutic effects might be short term. Tapering BZRAs improves cessation rates compared with usual care without serious harms. Patients might be more amenable to deprescribing conversations if they understand the rationale (potential for harm), are involved in developing the tapering plan, and are offered behavioural advice. This guideline provides recommendations for making decisions about when and how to reduce and stop BZRAs. Recommendations are meant to assist with, not dictate, decision making in conjunction with patients.


Isolating single stranded DNA using a microfluidic dialysis device.
Isolating a particular strand of DNA from a double stranded DNA duplex is an important step in aptamer generation as well as many other biotechnology applications. Here we describe a microfluidic, flow-through, dialysis device for isolating single-stranded DNA (ssDNA) from double-stranded DNA (dsDNA). The device consists of two channels fabricated in polydimethylsiloxane (PDMS) separated by a track etched polycarbonate membrane (800 nm pore size). To isolate ssDNA, dual-biotin labelled dsDNA was immobilized onto streptavidin-coated polystyrene beads. Alkaline treatment was used to denature dsDNA, releasing the non-biotinylated ssDNA. In the flow-through dialysis device the liberated ssDNA was able to cross the membrane and was collected in an outlet channel. The complementary sequence bound to the bead was unable to cross the membrane and was directed to a waste channel. The effect of NaOH concentration and flow rate on purity and yield were compared. >95% ssDNA purity was achieved at 25 mM NaOH. However, lower flow rates were necessary to achieve ssDNA yields approaching the 50% theoretical maximum of the concurrent-flow device. Under optimized conditions the microfluidic isolation achieved even higher purity ssDNA than analogous manual procedures.


Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis.
T helper (Th) 17 cells have recently been implicated in psoriasis pathogenesis, but mechanisms of how these cells traffic into inflamed skin are unknown. By immunostaining for interleukin (IL)-17A and IL-22, we show numerous cells present in psoriasis lesions that produce these cytokines. We next found that Th17 cytokines (IL-17A, IL-22, and tumor necrosis factor (TNF)-alpha) markedly increased the expression of CC chemokine ligand (CCL) 20, a CC chemokine receptor (CCR)6 ligand, in human keratinocyte monolayer and raft cultures in a dose- and time-dependent manner. Lastly, we showed in mice that subcutaneous injection with recombinant IL-17A, IL-22, or TNF-alpha led to the upregulation of both CCL20 and CCR6 expression in skin as well as cutaneous T-cell infiltration. Taken together, these data show that Th17 cytokines stimulate CCL20 production in vitro and in vivo, and thus provide a potential explanation of how CCR6-positive Th17 cells maintain their continual presence in psoriasis through a positive chemotactic feedback loop.


Modification of tomato breeding traits and plant hormone signaling by target-AID, the genome-editing system inducing efficient nucleotide substitution.
Target activation-induced cytidine deaminase (Target-AID), a novel CRISPR/Cas9-based genome-editing tool, confers the base-editing capability on the Cas9 genome-editing system. It involves the fusion of cytidine deaminase (CDA), which catalyzes cytidine (C) to uridine (U) substitutions, to the mutated nickase-type nCas9 or deactivated-type dCas9. To confirm and extend the applicability of the Target-AID genome-editing system in tomatoes (Solanum lycopersicum L.), we transformed the model tomato cultivar "Micro-Tom" and commercial tomato cultivars using this system by targeting SlDELLA, which encodes a negative regulator of the plant phytohormone gibberellic acid (GA) signaling pathway. We confirmed that the nucleotide substitutions were induced by the Target-AID system, and we isolated mutants showing high GA sensitivity in both "Micro-Tom" and the commercial cultivars. Moreover, by successfully applying this system to ETHYLENE RECEPTOR 1 (SlETR1) with single sgRNA targeting, double sgRNA targeting, as well as dual-targeting of both SlETR1 and SlETR2 with a single sgRNA, we demonstrated that the Target-AID genome-editing system is a promising tool for molecular breeding in tomato crops. This study highlights an important aspect of the scientific and agricultural potential of the combinatorial use of the Target-AID and other base-editing systems.


Left out axons make men right: a hypothesis for the origin of handedness and functional asymmetry.
The origin and underlying mechanisms of hand preference are still unresolved, despite extensive research and discussion. Numerous possibilities have been considered, including genetic and hormonal factors, brain insult and learning. We suggest here that naturally occurring loss of axons of the corpus callosum (either symmetric or asymmetric, with or without neuron death) may be one mechanism underlying the embryological development of hand preference and hemispheric anatomical and functional asymmetries in males. We note supporting evidence for this hypothesis from a report of increased prevalence of left-handedness in children born prematurely at the gestational age prior to the likely onset of axon loss. The practical implications of this hypothesis for clinical management in neonatal intensive care units are discussed. It is suggested that the course of loss of callosal axons may have a genetic component which is associated with a sex-related influence and which is modifiable by prenatal and early postnatal events.


Starch granular protein of high-amylose wheat gives innate resistance to amylolysis.
Granular protein is an important structural feature in determining starch digestibility. High-amylose wheat starch (HAWS) with >80% amylose content contains more granular protein than wild-type starch. As analyzed by mass spectrometry-based proteomics, granular-bound starch synthase (GBSS) is the major granular protein in isolated starch materials. GBSS content increases with amylose content (Spearman's correlation, p < 0.05), whereas the abundance relative to other proteins is similar among starches. Multiple amylase inhibitors were also identified. From Michaelis-Menten analysis, HAWS has a similar Km (Michaelis constant) as wild type, suggesting initial enzymatic binding is similar. After the pre-digestion of proteins, wild type had a greater change in starch digestibility than HAWS, probably due to the latter having 'thicker' granular-protein layers and higher enzymatic resistance of substrate per se. Overall, the study suggests that the greater granular protein content in HAWS is a factor that contributes to slower amylolysis compared to wild type.


