Facilitating resident community in nursing homes: a slippery slope? An analysis on collectivistic and individualistic approaches.
Residents in nursing homes are old and frail and are dependent on constant care, medical, or otherwise, by trained professionals. But they are also social beings, secluded in an institutional setting which is both total and foreign. In this setting, most of the residents most of the time must relate to other residents: other residents are the nursing home residents' peers, companions, and perhaps even significant others. In this article, we will discuss how resident communities in nursing homes are influenced by the approaches of nursing home staff. Two nursing homes have been included in this article-one from Canada and one from Norway. Participant observation was conducted at these two nursing homes, predominantly focusing on everyday-life activities. The cases from Norway and Canada are illustrative of two very different general approaches to residents: one collectivistic and one individualistic. These general approaches produce different contexts for the formation and content of resident communities, greatly affecting nursing home residents. The significance of these approaches to resident community is profound and also somewhat unanticipated; the approaches of staff provide residents with different opportunities and limitations and also yield unintended consequences for the social life of residents. The two different general approaches are, we suggest, "cultural expressions," conditioned by more than official preferences and recommendations. The difference between the institutions is, in other words, anchored in ideas and ideologies that are not explicitly addressed.


Speed of Sound Measurements in Dense Siloxane D6 Vapor at Temperatures up to 645 K by Means of a New Prismatic Acoustic Resonator.
Estimating the speed of sound for the dense vapor phase of D6 (dodecamethylcyclohexasiloxane, C12H36O6Si6) is particularly relevant to the study of nonideal compressible fluid dynamics (NICFD), the gas dynamics of fluids whose properties depart significantly from those related by the ideal gas model. If molecular complexity is sufficiently large, dense vapor flows may exhibit so-called nonclassical gasdynamic effects, and D6 is a candidate for experimental studies aimed at proving for the first time the existence of these exotic phenomena. More in general, speed of sound measurements in the dense vapor phase are important for NICFD applications: for example, complex organic compounds are employed as working fluids in organic Rankine cycle power plants and the correct prediction of the dense-vapor speed of sound is of paramount importance for the design of the supersonic turbines equipping these systems. This type of measurements is challenging and thus rare, especially in the case of complex organic molecules, given the high temperature at which they must be performed, close to the temperature at which the molecule thermally decomposes. Therefore, a new prismatic resonator (the OVAR, organic vapor acoustic resonator) has been conceived, designed, and realized. It is suitable for speed of sound measurements in the vapor phase of organic compounds at temperatures up to approximately 670 K and pressures up to about 1.5 MPa. The speed of sound of D6 (97.4% pure) has been measured along eight isotherms between 555 and 645 K and from nearly saturated density to densities close to ideal gas conditions (compressibility factor Z ≈ 0.95). The estimated relative uncertainty of these sound speed measurements is 0.14%. In addition, corresponding density values have been obtained with an estimated uncertainty between 0.2 kg·m-3 and 1.2 kg·m-3.


Safety and Long-term Outcomes of Congenital Ptosis Surgery: A Population-Based Study.
To report the long-term outcomes of childhood ptosis surgery in a population-based setting over a 46-year period. In this population-based cohort study, the medical records of all patients who were residents of Olmsted County, Minnesota, diagnosed as having blepharoptosis and having undergone surgical management prior to 19 years of age (between January 1, 1965, and December 31, 2010), were retrospectively reviewed. Age at time of surgery, type of surgery, duration of follow-up, number and nature of revisions, degree of amblyopia, and postoperative lagophthalmos and dry eye were documented. Forty-seven children meeting inclusion criteria underwent ptosis surgery. The median age at time of first surgery was 5.6 years (range: 1.5 to 17.7 years). Fifteen of 47 (31.9%) patients required a second procedure. Three of 47 (6.4%) patients underwent three procedures. The median time was 1.1 years (range: 0.03 to 7.8 years) between the first and second surgery and 6.0 years (range: 0.3 to 6.1 years) between the second and third procedure. Seven of 47 (14.9%) patients had amblyopia. Nineteen of 47 (40.4%) patients were noted to have lagophthalmos and 3 of 47 (6.4%) presented for symptomatic dry eye postoperatively. In this population-based setting, more than half of the children with ptosis required only a single surgical procedure, although a significant proportion required two procedures. Postoperative lagophthalmos is common, but symptomatic dry eye is rare. [J Pediatr Ophthalmol Strabismus. 2016;53(4):212-217.].


Contribution to the development of the heart, Part II: Morphogenesis of congenital heart diseases.
A concept for the explanation of the formal genesis of congenital cardiac malformations is introduced, based on the observation that 1. the septa in the outflow-tract of the heart are formed in spatial relation to changes in form of the external cardiac wall and always along the longer sides of the ovally deformed pathway of flow, 2. the muscular septa (ventricular and atrial septa) arise as protrusions due to different directions of ventricular growth. Accordingly, no septa develop when normal deformation fails to occur (e.g. truncus communis); septa are incompletely developed when the deformation is insufficient (e.g. aortico-pulmonary window); septa are formed in wrong positions where the direction of deformation deviates more or less from the normal direction (as in stenosis due to slight deviation, or transposition due to large deviation from the normal). The so-called ventricular inversions and atrio-ventricular discordance are regarded as consequences of dystopic development of the ventricular septum. This concept for the explanation of the formal genesis of cardiac malformations is exemplified by variants of transpositions (anatomically corrected and uncorrected), and by variants of double-outlet-right-ventricle and double-outlet-left-ventricle. Using a common anomaly (tetralogy of Fallot) and 2 rare ones (double-outlet-right-ventricle with complete AV canal, and criss-cross-heart) it is shown that the interpretation of the development of cardiac malformations as a consequence of dystopic development of the septa allows an understanding of the formal genesis of complex malformations without involving hitherto unproven developmental processes.


Significance of aberrant glial cell phenotypes in pathophysiology of amyotrophic lateral sclerosis.
Amyotrophic Lateral Sclerosis (ALS) is a paradigmatic neurodegenerative disease, characterized by progressive paralysis of skeletal muscles associated with motor neuron degeneration. It is well-established that glial cells play a key role in ALS pathogenesis. In transgenic rodent models for familial ALS reactive astrocytes, microglia and oligodendrocyte precursors accumulate in the degenerating spinal cord and appear to contribute to primary motor neuron death through a non-cell autonomous pathogenic mechanism. Furthermore in rats expressing the ALS-linked SOD1G93A mutation, rapid spread of paralysis coincides with emergence of neurotoxic and proliferating aberrant glia cells with an astrocyte-like phenotype (AbA cells) that are found surrounding damaged motor neurons. AbAs simultaneously express astrocytic markers GFAP, S100β and Connexin-43 along with microglial markers Iba-1, CD11b and CD163. Studies with cell cultures have shown that AbAs originate from inflammatory microglial cells that undergo phenotypic transition. Because AbAs appear only after paralysis onset and exponentially increase in parallel with disease progression, they appear to actively contribute to ALS progression. While several reviews have been published on the pathogenic role of glial cells in ALS, this review focuses on emergence and pro-inflammatory activity of AbAs as part of an increasingly complex neurodegenerative microenvironment during ALS disease development.