Allogeneic hematopoietic stem cell transplantation in congenital disorders: A single-center experience.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the treatment of choice for a variety of congenital disorders. We report the experience of children affected by congenital diseases other than bone marrow failure syndromes who received allo-HSCT over a period of 25 years at G. Gaslini Paediatric Research Institute. HSCTs were performed in 57 children with congenital diseases (25 with congenital immunodeficiencies, 10 with severe combined immunodeficiencies, and 22 with metabolic diseases). Overall survival rate at 3 years in the whole group of patients was 76.9%, with a trend in favor of better outcome in children with metabolic diseases and in those who received cord blood cells (85.9%) vs bone marrow cells (72.4%).


A Multiplex PCR Assay to Characterize Potato virus Y Isolates and Identify Strain Mixtures.
Potato virus Y (PVY) has become a serious problem for the seed potato industry, with increased incidence and rejection of seed lots submitted for certification. New PVY strains and strain variants have emerged in recent decades in Europe and North America, including the PVYN strain that causes veinal necrosis in tobacco, and strain variants that represent one or three recombination events between the common strain (PVYO) and PVYN. Several reverse transcription-polymerase chain reaction (RT-PCR) assays have been described that characterize PVY isolates as to strain type, but they are limited in their ability to detect some combinations of mixed strain infections. We report here the development of a single multiplex RT-PCR assay that can assign PVY strain type and detect mixed infections with respect to the major strain types. Validation of this assay was achieved using 119 archived PVY isolates, which had been previously characterized by serology and bioassay and/or previously published RT-PCR assays. Results for single-strain isolates were comparable to previous results in most cases. Interestingly, 16 mixed infections were distinguished that had previously gone undetected. The new multiplex RT-PCR assay will be useful for researchers and seed production specialists interested in determining PVY infection type using a single assay.


Marine forests of the Mediterranean-Atlantic Cystoseira tamariscifolia complex show a southern Iberian genetic hotspot and no reproductive isolation in parapatry.
Climate-driven range-shifts create evolutionary opportunities for allopatric divergence and subsequent contact, leading to genetic structuration and hybrid zones. We investigate how these processes influenced the evolution of a complex of three closely related Cystoseira spp., which are a key component of the Mediterranean-Atlantic seaweed forests that are undergoing population declines. The C. tamariscifolia complex, composed of C. tamariscifolia s.s., C. amentacea and C. mediterranea, have indistinct boundaries and natural hybridization is suspected. Our aims are to (1) infer the genetic structure and diversity of these species throughout their distribution ranges using microsatellite markers to identify ancient versus recent geographical populations, contact zones and reproductive barriers, and (2) hindcast past distributions using niche models to investigate the influence of past range shifts on genetic divergence at multiple spatial scales. Results supported a single, morphologically plastic species the genetic structure of which was incongruent with a priori species assignments. The low diversity and low singularity in northern European populations suggest recent colonization after the LGM. The southern Iberian genetic hotspot most likely results from the role of this area as a climatic refugium or a secondary contact zone between differentiated populations or both. We hypothesize that life-history traits (selfing, low dispersal) and prior colonization effects, rather than reproductive barriers, might explain the observed genetic discontinuities.


Generic lossless visible watermarking--a new approach.
A novel method for generic visible watermarking with a capability of lossless image recovery is proposed. The method is based on the use of deterministic one-to-one compound mappings of image pixel values for overlaying a variety of visible watermarks of arbitrary sizes on cover images. The compound mappings are proved to be reversible, which allows for lossless recovery of original images from watermarked images. The mappings may be adjusted to yield pixel values close to those of desired visible watermarks. Different types of visible watermarks, including opaque monochrome and translucent full color ones, are embedded as applications of the proposed generic approach. A two-fold monotonically increasing compound mapping is created and proved to yield more distinctive visible watermarks in the watermarked image. Security protection measures by parameter and mapping randomizations have also been proposed to deter attackers from illicit image recoveries. Experimental results demonstrating the effectiveness of the proposed approach are also included.


The effect of isoflavones extracted from red clover (Rimostil) on lipid and bone metabolism.
This study was undertaken to evaluate the effects of varying doses of phytoestrogens on lipid and bone metabolism in postmenopausal women. A novel red clover isoflavone preparation (Rimostil) containing genistein, daidzein, formononetin, and biochanin was administered to 46 postmenopausal women in a double-blind protocol after a single-blind placebo phase and followed by a single-blind washout phase. Patients were randomized to receive either 28.5 mg, 57 mg, or 85.5 mg of phytoestrogens daily for a 6-month period. At 6 months, the serum high-density lipoprotein cholesterol had risen significantly by 15.7-28.6% with different doses (p = 0.007, p = 0.002, p = 0.027), although the magnitude of the response was independent of the dose used. The serum apolipoprotein B fell significantly by 11.5-17.0% with different doses (p = 0.005, p = 0.043, p = 0.007) and the magnitude of the response was independent of the dose used. The bone mineral density of the proximal radius and ulna rose significantly by 4.1% over 6 months with 57 mg/day (p = 0.002) and by 3.0% with 85.5 mg/day (p = 0.023) of isoflavones. The response with 28.5 mg/day of isoflavones was not significant. There was no significant increase in endometrial thickness with any of the doses of isoflavone used. These results show that the administration of an isoflavone combination extracted from red clover was associated with a significant increase in high-density lipoprotein cholesterol, a significant fall in apolipoprotein B, and a significant increase in the predominantly cortical bone of the proximal radius and ulna after 6 months of treatment. Interpretation of the results is undertaken cautiously because of the absence of a simultaneously studied control group.


Regional cerebral blood flow assessed by 133Xe inhalation and emission tomography: normal values.
Regional cerebral blood flow (rCBF) in the cerebral hemispheres and the cerebellum was measured by single photon emission computed tomography with inhalation of 133Xe in 39 normal volunteers at test. The goal of this study was to assess the normal flow pattern and its variations. Five parallel tomographic slices through the brain were recorded with a resolution element of 1.7 X 1.7 X 2.0 cm (full width at half maximum). The blood flow distribution showed that the predominantly gray matter areas displayed flow approximately double that of the predominantly white matter regions. The CBF distribution was practically symmetrical with a side-to-side difference averaging 1.4 +/- 1.4 ml/100 g/min. This means that a difference exceeding 4.2 ml/100 g/min (approximately 9% of mean CBF) is abnormal with a confidence level of below 5%. The measured average CBF and cerebellar blood flow were 56 +/- 7 and 54 +/- 6 ml/100 g/min (mean +/- 1 SD), respectively. A significant correlation was found between CBF and PCO2, and between CBF and age. Repeat measurements in an additional 30 subjects showed a day-to-day variability of -0.2 +/- 6.4 ml/100 g/min of the difference between the first and the second measurement. This corresponds to random methodological and biological errors of 6.4/square root 2 = 4.6 ml/100 g/min and is a measure of the overall intraindividual variability. Xenon-133 tomography is atraumatic and affords rCBF images free of the superposition artifacts that practically invalidate the nontomographic approaches in the studies of cerebrovascular disease. The rCBF tomograms are blurred, particularly due to Compton scatter. Relative to this factor, the errors caused by local variations in the tissue:blood partition coefficient are less important.


Notch gain of function in mouse periocular mesenchyme downregulates FoxL2 and impairs eyelid levator muscle formation, leading to congenital blepharophimosis.
Notch signaling is pivotal for the morphogenesis and homeostasis of many tissues. We found that aberrant Notch activation in mouse neural-crest-derived periocular mesenchymal cells (POMCs), which contribute to the formation of corneal and eyelid stroma, results in blepharophimosis. Compound transgenic mice overexpressing the Notch1 intracellular domain (N1-ICD) in POMCs (POMC(N1-ICD)) showed relatively minor effects on the cornea, but increased cell apoptosis and decreased cell proliferation during eyelid morphogenesis. Eyelid closure at E15.5 and eyelid formation at birth were incomplete. In further analyses, overexpression of N1-ICD impaired eyelid levator smooth muscle formation by downregulating the transcription factor FoxL2. This is similar to the effect of haploinsufficiency of FOXL2 in humans, which results in type II BPES (blepharophimosis, ptosis and epicanthus inversus syndrome). In vitro studies showed that FoxL2 expression is augmented by a low dose of N1-ICD but was downregulated by a high dose, depending on the extent of Hes-1 and Hey-1 activation. Moreover, transfection of CMV-FoxL2 enhanced α-SMA promoter activity. These data strongly imply that a physiologically low level of Notch1 is crucial for proper FoxL2 expression in POMCs, which is, in turn, essential for Müeller muscle formation and normal eyelid development.


Developmental regulation of DNase I-hypersensitive sites in Dictyostelium discoideum.
We have studied two regions of Dictyostelium discoideum chromatin and identified several DNase I-hypersensitive sites in these regions. One of these sites is located about 300 to 500 bases upstream of the transcriptional start site of a gene that is expressed at all stages of development. This site is present in both vegetative cells and postaggregation cells. Another hypersensitive site is associated with a gene that is expressed only after the multicellular stage. This site is located about 400 bases upstream of the start site, and it is present only in postaggregation cells. Thus, much like higher eucaryotes, D. discoideum contains DNase I-hypersensitive sites that may be involved in the regulation of the genes with which they are associated.


A positive regulator of the ribosomal protein gene, beta factor, belongs to the ETS oncoprotein family.
The beta factor, which interacts with the rpL32 promoter, binds to the sequence 5'-GAGCCGGAAGTG and trans-activates this gene. Comparison of the DNA sequences bound by the beta factor with those bound by other known DNA-binding proteins revealed that the ETS proteins interact with similar DNA sequences. Consequently we have examined the relationship of the beta factor to the several ETS proteins so far reported. Antibody and oligonucleotide competition experiments, performed by using electrophoretic shift analysis, revealed that the beta factor contains ETS epitopes and that it is immunologically related to both of the GA-binding proteins (GABPs), implying that the beta factor may consist of two separate protein subunits.


Bone marrow stromal cell blockade of human leukemic cell differentiation.
Bone marrow (BM) stromal cell inhibition of leukemic cell differentiation was studied in cellular coculture experiments. In coculture, a significant percentage of cells from the human myeloid leukemic cell lines HL-60, PLB-985, and K562 adhere to fibroblastic KM-102 BM stromal cells. A sensitive two-color immunofluorescence assay was developed to monitor stromal cellular effects upon leukemic cell differentiation. After chemical induction with 1 alpha,25-dihydroxyvitamin D3, strongly adherent HL-60 and PLB-985 cells were inhibited from differentiating into more mature monocytic cells, as measured by the monocytic surface marker CD14. In contrast, loosely adherent and nonadherent HL-60 and PLB-985 leukemic cells in the same cocultures, as well as both adherent and nonadherent K562 cells induced with phorbol ester, were not blocked in their capacity to differentiate. Scanning electron microscopy and intercellular dye transfer experiments correlated intimate stromal cell/leukemic cell interaction and intercellular communication with the blockade of leukemic cell differentiation. These studies indicate that there is significant variability among leukemic lines with respect to the nature of their adhesion to stromal cells. Moreover, the data implicate gap-junction formation as a potentially significant event in stromal cell-mediated leukemic cell regulation.


ANF secretion and renal responses to volume expansion with equilibrated blood.
To evaluate the role of atrial natriuretic factor (ANF) in the renal response to acute blood volume expansion without hemodilution, a reservoir syringe filled with donor rat blood was connected to the femoral artery and vein of anesthetized Sprague-Dawley rats to allow rapid equilibration of the reservoir with the intravascular blood. Volume expansion with blood from the reservoir in two steps (of 1 and 1.5% body wt, separated by 1 h, n = 5 rats) produced a mean peak increase in plasma immunoreactive ANF from 99 +/- 21 to 1,310 +/- 230 pg/ml (P less than 0.001); plasma ANF levels throughout these experiments correlated significantly with simultaneously measured urine flow (r = 0.74, P less than 0.005) and sodium excretion (r = 0.65, P less than 0.005). Another group (n = 7) underwent the same two-step procedure; after the second volume expansion, high-dose atriopeptin III infusion (0.4 microgram.kg-1.min-1 did not further increase fractional excretion of sodium (3.17 +/- 0.27 to 2.50 + 0.39%, P = NS). In another group (n = 9 rats), the same dose of atriopeptin III was started before any blood volume expansion. After the resulting hypotension was corrected by restoration of blood volume, an additional 1.5% body weight blood volume expansion did not further augment sodium excretion. We conclude that the diuresis and natriuresis, which occur in response to volume expansion without hemodilution, rise and fall in parallel with immunoreactive ANF in the plasma, and that ANF and acute blood volume expansion act on the kidney through a similar, saturable mechanism.