Inspiratory and expiratory lung pressure-volume curve in healthy males and females.
Quasistatic lung inspiratory and expiratory pressure-volume curves were obtained in 58 healthy nonsmoking males (mean age +/- SD: 42.8 +/- 15.1 years; range 22.70) and 56 healthy nonsmoking females (mean age +/- SD: 41.4 +/- 15.6 years; range: 21-76). Inspiratory and expiratory lung recoil pressures were measured at fixed percentages of TLC (100, 95, 90, 80, 70, 60 and 50%). In both sexes, inspiratory as well as expiratory lung recoil pressures were found to decrease linearly with aging (p less than 0.01 for all r values). There was no significant difference between males and females. At and above the 70% TLC level, the slopes of the age-related decreases in lung recoil were similar for the inspiratory and expiratory curves. At the 60% TLC level, the decrease in expiratory lung recoil was significantly (p less than 0.01) faster than the decrease in inspiratory lung recoil, presumably reflecting the influence of airway opening on the inspiratory pressure in older subjects. The shape of the expiratory PV curve described by the K index of the exponential model was similar in both sexes and changed with aging, K increasing significantly (p less than 0.01). By contrast, the shape of the inspiratory limb of the PV curve did not vary with aging. Consequently, the shape of the inspiratory PV curve cannot be predicted from the expiratory one and has to be measured directly.


Mode selection in square resonator microlasers for widely tunable single mode lasing.
Mode selection in square resonator semiconductor microlasers is demonstrated by adjusting the width of the output waveguide coupled to the midpoint of one side. The simulation and experimental results reveal that widely tunable single mode lasing can be realized in square resonator microlasers. Through adjusting the width of the output waveguide, the mode interval of the high-Q modes can reach four times of the longitudinal mode interval. Therefore, mode hopping can be efficiently avoided and the lasing wavelength can be tuned continuously by tuning the injection current. For a 17.8-μm-side-length square microlaser with a 1.4-μm-width output waveguide, mode-hopping-free single-mode operation is achieved with a continuous tuning range of 9.2 nm. As a result, the control of the lasing mode is realized for the square microlasers.


Predictors of psychological well-being of nurses in Alexandria, Egypt.
As nursing has been previously identified as a stressful occupation, sources of job stress and levels of job satisfaction were extensively investigated. However, studies addressing issues of nurses' mental health are scarce. This work aims to assess psychological well-being of nurses in different job settings in Alexandria and to identify sociodemographic, psychosocial and workplace predictors. A total sample of 412 nurses represented nurses working in five different health organizations in Alexandria. A self-administered questionnaire was used to collect sociodemographic, occupational and health data, and the Standardized Arabic Version of General Health questionnaire (GHQ-30 items), Job Descriptive Index (JDI), and Social Support Scale (SSS) were also used. Results revealed that 21.67% of nurses recorded moderate to severe psychological symptoms on GHQ. Fewer years of experience, negative family and friend support, and negative total work satisfaction were found to be significant predictors of psychological ill health among nurses in a descending rank order. Implications for nursing intervention will be discussed.


Chirped laser dispersion spectroscopy for remote open-path trace-gas sensing.
In this paper we present a prototype instrument for remote open-path detection of nitrous oxide. The sensor is based on a 4.53 μm quantum cascade laser and uses the chirped laser dispersion spectroscopy (CLaDS) technique for molecular concentration measurements. To the best of our knowledge this is the first demonstration of open-path laser-based trace-gas detection using a molecular dispersion measurement. The prototype sensor achieves a detection limit down to the single-ppbv level and exhibits excellent stability and robustness. The instrument characterization, field deployment performance, and the advantages of applying dispersion sensing to sensitive trace-gas detection in a remote open-path configuration are presented.


Death and survival from executioner caspase activation.
Executioner caspases are evolutionarily conserved regulators of cell death under apoptotic stress. Activated executioner caspases drive apoptotic cell death through cleavage of diverse protein substrates or pyroptotic cell death in the presence of gasdermin E. On the other hand, activation of executioner caspases can also trigger pro-survival and pro-proliferation signals. In recent years, a growing body of studies have demonstrated that cells can survive from executioner caspase activation in response to stress and that the survivors undergo molecular and phenotypic alterations. This review focuses on death and survival from executioner caspase activation, summarizing the role of executioner caspases in apoptotic and pyroptotic cell death and discussing the potential mechanism and consequences of survival from stress-induced executioner caspase activation.


Rehabilitation with Esthetic Functional Fixed Space Maintainer: A Report of Two Cases.
Early loss of anterior primary teeth occurs mainly due to dental caries and trauma and may cause functional changes and negatively impact children's quality of life and social interaction. This article reports two cases in which pediatric patients with different dental losses were rehabilitated with esthetic functional fixed space maintainers with tube-bar system. In the first case, a 3-year-old boy with a missing upper central incisor due to dental trauma was rehabilitated with an esthetic functional fixed space maintainer with tube-bar system. In the second case, a 5-year-old boy lost three upper incisors, also due to dental trauma. He was likewise rehabilitated with an esthetic functional fixed space maintainer with tube-bar system. The rehabilitation of early losses of anterior primary teeth by fixed esthetic functional space maintainers with tube-bar system proved to be a favorable treatment option regardless of the age of the patient or the number of missing teeth. Early loss of anterior primary teeth may have a major impact on the pediatric patient and is still a challenge in clinical practice. This article presents an effective and inexpensive alternative to this clinical situation. Volpato LER, Crivelli ASB, Oliveira ETRT, et al. Rehabilitation with Esthetic Functional Fixed Space Maintainer: A Report of Two Cases. Int J Clin Pediatr Dent 2021;14(2):315-318.


Generic immunosuppressants.
Immunosuppressive drugs for solid organ transplantation are critical dose drugs with a narrow therapeutic index. Many of the most commonly used innovator drugs are off patent and have been replicated by generic counterparts, often at substantial cost-savings to the patient. However, serious adverse events caused by the transition from innovator to generic medications, specifically in pediatric solid organ transplant recipients, have questioned these autosubstitutions. The purpose of this review is to summarize the criteria set forth by the regulatory bodies, and to examine how major immunosuppressive drugs conform to these recommendations. Regulatory bodies have established inconsistent criteria to demonstrate bioequivalence between innovator and generic medications, causing approved generic variations to have varying levels of equivalence with the innovator drugs. In order to minimize the risk for under-immunosuppression, the following recommendations have been concluded. Brand prescribing of cyclosporine and tacrolimus are recommended due to evidence of adverse events after conversion to generic formulations and differences in dissolution parameters. Mycophenolate mofetil (MMF) shows better bioequivalence between innovator and generic formulations, however caution should be advised when switching between formulations. The institution of 'innovator only' policies may be appropriate at this time in order to minimize the risk of under-immunosuppressing patients until the evidence of more stringent bioequivalence has been established.


Epidemiology of Cardiorenal Syndrome.
Cardiorenal syndrome is a spectrum of disorders that emphasizes the bidirectional nature of cardiac and kidney injury. Observational and retrospective studies have helped us to understand the prevalence and burden of each of the 5 types of cardiorenal syndromes. Cardiorenal syndrome type 1 is the most common. The nature of epidemiologic data limits clear delineation between cardiorenal syndrome types 2 and 4. Overall, the presence of cardiac or renal dysfunction strongly predicts a poor outcome of the contrary organ.


Interferon inhibits the conversion of 3T3-L1 mouse fibroblasts into adipocytes.
Confluent Swiss mouse 3T3-L1 fibroblasts slowly differentiate functionally and morphologically into adipocytes, a conversion hastened by insulin. The cells are sensitive (although less than L929 cells) to the antiviral action of mouse fibroblast interferons but not to interferons from heterologous species (human and chicken). Cultures stimulated with insulin in the presence of partially purified or electrophoretically pure mouse interferons have a much lower percentage of cells accumulating lipid than do insulin-treated control cultures. Interferon-treated cell cultures also contain much less triglyceride, cholesterol, and cholesterol esters than do replicate control cultures stimulated by insulin to differentiate. Increased de novo lipid biosynthesis that occurs during differentiation is inhibited, as determined by incorporation of [14C]acetate into lipids extractable by the Folch method. This incorporation is a sensitive bioassay of the antidifferentiation effect of interferon; less than 1 antiviral unit is inhibitory. Variously inactivated or mock interferon preparations as well as interferons from several heterologous species fail to inhibit 3T3-L1 adipocyte conversion. Interferon is inhibitory even when applied as long as 3 days after insulin stimulation. The effect of interferon does not appear to depend upon its competition with insulin for cell surface receptors. Because interferon can alter the program of events involved in conversion of 3T3-L1 fibroblasts into adipose cells, it may be able to affect the regulation of eukaryotic cell differentiation.


[The Prevalence of Nontuberculous Mycobacterial Lung Disease with orwithout Reflux Esophagitis].
Gastrointestinal reflux disease (GERD) is defined as 'a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications'. It is associated with various lung diseases, including bronchial asthma, chronic bronchitis, and bronchiectasis. GERD may also affect nontuberculous mycobacterial (NTM) lung disease. We presumed that the normal mucosal barrier of the bronchial epithelium is broken due to the aspiration of gastric juice and consequent chronic bronchial inflammation. This study investigated the prevalence of GERD in accordance with the presence or absence of NTM lung disease and analyzed the difference. We screened patients with NTM lung disease in this hospital between January 2011 and December 2015. Among these patients, gastroscopic examinations as a health check-up were performed on 93 patients. We obtained the prevalence of Reflux esophagitis (RE) in patients with NTM and compared it with the prevalence of RE in the normal control subjects. Among 93 patients with NTM, patients without RE was 66.7% (62/93). RE-minimal change was diagnosed in 29.0% (27/93), and RE LA-A was diagnosed in 4.3% (4/93). Comparing the prevalence of RE minimal change, 29.0% (27/93) had NTM and 11.9% (3043/25536) did not have NTM. This was statistically significant. We showed a greater prevalence of RE minimal change in patients with NTM than those without NTM with statistical significance.


Detection and enumeration of Cryptosporidium sp. oocysts in sewage sludge samples from the city of Florianópolis (Brazil) by using immunomagnetic separation combined with indirect immunofluorescence assay.
In the last few decades, agricultural reclamation of sewage sludge has increased in many countries. However, this practice must be adopted under recommended conditions to limit the risks associated with the presence of potential pathogens, including protozoan parasites such as Cryptosporidium. In the present work, we evaluated immunomagnetic separation (IMS) combined with an indirect immunofluorescence assay (IFA) in order to detect Cryptosporidium oocysts in sewage sludge samples obtained from the Municipal Wastewater Treatment Plant (MWTP) operating in the city of Florianópolis, State of Santa Catarina, Brazil. Integrated application of spontaneous sludge sedimentation and centrifugation of the supernatant, purification and concentration of oocysts through immunomagnetic separation as well as detection and quantification by means of indirect immunofluorescence using highly specific monoclonal antibodies, proved to be an effective multiple-analysis tool for monitoring the presence of Cryptosporidium oocysts in urban sewage sludge samples. Among 27 samples collected from MWTP, 20 (74.07%) were positive for Cryptosporidium sp. The efficiency of recovery by using the internal control ColorSeed (Biotechnology Frontiers Inc., Sydney, NSW, Australia) was medially 39.96 +/- 11.20%. Actually, oocysts were recovered from 100% of the positive samples tested and the number of Cryptosporidium oocysts found in the samples ranged from one to four. These results demonstrated a high recovery rate of Cryptosporidium oocysts in sewage sludge samples by using IMS-IFA analysis. In conclusion, such an approach can be applied to monitor the presence of the parasite and to determine the potential contamination of sludge destined for soil application.


The Role of Inhibitory Control Mechanisms in the Regulation of Sexual Behavior.
Sexual behavior is the open manifestation of a complex interplay between psychophysiological mechanisms that either facilitate or inhibit sexual thoughts, desires, and associated behaviors. Whereas sexual excitation has been widely studied, less is known about the impact of inhibitory control mechanisms that enable individuals to refrain from sexual cognition and behavior. The present study examined: (1) the relationship between general and sexual inhibitory mechanisms (as measured through self-reports and computer-based tasks), (2) the relation between sexual inhibitory processes at cognitive and motor-motivational levels and with sexual inhibition as an individual trait, and (3) the predictive value of these parameters on sexual thoughts (cognition) and behavior. We demonstrate that general inhibitory control (i.e., the ability to suppress any preponderant response) and the specific inhibition of sexual responses represent distinct processes that require at least partly different control mechanisms. Similarly, the ability to inhibit sexual visual input and the ability to suppress sexually driven responses seem to be two independent processes. The different inhibitory processes distinctively predicted the frequency of sexual thoughts and sexual behavior. We propose that these different inhibitory mechanisms are at play during different phases of sexual regulation (before and after the generation and unfolding of sexual arousal) and that a specific deficit in one of these processes may underlie the distinctive symptomatology and comorbidity of sexual disorders.


Surface Modification of Two-Dimensional Metal-Organic Layers Creates Biomimetic Catalytic Microenvironments for Selective Oxidation.
Microenvironments in enzymes play crucial roles in controlling the activities and selectivities of reaction centers. Herein we report the tuning of the catalytic microenvironments of metal-organic layers (MOLs), a two-dimensional version of metal-organic frameworks (MOFs) with thickness down to a monolayer, to control product selectivities. By modifying the secondary building units (SBUs) of MOLs with monocarboxylic acids, such as gluconic acid, we changed the hydrophobicity/hydrophilicity around the active sites and fine-tuned the selectivity in photocatalytic oxidation of tetrahydrofuran (THF) to exclusively afford butyrolactone (BTL), likely a result of prolonging the residence time of reaction intermediates in the hydrophilic microenvironment of catalytic centers. Our work highlights new opportunities in using functional MOLs as highly tunable and selective two-dimensional catalytic materials.


A role for LRIG1 in the regulation of malignant glioma aggressiveness.
The molecular mechanisms that drive the development and aggressive progression of malignant astrocytic tumors remain obscure. Recently, in the search for endogenous negative regulators of EGF receptor, LRIG1 was cloned and characterized as a putative tumor suppressor gene often downregulated in various human tumors, including astrocytic tumors. Although several studies have implicated the function of LRIG1 in the inhibition of tumorigenesis, its precise role and potential underlying mechanisms remain obscure. Therefore, we generated a full-length expression vector to overexpress LRIG1 in the U251 malignant glioma cell line. Introduction of exogenous LRIG1 into glioma cells inhibited cell proliferation manifested by MTT and soft agar clone assay in vitro and subcutaneously tumor xenografts. On the other hand, LRIG1 overexpression inhibited glioma growth by significantly changing the expression pattern of cyclins, resulting in delayed cell cycle. Employing transwell invasion and wound scratch assay and gelatin zymography, LRIG1 inhibited U-251 MG cell invasion and migration by attenuating MMP2 and MMP9 production. Under ligand-stimulated conditions, p-ERK levels did not change, whereas p-AKT levels were inhibited in cells with LRIG1 upregulation, indicating that LRIG1 exerts more inhibiting effects on the PI3K/AKT pathway. Our findings suggest that LRIG1 restricted glioma aggressiveness by inhibiting cell proliferation, migration and invasion. Restoration of LRIG1 to glioma cells could offer a novel therapeutic strategy.