The puzzling clinical spectrum and course of juvenile sarcoidosis.
Juvenile sarcoidosis is a rare, chronic, multisystem, granulomatous disease of obscure etiology which is seen in childhood and adulthood. The disease in childhood has a course different from that in adulthood. PubMed database was searched using terms sarcoidosis, children or childhood sarcoidosis or juvenile sarcoidosis in combination with one of the following terms: epidemiology, clinical manifestations, genetics, diagnosis, treatment, and prognosis. We also retrieved the terms such as early onset sarcoidosis and Blau syndrome. Furthermore, e-medicine and European Respiratory Society monographs for sarcoidosis were reviewed. Sarcoidosis in childhood presents with two age dependent, distinct forms. In younger children it is clinically evident before the age of four years and characterized by the triad of rash, arthritis and uveitis. In their older counterparts, the juvenile late onset sarcoidosis involves several organs and its clinical appearance resembles the adult type of the disease, with the respiratory system being most frequently affected (hilar lymphadenopathy, pulmonary infiltrations). Steroid is the main agent of treatment whereas methotrexate is also used for beneficial steroid sparing effects. New, novel therapies may change the outcome of the disease especially in difficult morbid cases. Sarcoidosis in childhood is recognized as a systemic disease affecting various organs and having diverse clinical course depending on the age of onset.


Comparison of CD20 expression in B-cell lymphoma between newly diagnosed, untreated cases and those after rituximab treatment.
Few studies have statistically investigated reduced CD20 expression in B-cell lymphoma after rituximab therapy and genomic mutation of CD20 associated with reduction. We examined CD20-positive rate in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) by flow cytometry (FCM) and immunohistochemical staining (IHS), comparing 138 cases after rituximab therapy with 360 initial, not yet treated cases. Sequence analysis of exons 3 to 8 of CD20 was performed on 22 cases with low CD20-positive rate after rituximab treatment. The results showed a statistical correlation between CD20-positive rate in FCM and IHS. By FCM, the CD20-positive rate among post-rituximab cases was significantly lower than among initial cases in DLBCL, non-germinal center origin B-cell type (average values [avg] 57.8 and 87.9, respectively) (P < 0.0001), FL2 (avg, 93.9; 103.2) (P = 0.0083), and FL3A (avg, 90.6; 100.7) (P = 0.033). Stratified analyses of post-rituximab cases showed significantly lower CD20-positive rate in cases that were resistant at the start of the treatment and cases with progressive disease during rituximab therapy before biopsy. Sequence analysis showed silent mutation of exon 4 (632 C/T) in seven cases, although this number was not statistically significant. These results suggest the influence of B-lymphoma subtype and a therapeutic effect before biopsy on CD20 expression at relapse and contribute to a better therapeutic approach for relapse cases after rituximab therapy.


Combination Therapy with Cinnamaldehyde and Hyperthermia Induces Apoptosis of A549 Non-Small Cell Lung Carcinoma Cells via Regulation of Reactive Oxygen Species and Mitogen-Activated Protein Kinase Family.
Lung cancer is the largest cause of cancer-induced deaths. Non-small cell lung cancer (NSCLC) is the most frequently observed subtype of lung cancer. Although recent studies have provided many therapeutic options, there is still a need for effective and safe treatments. This paper reports the combined effects of cinnamaldehyde (CNM), a flavonoid from cinnamon, together with hyperthermia, a therapeutic option for cancer treatment, on the A549 NSCLC cell line. A hyperthermia treatment of 43 °C potentiated the cytotoxicity of CNM in A549 cells. This was attributed to an increase in the apoptosis markers and suppression of the survival/protective factors, as confirmed by Western blot assays. Flow cytometry supported this result because the apoptotic profile, cell health profile, and cell cycle profile were regulated by CNM and hyperthermia combination therapy. The changes in reactive oxygen species (ROS) and its downstream target pathway, mitogen-activated protein kinases (MAPK), were evaluated. The CNM and hyperthermia combination increased the generation of ROS and MAPK phosphorylation. N-acetylcysteine (NAC), a ROS inhibitor, abolished the apoptotic events caused by CNM and hyperthermia co-treatment, suggesting that the cytotoxic effect was dependent of ROS signaling. Therefore, we suggest CNM and hyperthermia combination as an effective therapeutic option for the NSCLC treatment.


Characterization of voltage-activated currents in Hermissenda type B-photoreceptors.
Two distinct voltage-dependent K+ currents have been previously identified in the type B-photoreceptors of Hermissenda: an early, rapidly inactivating K+ current (IA), and a late, 4-AP- and TEA-resistant voltage and Ca(2+)-dependent current (IK(Ca)). Using conventional two-electrode voltage-clamp techniques, we have characterized two additional currents, a late voltage-dependent outward K+ current (IK(v)) and a voltage-dependent inward current identified as an inward rectifier (Iir). In addition, we have further studied the activation-inactivation kinetics of IA. In 0-Na+ ASW, Iir activates at a potential of > -50 mV, is steeply voltage-dependent and noninactivating, and reaches steady-state within 800 msec to 3 sec at -100 mV. In addition to the variability in activation kinetics, there was also considerable variability in Iir magnitude (-5 to -80 nA, at -100 mV). Iir was blocked by external 4-AP (5 mM), external and internal TEA, internal Cs+, but not external Ba2+. The major component of outward K+ current in type B-photoreceptors is IK(v), the delayed rectifier. IK(v) was isolated after removal of IA and IK(Ca). IK(v) activates at around -25 mV or more positive membrane potentials and its activation and inactivation are strongly voltage dependent. IK(v) inactivation to steady state is reached within 1.5-2.5 sec. The wide range of activation-inactivation rates suggests that there may be kinetic subtypes of IK(v). The proposed "slow" IK(v) peaked in 50-90 msec at +30 mV, and decayed with a single exponential component with an average tau off of 279 msec. Proposed "intermediate" and "fast" IK(v) subtypes peaked within 12-50 msec at +30 mV, and had a decay fitted by two exponentials, with an average tau 1 of 147 msec and tau 2 of 275 msec, respectively. IK(v) exhibited marked twin-pulse inactivation with a recovery time of 30-40 sec, and also exhibited time- and voltage-dependent cumulative inactivation to repeated depolarizing pulses. Both types of inactivation were quickly removed by a prepulse hyperpolarization. 4-AP (5 mM) produced partial to complete block of the inactivating component of IK(v), leaving only a residual sustained component. Complete block of the transient and sustained components of IK(v) was obtained by 100 mM TEA. Reliable voltage separation of IA from IK(v) was achieved by activating IA in the range of -50 to -20 mV, from a Vh of -80 mV. Voltage-dependent steady-state inactivation curves for IA were determined, yielding an average h0.5 value of -56 mV.(ABSTRACT TRUNCATED AT 250 WORDS)


[Vinpotropil in the treatment of dyscirculatory encephalopathy with cognitive impairment without dementia].
The fixed combination containing 5 mg of vinpocetine and 400 mg of pyracetam (vinpotropil) was prescribed to 349 patients with dyscirculatory encephalopathy, I-II stages in dose one capsule three times a day during 3 months. After this treatment, repeated neuropsychological testing showed significant diminishing of dysexecutive cognitive impairment linked with frontal lobes dysfunction. The cognitive improvement was associated with the regress of subjective neurological symptoms like headache, dizziness, tinnitus, fatigue and insomnia. Vinpotropil was safe and well tolerated in elderly patients with chronic cerebral vascular insufficiency.


Spontaneous facial expressions of happy bowlers and soccer fans.
Kraut and Johnston (1979) found surprisingly few smiles in large samples of bowlers and hockey fans during happy events--unless they were simultaneously engaged in social interaction. A limitation of their studies is that there was no direct test of subjects' actual emotional experience at the moments in which they were observed. This article reports two field studies in which emotions were reported by bowlers and by soccer fans. Analysing facial behaviour of those who reported happiness, we found a low probability of smiling in the absence of social interaction (.09 for bowlers and .07 for soccer fans) and a high probability of smiling during social interaction (.78 and .70). These findings question the common assumption that smiles are an indicator of happiness per se, and support the alternative hypothesis of a more complex and indirect relationship between smiling and happiness.


[Efficacy and stability of ammoniation process as aflatoxin B1 decontamination technology in rice].
Rice, a cereal widely used in Venezuela for human and animal nutrition, is susceptible to aflatoxin contamination in the field and during storage. Therefore, the goal of this research was the evaluation of the efficacy and permanence of the ammoniation process through high pressure/high temperature (HP/HT) and atmospheric pressure/moderate temperature (AP/MT) conditions applied to rice samples artificially contaminated with aflatoxin B1. For this purpose a 2k design was drawn up considering the temperature, the rice moisture and the process time as variables. Under both sets of conditions, aflatoxin B1 concentration was reduced in a range of 90% to 100%. After in vitro stomach digestion simulation, toxin reversion ranged from 0% to 19%. In conclusion, the process efficacy and permanence were achieved through the use of high temperature and long process time for both sets of conditions (HP/HT and AP/MT), respectively.


Intraarticular corticosteroids, supervised physiotherapy, or a combination of the two in the treatment of adhesive capsulitis of the shoulder: a placebo-controlled trial.
To compare the efficacy of a single intraarticular corticosteroid injection, a supervised physiotherapy program, a combination of the two, and placebo in the treatment of adhesive capsulitis of the shoulder. Ninety-three subjects with adhesive capsulitis of <1 year's duration were randomized to 1 of 4 treatment groups: group 1, corticosteroid injection (triamcinolone hexacetonide 40 mg) performed under fluoroscopic guidance followed by 12 sessions of supervised physiotherapy; group 2, corticosteroid injection alone; group 3, saline injection followed by supervised physiotherapy; or group 4, saline injection alone (placebo group). All subjects were taught a simple home exercise program. Subjects were reassessed after 6 weeks, 3 months, 6 months, and 1 year. The primary outcome measure was improvement in the Shoulder Pain and Disability Index (SPADI) score. At 6 weeks, the total SPADI scores had improved significantly more in groups 1 and 2 compared with groups 3 and 4 (P = 0.0004). The total range of active and passive motion increased in all groups, with group 1 having significantly greater improvement than the other 3 groups. At 3 months, groups 1 and 2 still showed significantly greater improvement in SPADI scores than group 4. There was no difference between groups 3 and 4 at any of the followup assessments except for greater improvement in the range of shoulder flexion in group 3 at 3 months. At 12 months, all groups had improved to a similar degree with respect to all outcome measures. A single intraarticular injection of corticosteroid administered under fluoroscopy combined with a simple home exercise program is effective in improving shoulder pain and disability in patients with adhesive capsulitis. Adding supervised physiotherapy provides faster improvement in shoulder range of motion. When used alone, supervised physiotherapy is of limited efficacy in the management of adhesive capsulitis.


Creation of fragrant rice by targeted knockout of the OsBADH2 gene using TALEN technology.
Fragrant rice is favoured worldwide because of its agreeable scent. The presence of a defective badh2 allele encoding betaine aldehyde dehydrogenase (BADH2) results in the synthesis of 2-acetyl-1-pyrroline (2AP), which is a major fragrance compound. Here, transcription activator-like effector nucleases (TALENs) were engineered to target and disrupt the OsBADH2 gene. Six heterozygous mutants (30%) were recovered from 20 transgenic hygromycin-resistant lines. Sanger sequencing confirmed that these lines had various indel mutations at the TALEN target site. All six transmitted the BADH2 mutations to the T1 generation; and four T1 mutant lines tested also efficiently transmitted the mutations to the T2 generation. Mutant plants carrying only the desired DNA sequence change but not the TALEN transgene were obtained by segregation in the T1 and T2 generations. The 2AP content of rice grains of the T1 lines with homozygous mutations increased from 0 to 0.35-0.75 mg/kg, which was similar to the content of a positive control variety harbouring the badh2-E7 mutation. We also simultaneously introduced three different pairs of TALENs targeting three separate rice genes into rice cells by bombardment and obtained lines with mutations in one, two and all three genes. These results indicate that targeted mutagenesis using TALENs is a useful approach to creating important agronomic traits.