Copper(I) Bromide: An Alternative Emitter for Blue-Colored Flame Pyrotechnics.
Copper(I) bromide was evaluated as an alternative emitter for blue flame pyrotechnic compositions. CuBr and CuCl emission spectra were recorded from a butane torch flame and compared. Cu(BrO3 )2 was synthesized and used in pyrotechnic compositions as an oxidizer and the source for the generation of CuBr species. Pyrotechnic compositions, which contained copper and potassium bromates as oxidizers, were optimized for the generation of blue flames. The experimental data, including emission spectra of the flames, chromaticity coordinates, burning rates, luminous intensities, and sensitivity tests, were analyzed and compared.


Communication and synchronization in, disconnected networks with dynamic topology: moving neighborhood networks.
We consider systems that are well modelled as networks that evolve in time, which we call Moving Neighborhood Networks. These models are relevant in studying cooperative behavior of swarms and other phenomena where emergent interactions arise from ad hoc networks. In a natural way, the time-averaged degree distribution gives rise to a scale-free network. Simulations show that although the network may have many noncommunicating components, the recent weighted time-averaged communication is sufficient to yield robust synchronization of chaotic oscillators. In particular, we contend that such time-varying networks are important to model in the situation where each agent carries a pathogen (such as a disease) in which the pathogen's lifecycle has a natural time-scale which competes with the time-scale of movement of the agents, and thus with the networks communication channels.


Terpinen-4-ol: A Novel and Promising Therapeutic Agent for Human Gastrointestinal Cancers.
Terpinen-4-ol, a naturally occurring monoterpene is the main bioactive component of tea-tree oil and has been shown to have many biological activities. To study the antitumor effects of terpinen-4-ol and its mechanism of action in prostate and GI malignancies, alone and in combination with chemotherapeutic and biological agents. Terpinen-4-ol was administrated alone or combined with standard chemotherapy (Oxaliplatin, Fluorouracil, Gemcitabine, Tarceva) and biological agent (Cetuximab). It was also combined with humanized anti-CD24 mAbs (was developed by us). Killing effects were measured qualitatively by light microscopy and quantitatively using the MTT and FACS analysis, following treatment of colorectal, pancreatic, gastric and prostate cancer cells. Terpinen-4-ol effect on tumor development was evaluated in xenograft model. Terpinen-4-ol induces a significant growth inhibition of colorectal, pancreatic, prostate and gastric cancer cells in a dose-dependent manner (10-90% in 0.005-0.1%). Terpinen-4-ol and various anti-cancer agents (0.2μM oxaliplatin and 0.5μM fluorouracil) demonstrated a synergistic inhibitory effect (83% and 91%, respectively) on cancer cell proliferation. In KRAS mutated colorectal cancer cells, which are resistant to anti-EGFR therapy, combining of terpinen-4-ol with cetuximab (1 μM) resulted in impressive efficacy of 80-90% growth inhibition. Sub-toxic concentrations of terpinen-4-ol potentiate anti-CD24 mAb (150μg/ml)-induced growth inhibition (90%). Considerable reduction in tumor volume was seen following terpinen-4-ol (0.2%) treatment alone and with cetuximab (10mg/kg) (40% and 63%, respectively) as compare to the control group. Terpinen-4-ol significantly enhances the effect of several chemotherapeutic and biological agents. The possible molecular mechanism for its activity involves induction of cell-death rendering this compound as a potential anti-cancer drug alone and in combination in the treatment of numerous malignancies. Terpinen-4-ol restores the activity of cetuximab in cancers with mutated KRAS.


Carcinogenicity and chronic toxicity in rats and mice exposed by inhalation to 1,2-dichloroethane for two years.
Carcinogenicity and chronic toxicity of 1,2-dichloroethane (DCE) were examined by inhalation exposure of groups of 50 F344 rats and 50 BDF1 mice of both sexes to DCE vapor or clean air as control for 6 h/d, 5 d/wk and 104 wk. The rats were exposed to 10, 40 or 160 ppm (v/v) DCE, while the mice were exposed to 10, 30 or 90 ppm. The 2-yr exposure to DCE produced a dose-dependent increase in incidences of benign and malignant tumors, including subcutaneous fibroma, mammary gland fibroadenoma and peritoneal mesothelioma in male rats; subcutaneous fibroma and mammary gland adenoma, fibroadenoma and adenocarcinoma in female rats; and bronchiolo-alveolar adenoma and carcinoma, endometrial stromal polyp, mammary gland adenocarcinoma and hepatocellular adenoma in female mice. No exposure-related change in the incidence of non-neoplastic lesions or in any hematological, blood biochemical or urinary parameter occurred in any DCE-exposed rat or mouse group. The types of tumors and their target organs found in this study were consistent with those observed in rats and mice administered DCE by gavage in a NCI study. Selection of the exposure concentrations was considered appropriate with reference to the maximum tolerated dose for the highest doses and an occupational exposure limit of DCE for the lowest dose. The present findings suggest that those carcinogenic responses be primarily considered for standard setting of occupational and environmental exposure to DCE.


Relating the outcome of HCV infection and different host SNP polymorphisms in a Majorcan population coinfected with HCV-HIV and treated with pegIFN-RBV.
Hepatitis C virus (HCV) is one of the major causes of chronic hepatitis, cirrhosis, and hepatocellular carcinoma, and the development of HCV-related disease is accelerated in individuals coinfected with human immunodeficiency-1 virus (HIV). In the present study, we correlated different host single-nucleotide polymorphisms (SNPs) in the IL28B, CTLA4, LDLr, and HFE genes and mitochondrial DNA (mtDNA) haplogroups with the outcome of HCV infection and the response to pegylated-interferon plus ribavirin (pegIFN-RBV) treatment. Our study population consisted of 63 Majorcan patients coinfected with HCV and HIV and 59 anonymous unrelated controls. Whereas the population frequency of IL28B alleles was similar to that found in a North-American cohort of European descent, the frequency of the rs12979860 C allele was lower than that determined in other cohorts from Spain. The frequencies of CTLA4 and LDLr polymorphisms were comparable to those reported in other populations. Significant differences between cases and control cohorts occurred only for the H63D mutation of the HFE gene. There were no other differences in the frequencies of other polymorphisms or mtDNA haplogroups. The IL28B rs12979860 CC genotype was shown to be associated with a rapid virological response, and the spontaneous viral clearance rate for HCV was higher in patients with the CTLA4+49 G allele. There was no relationship between SNPs in the LDLr and HFE genes and mtDNA haplogroups and the response to treatment. Our results suggest that the host genetic background plays a significant role in the pegIFN-RBV response of patients coinfected with HCV and HIV.


Patterns of Gesture Use in Adolescents With Autism Spectrum Disorder.
The purpose of this study was to examine patterns of spontaneous gesture use in a sample of adolescents with autism spectrum disorder (ASD). Thirty-five adolescents with ASD ages 11 to 16 years participated (mean age = 13.51 years; 29 boys, 6 girls). Participants' spontaneous speech and gestures produced during a narrative task were later coded from videotape. Parents were also asked to complete questionnaires to quantify adolescents' general communication ability and autism severity. No significant subgroup differences were apparent between adolescents who did not gesture versus those who produced at least 1 gesture in general communication ability and autism severity. Subanalyses including only adolescents who produced gesture indicated a statistically significant negative association between gesture rate and general communication ability, specifically speech and syntax subscale scores. Adolescents who gestured produced higher proportions of iconic gestures and used gesture mostly to add information to speech. The findings relate spontaneous gesture use to underlying strengths and weaknesses in adolescents' speech and syntactical language development. More research examining cospeech gesture in fluent speakers with ASD is needed.


New sesquiterpenes from Ligularia macrophylla.
From the roots of Ligularia macrophylla, a bisesquiterpene, ligumacrophyllal (1), and an eremophilane sesquiterpene, ligumacrophyllatin (2) were isolated. Their structures were elucidated by 2D-NMR herein. Additionally, seven known compounds (3-9) were afforded from the plant, and compound 3 was found as natural product for the first time.


Properties of the macula densa mechanism for renin release in the dog.
To study the macula densa mechanism for renin release, both the macula densa and the haemodynamic mechanisms were activated in anaesthetized dogs with denervated kidneys, either by renal arterial constriction to a renal arterial pressure (RAP) of 52 +/- 2 mmHg or by ureteral occlusion to a ureteral pressure of 95-105 mmHg, 20-25 mmHg below RAP. Renal arterial constriction increased renin release from 0.3 +/- 0.2 to 16 +/- 4 micrograms AI min-1. At low RAP, renin release was subsequently reduced to 7 +/- 3 micrograms AI min-1 when sodium excretion was raised far above control values by plasma volume expansion and acetazolamide infusion. Ethacrynic acid (3 mg kg-1 body wt.) restored renin release to pre-expansion values, and a large dose (25 mg kg-1 body wt.) prevented renin release from falling even after unclamping the artery. During ureteral occlusion with stopped glomerular filtration, plasma volume expansion, acetazolamide and ethacrynic acid infusion did not alter renin release. On the other hand, beta-adrenergic stimulation by isoproterenol raised renin release equally (by 30-40 micrograms AI min-1) before and after plasma volume expansion, during both renal arterial constriction and ureteral occlusion. Indomethacin (10 mg kg-1 body wt.) abolished renin release induced by ethacrynic acid infusion and ureteral occlusion. We conclude that the macula densa mechanism for renin release is inactivated by high NaCl reabsorption during plasma volume expansion and acetazolamide infusion, reactivated by inhibition of NaCl reabsorption with ethacrynic acid and completely inhibited by indomethacin. The degree of activation does not influence the renin release induced by beta-adrenergic stimulation.


Integrating MOUD and Primary Care: Outcomes of a Multicenter Learning Collaborative.
Opioid use and overdose remain a central and worsening public health emergency in the United States and abroad. Efforts to expand treatment have struggled to match the rising incidence of opioid use disorder (OUD), and treating patients in primary care settings represents one of the most promising opportunities to meet this need. Learning collaboratives (LCs) are one evidence-based strategy to improve implementation of medication treatment for opioid use disorder (MOUD) in primary care. We developed and studied a multidisciplinary MOUD learning collaborative involving six underserved primary care clinics. We used a mixed-methods approach to assess needs, develop curriculum, and evaluate outcomes from these clinics. We recruited six clinics to participate in the collaborative. Half had an established MOUD program. Approximately 80% of participants achieved their organizational quality improvement goals for the collaborative. After the collaborative, participants also reported a significant increase in their perceived competence to implement/improve a MOUD program (pre-LC competence=2.80, post-LC competence=6.33/10, P=.02). The most consistent barrier we identified was stigma around OUD and its effects on patients' ability to access services and staff/provider ability to provide services. The most frequent enablers of program success were trainee interest, organizational leadership support, and a dedicated MOUD care team. Organizations used clinical and systems improvement knowledge to enhance their existing programs or to take steps to create new programs. All participants identified the need for additional staff/clinician training, especially to overcome stigma around OUD. The outcomes demonstrated the crucial importance of long-term organizational support for program success.


Perovskite light-emitting diodes based on spontaneously formed submicrometre-scale structures.
Light-emitting diodes (LEDs), which convert electricity to light, are widely used in modern society-for example, in lighting, flat-panel displays, medical devices and many other situations. Generally, the efficiency of LEDs is limited by nonradiative recombination (whereby charge carriers recombine without releasing photons) and light trapping1-3. In planar LEDs, such as organic LEDs, around 70 to 80 per cent of the light generated from the emitters is trapped in the device4,5, leaving considerable opportunity for improvements in efficiency. Many methods, including the use of diffraction gratings, low-index grids and buckling patterns, have been used to extract the light trapped in LEDs6-9. However, these methods usually involve complicated fabrication processes and can distort the light-output spectrum and directionality6,7. Here we demonstrate efficient and high-brightness electroluminescence from solution-processed perovskites that spontaneously form submicrometre-scale structures, which can efficiently extract light from the device and retain wavelength- and viewing-angle-independent electroluminescence. These perovskites are formed simply by introducing amino-acid additives into the perovskite precursor solutions. Moreover, the additives can effectively passivate perovskite surface defects and reduce nonradiative recombination. Perovskite LEDs with a peak external quantum efficiency of 20.7 per cent (at a current density of 18 milliamperes per square centimetre) and an energy-conversion efficiency of 12 per cent (at a high current density of 100 milliamperes per square centimetre) can be achieved-values that approach those of the best-performing organic LEDs.


Genetic analysis of Fasciclin II in Drosophila: defasciculation, refasciculation, and altered fasciculation.
The Drosophila neural cell adhesion molecule Fasciclin II (Fas II) is expressed dynamically on a subset of embryonic CNS axons, many of which selectively fasciculate in the vMP2, MP1, and FN3 pathways. Here we show complementary fasII loss-of-function and gain-of-function phenotypes. Loss-of-function fasII mutations lead to the complete or partial defasciculation of all three pathways. Gain-of-function conditions, using a specific control element to direct increased levels of Fas II on the axons in these three pathways, rescue the loss-of-function phenotype. Moreover, the gain-of-function can alter fasciculation by abnormally fusing pathways together, in one case apparently by preventing normal defasciculation. These results define an in vivo function for Fas II as a neuronal recognition molecule that controls one mechanism of growth cone guidance-selective axon fasciculation--and genetically separates this function from other aspects of outgrowth and directional guidance.


Understanding impacts of organic contaminants from aquaculture on the marine environment using a chemical fate model.
As demand for sustainable marine aquaculture (mariculture) and marine food supply surges worldwide, there is a growing need for new tools to assess mariculture impacts on local ecosystems, including the cycling of toxic organic contaminants. With this in mind, we developed the Contaminant Fate in Aquaculture-Modified Ecosystems (CFAME) model. The current model was designed to explore the fate of mariculture-derived organic contaminants in the Marlborough Sounds, New Zealand, known for its Chinook salmon farming industry. Model evaluation indicated robust model design, with 80% of modeled concentrations falling within a factor of ten of measured ones for native biota. Model results showed that mariculture was a source of organic contaminants in the sediment even at the Marlborough Sounds regional level and in wild marine fishes with high trophic levels near the farm area. Future research attention should be directed toward measuring chemicals with low log KAW (<0) and high log KOW values (e.g., >3) in sediment, and chemicals with log KOW values of 3-9 in wild fish.


A comparison of the effects of Angiotensin IV on androgen-dependent and androgen-independent prostate cancer cell lines.
Angiotensin IV is one of the biologically active peptides of the renin-angiotensin system. Limited data suggests that this hexapeptide could contribute to cancer development and/or progression. Using the MTT reduction assay as an indicator of cell viability, and the bromodeoxyuridine incorporation assay as an indicator of cell proliferation, the influence of Angiotensin IV was evaluated on two human prostate cancer lines: androgen-dependent (LNCaP) and androgen-independent (DU-145). The potential effect of Angiotensin IV classic angiotensin receptors was examined by using the selective antagonists losartan and PD123319. Finally, the changes in expression levels of AT1 and AT2 receptors were compared, before and after angiotensin treatment. Angiotensin IV caused significant changes in cell viability and proliferation in LNCaP cells but not in DU-145. It was found that AT2 receptor blocker (PD123319) was able to diminish the suppressor effect of Angiotensin IV on bromodeoxyuridine incorporation into the DNA of androgen-dependent prostate cancer cells. Simultaneously, it was reported that Angiotensin IV is the factor that modulates the density of AT1 and AT2 receptors in prostate cancer cells. These findings suggested that Angiotensin IV can modulate tumour cell proliferation in the early stage of androgen-dependent prostate cancer. The effect might be promoted by the change of the angiotensin receptor level.