Involvement of PARK2-Mediated Mitophagy in Idiopathic Pulmonary Fibrosis Pathogenesis.
Fibroblastic foci, known to be the leading edge of fibrosis development in idiopathic pulmonary fibrosis (IPF), are composed of fibrogenic myofibroblasts. Autophagy has been implicated in the regulation of myofibroblast differentiation. Insufficient mitophagy, the mitochondria-selective autophagy, results in increased reactive oxygen species, which may modulate cell signaling pathways for myofibroblast differentiation. Therefore, we sought to investigate the regulatory role of mitophagy in myofibroblast differentiation as a part of IPF pathogenesis. Lung fibroblasts were used in in vitro experiments. Immunohistochemical evaluation in IPF lung tissues was performed. PARK2 was examined as a target molecule for mitophagy regulation, and a PARK2 knockout mouse was employed in a bleomycin-induced lung fibrosis model. We demonstrated that PARK2 knockdown-mediated mitophagy inhibition was involved in the mechanism for activation of the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT signaling pathway accompanied by enhanced myofibroblast differentiation and proliferation, which were clearly inhibited by treatment with both antioxidants and AG1296, a PDGFR inhibitor. Mitophagy inhibition-mediated activation of PDGFR signaling was responsible for further autophagy suppression, suggesting the existence of a self-amplifying loop of mitophagy inhibition and PDGFR activation. IPF lung demonstrated reduced PARK2 with concomitantly increased PDGFR phosphorylation. Furthermore, bleomycin-induced lung fibrosis was enhanced in PARK2 knockout mice and subsequently inhibited by AG1296. These findings suggest that insufficient mitophagy-mediated PDGFR/PI3K/AKT activation, which is mainly attributed to reduced PARK2 expression, is a potent underlying mechanism for myofibroblast differentiation and proliferation in fibroblastic foci formation during IPF pathogenesis.


Fall prediction index for patients in stroke rehabilitation.
The identification of stroke patients who are prone to falls is essential to the development of prevention strategies. This study aimed at developing an easily administered fall risk index for patients in stroke rehabilitation. A consecutive series of 135 patients in geriatric stroke rehabilitation was studied. Patient characteristics viewed as potential fall predictor variables were assessed at admission. Univariate and multiple Cox regression analyses of these variables were used in the development of a fall prediction index. The final index included the following items: male sex, poor performance of activities of daily living, urinary incontinence, impaired postural stability, bilateral motor impairment, presence of bilateral cortical or white matter lesions, visuospatial hemineglect, and use of diuretics, antidepressants, or sedatives. The index score correlated significantly with the fall risk (odds ratio, 1.46; 95% confidence interval, 1.26 to 1.69). The score was also used to classify individuals into low-, intermediate-, and high-risk groups, among which the fall rates differed significantly (log rank statistics, 29.86; P < .001). An easily administered fall risk index is suggested, which might serve as a basis for prevention strategies among patients in stroke rehabilitation.


[The adiponectin to leptin ratio, a still unrecognized biomarker of insulin resistance and cardiometabolic risk].
Leptin and adiponectin are two adipokines. Their circulating concentrations, high for leptin and low for adiponectin, are predictive of insulin resistance and of an unfavorable cardiometabolic evolution in patients with obesity, metabolic syndrome or type 2 diabetes. In addition, recently, the adiponectin/leptin ratio has been proposed as an index of adipose tissue dysfunction together with threshold values for cardiometabolic risk for this index. The relevance and potential applications of the adiponectin/leptin and leptin/adiponectin ratios are discussed in the light of recent literature in this brief update.


Size-Exclusion Chromatography for the Analysis of Protein Biotherapeutics and their Aggregates.
In recent years, the use and number of biotherapeutics has increased significantly. For these largely protein-based therapies, the quantitation of aggregates is of particular concern given their potential effect on efficacy and immunogenicity. This need has renewed interest in size-exclusion chromatography (SEC). In the following review we will outline the history and background of SEC for the analysis of proteins. We will also discuss the instrumentation for these analyses, including the use of different types of detectors. Method development for protein analysis by SEC will also be outlined, including the effect of mobile phase and column parameters (column length, pore size). We will also review some of the applications of this mode of separation that are of particular importance to protein biopharmaceutical development and highlight some considerations in their implementation.


Eosin: a versatile organic dye whose synthetic uses keep expanding.
Organic dyes, which absorb light in the visible region of the electromagnetic spectrum, offer a lower cost, greener alternative to precious metals in photocatalysis. In this context, the organic dye eosin's uses are currently expanding at a significant rate. For a long time, its action as an energy transfer agent dominated, more recently, however, there has been a growing interest in its potential as an electron transfer agent. In this short review, we highlight some recent (from 2016 onwards) contributions to the field with a focus on the breadth of the reactions eosin can catalyse.


Evaluation of fatigue scales in stroke patients.
There is little information on how to best measure poststroke fatigue. Our aim was to identify which currently available fatigue scale is most valid, feasible, and reliable in stroke patients. Fatigue scales were identified by systematic search, and the 5 with the best face validity were identified by expert consensus. Feasibility (ie, did patients provide answers?) and internal consistency (an aspect of reliability) of these scales were evaluated by interviewing 55 stroke patients. Test-retest reliability was assessed by reinterviewing 51 patients, interrater reliability was assessed by rerating audio recordings, and convergent validity was assessed by measuring the correlation between scale scores. Of the 52 scales identified, the SF-36v2 (vitality component), the fatigue subscale of the Profile of Mood States, the Fatigue Assessment Scale, the general subscale of the Multidimensional Fatigue Symptom Inventory, and the Brief Fatigue Inventory had the best face validity. The Brief Fatigue Inventory was unfeasible to administer and was omitted. Of the remaining 4 scales, the Fatigue Assessment Scale had the poorest internal consistency. Test-retest reliability for individual scale questions ranged from fair to good; the Fatigue Assessment Scale had the narrowest limits of agreement for the total score, indicating the best test-retest reliability. Interrater reliability for individual questions ranged from good to very good, and there was no significant mean difference in total scores for any scale. Convergent validity was moderate to high for the total scores of the 4 scales. All four scales were valid and feasible to administer to stroke patients. The Fatigue Assessment Scale had the best test-retest reliability but the poorest internal consistency.