Di-(2-ethylhexyl) phthalate enhances cytokine release from group 2 innate lymphoid cells in the presence of interleukin-33.
Epidemiological and experimental studies have shown that di-(2-ethylhexyl) phthalate (DEHP), a plasticizer, can aggravate allergic diseases. DEHP promotes adaptive immune responses, although its effect on the innate immune system remains largely unknown. The present study investigated the effects of DEHP on group 2 innate lymphoid cells (ILC2) that produce Th2 cytokines in response to epithelial cell-derived cytokines, such as interleukin (IL)-33. ILC2 (lineage-negative, CD45.2+, Sca1+, KLRG1+) were isolated from the lungs of C57BL/6 J mice. Co-exposure to DEHP and IL-33 significantly increased IL-5 release from ILC2, whose level was higher than that of the vehicle and IL-33 alone. The effects of DEHP in the presence of IL-33 showed an inverted-U dose-response. The present is the first report showing that DEHP exacerbates allergy through the innate immune system.


Low-dose X-ray depilatory treatment induces trichoblastic tumors of the scalp.
Depilatory radiotherapy for ringworm was largely used before antifungals were available. Patients who underwent this treatment are at high risk of developing scalp tumors or other cancers. The aim of this study was to characterize scalp tumors occurring after X-ray therapy for ringworm. We included cases of postradiotherapy scalp tumors recorded at the Dermatology Department of the Charles Nicolle Hospital, Tunis between 1988 and 2001. We recorded clinical descriptions and all cases were resubmitted to microscopic analysis. Sixty-one tumors occurred in 33 men and 12 women with a mean age of 49.8 years. Radiodermatitis was present in 21% of patients. Tumors were basal cell carcinomas in 47 cases, trichoblastomas in 10 cases and trichoblastic carcinomas in 4 cases. Twelve patients had 2-5 tumors, with combinations of tumor types in 3 of them. Mean delay of onset of tumors after radiotherapy was 39.4 years in basal cell carcinoma cases, 38.3 years in trichoblastoma cases and 35.6 years in trichoblastic carcinoma cases. This series shows that although basal cell carcinoma is the most frequent tumor in this situation, trichoblastomas are common. We describe, for the first time, radio-induced trichoblastic carcinomas. Trichoblastic tumors have not yet been described in this context because this concept is relatively recent.


COVID-19 vaccine hesitancy among people living with HIV in a low-resource setting: A multi-center study of prevalence, correlates and reasons.
Hesitancy to COVID-19 vaccine may worsen the burden of COVID-19 among people living with HIV (PLHIV), who are at a higher risk of COVID-19-related hospitalization and death, compared to HIV non-infected individuals. Therefore, we evaluate the predictors and reasons for COVID-19 vaccine hesitancy among unvaccinated PLHIV in six antiretroviral therapy (ART) clinics across northern Nigeria. In this cross-sectional study, conducted between October 2021 and February 2022 in six hospitals across two geopolitical regions of Nigeria, we utilized interviewer-administered questionnaires to assess COVID-19 vaccine hesitancy among a convenience sample of 790 eligible adult PLHIV. Hesitancy was defined as answering 'no' or 'maybe' to a question asking participants their willingness to accept the COVID-19 vaccine. A multivariate logistic regression model was used to estimate the adjusted odds ratio (aOR) and 95% confidence interval (CI) of the factors associated with COVID-19 vaccine hesitancy among PLHIV. Of the total 660 unvaccinated participants included in the analysis (61.82% female, mean age [SD] of 39.76 [10.75]), 381 (57.72%) were hesitant to COVID-19 vaccine. Being 50 years and older (aOR: 0.43; 95% CI: 0.21-0.89), being unemployed (aOR: 0.57; 95% CI: 0.34-0.95), experiencing the adverse effects of ART (aOR: 0.36; 95% CI: 0.15-0.86), and perception of being at high risk of contracting COVID-19 (aOR: 0.22; 95% CI: 0.13-0.37) were associated with significantly lower odds of hesitancy. Conversely, being female (aOR: 1.64; 95% CI: 1.02-2.61) and attending ART clinics at state administrative capital cities (IIDH Kano [aOR: 2.40; 95% CI: 1.10-5.25], MMSH Kano [aOR: 5.59; 95% CI: 1.97-10.66], YSSH Damaturu [aOR: 9.88; 95% CI: 4.02-24.29] vs. GH Gashua) were associated with significantly higher odds of hesitancy. The most common reasons for hesitancy include fear of potential adverse effects, skepticism about vaccine efficacy, the rapid development of the COVID-19 vaccine, and the perceived lack of effort to develop a cure or vaccine for HIV/AIDS. Interventions aimed at combating misperceptions and misinformation regarding the COVID-19 vaccination program may reduce the prevalence of COVID-19 vaccine hesitancy among unvaccinated PLHIV.


Technology-Enhanced Stepped Collaborative Care Targeting Posttraumatic Stress Disorder and Comorbidity After Injury: A Randomized Controlled Trial.
Posttraumatic stress disorder (PTSD) and its comorbidities are endemic among injured trauma survivors. Previous collaborative care trials targeting PTSD after injury have been effective, but they have required intensive clinical resources. The present pragmatic clinical trial randomized acutely injured trauma survivors who screened positive on an automated electronic medical record PTSD assessment to collaborative care intervention (n = 60) and usual care control (n = 61) conditions. The stepped measurement-based intervention included care management, psychopharmacology, and psychotherapy elements. Embedded within the intervention were a series of information technology (IT) components. PTSD symptoms were assessed with the PTSD Checklist at baseline prerandomization and again, 1-, 3-, and 6-months postinjury. IT utilization was also assessed. The technology-assisted intervention required a median of 2.25 hours (interquartile range = 1.57 hours) per patient. The intervention was associated with modest symptom reductions, but beyond the margin of statistical significance in the unadjusted model: F(2, 204) = 2.95, p = .055. The covariate adjusted regression was significant: F(2, 204) = 3.06, p = .049. The PTSD intervention effect was greatest at the 3-month (Cohen's effect size d = 0.35, F(1, 204) = 4.11, p = .044) and 6-month (d = 0.38, F(1, 204) = 4.10, p = .044) time points. IT-enhanced collaborative care was associated with modest PTSD symptom reductions and reduced delivery times; the intervention model could potentially facilitate efficient PTSD treatment after injury.