[An improvement in information support in the interests of the epidemiological health welfare of the troops].
The information acquisition, decision-making and control system must be the basic tool for optimizing the information procedures in the interests of sanitary-epidemiological welfare of troops. It's necessary to make a thorough revision of the existing account and record documentation in order to study its value. Each pattern of record cards must be scientifically substantiated depending on its effectiveness for further decision making. It's necessary to exclude all futile information. Record and account procedures must be automated and computerized throughout all chains of command beginning from a single military unit. Special systems must be developed for this matter. Realization of these goals will completely assure the monitoring of health status indices of servicemen and the environmental situation, as well as monitoring of risk factors influence upon the health of personnel.


[Clinical features of paroxysmal nocturnal hemoglobinuria (PNH) in China as compared with those in United Kingdom].
The clinical features of 26 patients of PNH in Sheffield Blood Centre, UK and 50 cases in our hospital, observed in the same period, were compared. Each case was analysed according to the same criteria, and then comparison was made between the two groups. Results showed that in our group: male patients were more common; patients usually had mild or moderate bleeding tendency; the appearance of hemoglobinuria was delayed; abdominal pain was mostly related to hemoglobinuria but not thrombosis; pancytopenia was encountered more frequently and leucopenia as well as thrombocytopenia more remarkable; the incidence of thrombosis was not rare, but occurred rather late: thrombosis was mainly seen in superficial veins, but not veins of viscera; the major cause of death was not thromboembolism but infection. About 25% of the patients achieved long term clinical remission in both groups. None of the patients in these two series transformed to myeloproliferative disorders including acute leukemia. PNH can be considered a benign and chronic hematologic disease.


Safety and efficacy of long-term disulfiram aftercare.
Disulfiram is effective in relapse prevention in alcoholism. However, the optimal therapeutic aftercare regimen for patients is still unclear, and disulfiram is associated with numerous adverse events. Also, it is not clear if supervised long-term disulfiram treatment is safe and sufficiently efficient in the long run. We evaluated the clinical outcome data of 10 alcohol-dependent patients who underwent supervised treatment with disulfiram for more than 50 weeks. Seven of 10 patients remained completely abstinent during the supervised disulfiram therapy for a mean (SD) period of 70.1 ± 23.5 months. For the 3 patients with relapse, the first relapse occurred after a mean (SD) of 34.7 ± 15.5 months. Liver enzymes in the blood decreased markedly under treatment with disulfiram. The overall tolerability was considered to be high; only dizziness and fatigue were observed in 4 patients in the initial phase of the therapy. No serious adverse events were recorded. Although case observations should be interpreted with caution, the present results suggest that disulfiram is safe and efficient in supervised long-term treatment of alcohol-dependent patients.


Evaluation of Diaphragmatic Function after Interscalene Block with Liposomal Bupivacaine: A Randomized Controlled Trial.
Interscalene blocks provide analgesia for shoulder surgery but also cause phrenic nerve paralysis. Liposomal bupivacaine is approved for use in interscalene blocks with the potential to provide longer pain control. However, the impact of liposomal bupivacaine on the phrenic nerve has not been evaluated. It was hypothesized that patients who received an interscalene block with both bupivacaine and liposomal bupivacaine would have a decreased diaphragmatic excursion when compared to bupivacaine alone at 24 h. This was a double-blinded study of adult patients who were randomized to receive an interscalene block with either 20 ml 0.5% bupivacaine (bupivacaine group) or 10 ml 0.5% bupivacaine plus 10 ml liposomal bupivacaine (liposomal bupivacaine group). Twenty-six patients were randomized with 22 included in the analysis. Diaphragmatic excursion (via ultrasound) and spirometry were assessed before the block, in the postanesthesia care unit, and at 24 h postblock. The primary outcome was diaphragm excursion with sigh. No adverse events were observed. At 24 h, the liposomal bupivacaine group median [25th, 75th], had a greater percent change in diaphragmatic excursion during sigh breath compared to the bupivacaine group, -24% [-30, -9] versus 9% [-8, 26], difference in location, 32 (95% CI, 12 to 52), P = 0.007. Five patients in the liposomal bupivacaine group had a greater than 25% reduction in diaphragmatic excursion at 24 h versus zero in the bupivacaine group. They also had a significantly greater percent reduction in forced expiratory volume in 1 s and forced vital capacity compared with the bupivacaine group at 24 h (median decrease of 22% vs. 2%, P = 0.006, and median decrease of 19% vs. 1%, P = 0.049, respectively). The addition of liposomal bupivacaine to bupivacaine in an interscalene block results in statistically significant reductions in diaphragm excursion and pulmonary function testing 24 h after block placement when compared to bupivacaine alone. This reduction, however, falls within the range of normal diaphragmatic function.


Large-Scale Analysis Reveals Gene Signature for Survival Prediction in Primary Glioblastoma.
Glioblastoma multiforme (GBM) is the most aggressive and common primary central nervous system tumour. Despite extensive therapy, GBM patients usually have poor prognosis with a median survival of 12-15 months. Novel molecular biomarkers that can improve survival prediction and help with treatment strategies are still urgently required. Here we aimed to robustly identify a gene signature panel for improved survival prediction in primary GBM patients. We identified 2166 differentially expressed genes (DEGs) using meta-analysis of microarray datasets comprising of 955 samples (biggest primary GBM cohort for such studies as per our knowledge) and 3368 DEGs from RNA-seq dataset with 165 samples. Based on the 1443 common DEGs, using univariate Cox and least absolute shrinkage and selection operator (LASSO) with multivariate Cox regression, we identified a survival associated 4-gene signature panel including IGFBP2, PTPRN, STEAP2 and SLC39A10 and thereafter established a risk score model that performed well in survival prediction. High-risk group patients had significantly poorer survival as compared with those in the low-risk group (AUC = 0.766 for 1-year prediction). Multivariate analysis demonstrated that predictive value of the 4-gene signature panel was independent of other clinical and pathological features and hence is a potential prognostic biomarker. More importantly, we validated this signature in three independent GBM cohorts to test its generality. In conclusion, our integrated analysis using meta-analysis approach maximizes the use of the available gene expression data and robustly identified a 4-gene panel for predicting survival in primary GBM.


Heparin-induced thrombocytopenia in a hemodialysis patient treated with fondaparinux: nephrologists between two fires.
Heparin-induced thrombocytopenia (HIT) is caused by heparin exposure and presents with reduced platelet count. Patients undergoing hemodialysis (HD) treatment have increased risk of developing HIT due to prolonged exposure to unfractionated heparin or low-molecular weight heparin. We report a 79-year-old male patient with end-stage renal disease who developed type-II HIT during maintenance HD. Platelet count of the patient decreased gradually and antiplatelet factor IV antibody was found to be positive. The patient was treated with fondaparinux and continued heparin-free HD. Unfortunately, despite favorable initial response without any thrombotic episodes, the patient died due to severe sepsis complicated by gastrointestinal hemorrhage.


Obesity Modulates the Gut Microbiome in Triple-Negative Breast Cancer.
Triple-negative breast cancer (TNBC) is an aggressive, molecularly heterogeneous subtype of breast cancer. Obesity is associated with increased incidence and worse prognosis in TNBC through various potential mechanisms. Recent evidence suggests that the gut microbiome plays a central role in the progression of cancer, and that imbalances or dysbiosis in the population of commensal microbiota can lead to inflammation and contribute to tumor progression. Obesity is characterized by low-grade inflammation, and gut dysbiosis is associated with obesity, chronic inflammation, and failure of cancer immunotherapy. However, the debate on what constitutes a "healthy" gut microbiome is ongoing, and the connection among the gut microbiome, obesity, and TNBC has not yet been addressed. This study aims to characterize the role of obesity in modulating the gut microbiome in a syngeneic mouse model of TNBC. 16S rRNA sequencing and metagenomic analyses were performed to analyze and annotate genus and taxonomic profiles. Our results suggest that obesity decreases alpha diversity in the gut microbiome. Metagenomic analysis revealed that obesity was the only significant factor explaining the similarity of the bacterial communities according to their taxonomic profiles. In contrast to the analysis of taxonomic profiles, the analysis of variation of functional profiles suggested that obesity status, tumor presence, and the obesity-tumor interaction were significant in explaining the variation of profiles, with obesity having the strongest correlation. The presence of tumor modified the profiles to a greater extent in obese than in lean animals. Further research is warranted to understand the impact of the gut microbiome on TNBC progression and immunotherapy.


Interstitial ions: A key regulator of state-dependent neural activity?
Throughout the nervous system, ion gradients drive fundamental processes. Yet, the roles of interstitial ions in brain functioning is largely forgotten. Emerging literature is now revitalizing this area of neuroscience by showing that interstitial cations (K+, Ca2+ and Mg2+) are not static quantities but change dynamically across states such as sleep and locomotion. In turn, these state-dependent changes are capable of sculpting neuronal activity; for example, changing the local interstitial ion composition in the cortex is sufficient for modulating the prevalence of slow-frequency neuronal oscillations, or potentiating the gain of visually evoked responses. Disturbances in interstitial ionic homeostasis may also play a central role in the pathogenesis of central nervous system diseases. For example, impairments in K+ buffering occur in a number of neurodegenerative diseases, and abnormalities in neuronal activity in disease models disappear when interstitial K+ is normalized. Here we provide an overview of the roles of interstitial ions in physiology and pathology. We propose the brain uses interstitial ion signaling as a global mechanism to coordinate its complex activity patterns, and ion homeostasis failure contributes to central nervous system diseases affecting cognitive functions and behavior.


Serum her-2/neu and survivin levels and their relationship to histological parameters in early-stage breast cancer.
This study was conducted to investigate the serum levels of her-2/neu and survivin in patients with early-stage breast cancer and their relationship with known histological parameters. Forty-one patients with early-stage breast cancer were investigated. Serum samples were collected from patients on their first admission before adjuvant chemotherapy, and from healthy controls. Serum her-2/neu and survivin levels were determined using an enzyme-linked immunosorbent assay. There was no difference in the levels of serum her-2/neu and survivin between the breast cancer patients and the control group. Serum her-2/neu concentration showed moderate correlations with disease stage and the Ki-67 level, and the serum survivin level showed a moderate correlation with progesterone receptor concentration. Serum levels of her-2/neu and survivin were not significantly related to age and histological parameters in patients with early-stage breast cancer. However, much research continues on the prognostic value of serum her-2/neu and survivin levels, and important new knowledge may ultimately emerge.


SAW Humidity Sensor Sensitivity Enhancement via Electrospraying of Silver Nanowires.
In this research, we investigated the influence of the surface coatings of silver nanowires on the sensitivity of surface acoustic wave (SAW) humidity sensors. Silver nanowires, with poly(vinylpyrrolidone) (PVP), which is a hydrophilic capping agent, were chemically synthesized, with an average length of 15 µm and an average diameter of 60 nm. Humidity sensors, with 433 MHz frequency dual-port resonator Rayleigh-SAW devices, were coated by silver nanowires (AgNWs) using the electrospray coating method. It was demonstrated that increasing thickness of coated AgNW on the surfaces of SAW devices results in increased sensitivity. The highest frequency shift (262 kHz) in these SAW devices was obtained with an injection of 0.5 mL of the AgNW solution with a concentration of 0.5 mg/mL at an injection rate of 1 mL/h. It also showed the highest humidity sensitivity among the other prepared SAW devices.