Mometasone fuoroate 0.1% ointment in the treatment of vulvar lichen sclerosus: a study of efficacy and safety on a large cohort of patients.
Guidelines identify a 3-month topical application of an ultra-potent corticosteroid ointment as the mainstay of medical treatment for vulvar lichen sclerosus (VLS). However, there are no trials providing evidence that any specific corticosteroid is superior to another. To assess the effectiveness and safety of a 12-week application of mometasone furoate (MMF) 0.1% ointment, with a tapering regimen, in achieving control of VLS signs and symptoms and to detect potential risk factors for VLS non-response. 147 patients affected with VLS were enrolled in a 12-week active treatment phase (ATP) with topical 0.1% MMF. The primary efficacy endpoint was the rate of patients achieving clinical response, as defined by protocol parameters. The secondary efficacy endpoint was to assess the changes of mean VLS-related symptoms after the 12-week ATP compared with baseline. By the end of the ATP, 113 patients (80.7%) experienced a treatment response, whereas 27 women (19.3%) were judged as non-responders. Mean symptom scores decreased significantly in the study patients, regardless of their clinical response at the end of the ATP. Among all the epidemiological and clinical data considered, only the absence of previous medical therapies was found to be related to a significantly higher risk of non-response to treatment. Application of 0.1% MMF ointment for 12 weeks on a tapering regimen was found to be an effective and safe therapy option in the ATP of VLS and could represent an alternative first-line treatment to an ultra-potent molecule.


Domain architecture of the catalytic subunit in the ISW2-nucleosome complex.
ATP-dependent chromatin remodeling has an important role in the regulation of cellular differentiation and development. For the first time, a topological view of one of these complexes has been revealed, by mapping the interactions of the catalytic subunit Isw2 with nucleosomal and extranucleosomal DNA in the complex with all four subunits of ISW2 bound to nucleosomes. Different domains of Isw2 were shown to interact with the nucleosome near the dyad axis, another near the entry site of the nucleosome, and another with extranucleosomal DNA. The conserved DEXD or ATPase domain was found to contact the superhelical location 2 (SHL2) of the nucleosome, providing a direct physical connection of ATP hydrolysis with this region of nucleosomes. The C terminus of Isw2, comprising the SLIDE (SANT-like domain) and HAND domains, was found to be associated with extranucleosomal DNA and the entry site of nucleosomes. It is thus proposed that the C-terminal domains of Isw2 are involved in anchoring the complex to nucleosomes through their interactions with linker DNA and that they facilitate the movement of DNA along the surface of nucleosomes.


Pathophysiology, Diagnosis, and Ablation of Atrioventricular Node-dependent Long-R-P Tachycardias.
Atrioventricular (AV) node-dependent long-R-P tachycardias are a unique group of supraventricular tachycardias that include atypical AV nodal reentrant tachycardia (AVNRT), atypical AVNRT with a concealed bystander nodofascicular (NF)/nodoventricular (NV) accessory pathway inserting into the slow pathway of the AV node, the permanent form of junctional reciprocating tachycardia, and orthodromic NF/NV reciprocating tachycardia. Here, we discuss the complex pathophysiology, diagnosis, and ablation of these intriguing arrhythmias.


Genes, cells, and biobanks: Yes, there's still a consent problem.
From a research perspective, the interest in biobanking continues to intensify. Governments and industry have invested heavily in biobanks, as exemplified by initiatives like the United Kingdom Biobank and United States' Precision Medicine Initiative. But despite this enthusiasm, many profound legal and ethical challenges remain unresolved. Indeed, there continues to be disagreements about how best to obtain consent and the degree and nature of control that research participants retain over donated samples and health information. Emerging social trends-including concerns about commercialization and perceived rights of continuing control ("biorights")-seem likely to intensify these issues.


What do surgeons see: capturing and synchronizing eye gaze for surgery applications.
Recording eye motions in surgical environments is challenging. This study describes the authors' experiences with performing eye-tracking for improving surgery training, both in the laboratory and in the operating room (OR). Three different eye-trackers were used, each with different capabilities and requirements. For monitoring eye gaze shifts over the room scene in a simulated OR, a head-mounted system was used. The number of surgeons' eye glances on the monitor displaying patient vital signs was successfully captured by this system. The resolution of the head-mounted eye-tracker was not sufficient to obtain the gaze coordinates in detail on the surgical display monitor. The authors then selected a high-resolution eye-tracker built in to a 17-inch computer monitor that is capable of recording gaze differences with resolution of 1° of visual angle. This system enables one to investigate surgeons' eye-hand coordination on the surgical monitor in the laboratory environment. However, the limited effective tracking distance restricts the use of this system in the dynamic environment in the real OR. Another eye-tracker system was found with equally high level of resolution but with more flexibility on the tracking distance, as the eye-tracker camera was detached from the monitor. With this system, the surgeon's gaze during 11 laparoscopic procedures in the OR was recorded successfully. There were many logistical challenges with unobtrusively integrating the eye-tracking equipment into the regular OR workflow and data processing issues in the form of image compatibility and data validation. The experiences and solutions to these challenges are discussed.


Influenza Plasmid DNA Vaccines: Progress and Prospects.
Current influenza vaccines have long been used to fight flu infectious; however, recent advances highlight the importance of produce new alternatives. Even though traditional influenza vaccines are safe and usually effective, they need to be uploaded every year to anticipate circulating flu viruses. This limitation together with the use of embryonated chicken eggs as the substrate for vaccine production, is time-consuming and could involve potential biohazards in growth of new virus strains. Plasmid DNA produced by prokaryote microorganisms and encoding foreign proteins had emerged as a promising therapeutic tool. This technology allows the expression of a gene of interest by eukaryotic cells in order to induce protective immune responses against the pathogen of interest. In this review, we discuss the strategies to choose the best DNA vaccine to be applied in the treatment and prevention of influenza. Specifically, we give an update of influenza DNA vaccines developments, all involved techniques, their main characteristics, applicability and technical features to obtain the best option against influenza infections.


Effect of hydrocarbon chain length in 1,2-alkanediols on percutaneous absorption of metronidazole: toward development of a general vehicle for controlled release.
The objective of the present study is to investigate the effect of hydrocarbon chain length in 1,2-alkanediols on percutaneous absorption of metronidazole (MTZ). Twelve formulations (1,2-propanediol, 1,2-butanediol, 1,2-pentanediol, 1,2-hexanediol in 4% concentration, 1,2-hexanediol, and 1,2-heptanediol in 1% concentration, in the absence and presence of 1,4-cyclohexanediol, respectively) were studied in an in vitro hairless mouse skin model using Franz diffusion cell. Based on the flux values and retardation ratios (RR), a penetration retardation effect on percutaneous absorption of MTZ was observed for the formulations containing 1,2-diols having six- to seven-carbon chain in the presence of 1,4-cyclohexanediol (1,2-hexanediol with chain length of six hydrocarbons, RRs are 0.69 and 0.76 in the concentration of 4% and 1%, respectively; 1,2-heptanediol with chain length of seven hydrocarbons, RR is 0.78 in the concentration of 1%). On the other hand, no retardation effect was observed in formulations containing short alkyl chains (RRs of 1,2-propanediol, 1,2-butanediol, and 1,2-pentanediol are 0.99, 1.61, and 0.96, respectively). Instead, a penetration enhancement effect was observed for 1,2-diols having four and five carbons. In other words, effect of 1,2-alkanediols on percutaneous absorption of MTZ can be systematically modulated by simply varying number of -CH2 groups in the hydrocarbon chain-from being a penetration enhancer to retardant. These observations shed light on mechanism of the penetration enhancement and retardation effect and provide insight into rational design of penetration enhancers and retardants. Furthermore, the combination of 1,2-alkanediols and 1,4-cyclohexanediol could become a general vehicle for controlled release of pharmaceutical and cosmetic active ingredients.


A novel single-photon counting technique applied to highly sensitive measurement of [Ca2+]i transient in human aortic smooth muscle cells.
This study demonstrates that aequorin, a luminescent natural dye, is useful for vascular cell intracellular Ca2+ concentration ([Ca2+]i) determination. A new single-photon counting technique was developed to resolve the effects of fluid flow shear stress on [Ca2+]i in human aortic smooth muscle cells (HASMCs). Confluent HASMCs were grown on petri dishes loaded with aequorin. Then the dishes were placed in a luminometer chamber after the physiological level of shear stress was applied to the HASMC surfaces. The chamber was housed inside a highly sensitive photomultiplier tube. It detected ultraweak photon emission in response to the [Ca2+]i transient. In the presence of 2.0 mM extracellular Ca2+, a shear stress of 12 dyn cm2, applied for 60 s to the top surface of the HASMC monolayer, elicited a sharp increase in [Ca2+]i.


Layer-by-layer rose petal mimic surface with oleophilicity and underwater oleophobicity.
Surfaces designed with specific wetting properties are still a key challenge in materials science. We present here a facile preparation of a surface assembled by the layer-by-layer technique, using a colloidal dispersion of ionomer particles and linear polyethylene imine. The colloidal ethylene-co-methacrylic acid (EMAA) particles are on the order of half a micron in size with surface features from 40 to 100 nm in width. The resultant surface has roughness on two length scales, one on the micron scale due to the packing of particles and one on the nanoscale due to these surface features on the EMAA particles. This hierarchical structure results in a hydrophobic surface with good water pinning properties (∼550 μN). We show that there is a balance between maximizing contact angle and water pinning force. Furthermore, this surface is oleophilic with regard to many organic solvents, also demonstrating underwater oleophobicity, and given the difference in wetting between aqueous and organic phases, this material may be a candidate material for oil/water separations.


Spinal anesthesia in a patient with severe thoracolumbar kyphoscoliosis.
Patients with spine abnormalities, present unique challenges to the health care provider responsible for administrating sedation and anesthesia during surgical and technical procedures. Spinal deformities may cause difficulties with both tracheal intubation and regional anesthesia. This report describes the anesthetic management for two urological operations that were performed in a patient with extremely severe thoracolumbar kyphoscoliosis. After examining the risk factors, spinal block by injecting single dose local anesthetic solution to the intratechal space was chosen to provide anesthesia. It has been suggested that hyperbaric solution, which is of high density compared with cerebrospinal fluid, can safely produce blocks for many operations under spinal anesthesia. In the first procedure, intrathecal injection of 6 mg hyperbaric bupivacaine, a local anesthetic solution (1.2 ml total volume), resulted in inadequate motor and sensory blockade, but the successful motor and sensory blockade at the level of Th10 was achieved in a second attempt with 6.25 mg hypobaric bupivacaine (2 ml). Because of this unexpected effect of local anesthetic solution, in the second operation, the technique was changed to intrathecal injection of 12.5 mg hypobaric bupivacaine (4 ml), and the motor and sensory blockade at Th10 was achieved again. The patient reported satisfactory anesthesia each time, and developed no complications. In conclusion, spinal anesthesia can be successful even in cases of severe thoracolumbar kyphoscoliosis.


Zero-temperature properties of RNA secondary structures.
We analyze different microscopic RNA models at zero temperature. We discuss both the most simple model, which suffers a large degeneracy of the ground state, and models in which the degeneracy has been removed in a more or less severe manner. We calculate low-energy density of states using a coupling perturbing method, where the ground state of a modified Hamiltonian, that repels the original ground state, is determined. We evaluate scaling exponents starting from measurements of overlaps and energy differences. In the case of models without accidental degeneracy of the ground state we are able to clearly establish the existence of a glassy phase with theta approximately 1/3. 87.15.Aa, 64.60.Fr


[The development of cytotoxic T lymphocytes in HLA-D/DR identity].
The development of cytotoxic T-lymphocytes is controlled by genes of the HLA complex and occurs, in the majority of cases, when the responding and stimulating subjects differ both in HLA-A, -B and HLA-D/DR antigens. We examined a married couple for kidney transplantation and found that they differed in HLA-A, -B antigens and were identical in HLA-DR antigens. The negative results of the MLC test confirmed the serological findings. Nevertheless, cytotoxic T-lymphocytes developed despite HLA-D/DR identity. The presented case is one of the few published exceptions to the rule governing the development of cytotoxic T-lymphocytes.


Diabetic Retinopathy-Update on Prevention Techniques, Present Therapies, and New Leads.
Diabetic retinopathy is the major ocular complication associated with diabetes, and represents the leading cause of legal blindness in the working-age population of developed countries. Although classically diagnosed based on abnormalities of the retinal microvasculature, diabetic retinopathy is now widely recognized as a neurovascular disease. While all patients with diabetes are at increased risk for eye disease including diabetic retinopathy, proactive measures, and timely intervention can prevent or delay subsequent vision loss. Systemic management of diabetes by combined control of glycemia, blood pressure, and serum lipid levels remains the most important method of preventing diabetic retinopathy onset and progression. Once detected, surgical and medical interventions including photocoagulation, vitrectomy, and intravitral drug injection can help preserve vision. However, the need for improved detection methods and therapies that will allow earlier diagnosis and treatment remains apparent. This review summarizes current techniques for the prevention and intervention for diabetic retinopathy, and examines ongoing developments in the search for new endpoints and therapies as they apply to preventing vision loss associated with diabetes.


Comparison of radical prostatectomy techniques: open, laparoscopic and robotic assisted.
To review the current status of laparoscopic radical prostatectomy (LRP) and robotic assisted radical prostatectomy (RALP) in relation to radical retropubic prostatectomy (RRP) in the management of localized prostate cancer. Between 1982 and 2007 published literature was reviewed using the National Library of Medicine database and the following key words: retropubic, laparoscopic, robotic, robot-assisted, and radical prostatectomy. Special emphasis was given to the technical and cost considerations as well as operative, functional and oncologic outcomes. In particular, reports with pioneering work that have contributed to the evolution of the technique, presenting comparative outcomes and with large series encompassing intermediate/long term follow-up, were taken into account. After intermediate term follow-up, LRP and RALP achieved similar oncologic and functional results compared to RRP. However, LRP and RALP were associated with decreased blood loss, faster convalescence and better cosmetics when compared to RRP. The RALP technique is undoubtedly more expensive. The oncologic and functional outcomes for LRP and RALP are similar to RRP after intermediate term follow-up. Long term follow-up and adequately designed studies will determine the inherent advantages and disadvantages of the individual techniques in the management of localized prostate cancer.


Recovery of large carnivores in Europe's modern human-dominated landscapes.
The conservation of large carnivores is a formidable challenge for biodiversity conservation. Using a data set on the past and current status of brown bears (Ursus arctos), Eurasian lynx (Lynx lynx), gray wolves (Canis lupus), and wolverines (Gulo gulo) in European countries, we show that roughly one-third of mainland Europe hosts at least one large carnivore species, with stable or increasing abundance in most cases in 21st-century records. The reasons for this overall conservation success include protective legislation, supportive public opinion, and a variety of practices making coexistence between large carnivores and people possible. The European situation reveals that large carnivores and people can share the same landscape.


CYP116B5: a new class VII catalytically self-sufficient cytochrome P450 from Acinetobacter radioresistens that enables growth on alkanes.
A gene coding for a class VII cytochrome P450 monooxygenase (CYP116B5) was identified from Acinetobacter radioresistens S13 growing on media with medium (C14, C16) and long (C24, C36) chain alkanes as the sole energy source. Phylogenetic analysis of its N- and C-terminal domains suggests an evolutionary model involving a plasmid-mediated horizontal gene transfer from the donor Rhodococcus jostii RHA1 to the receiving A. radioresistens S13. This event was followed by fusion and integration of the new gene in A. radioresistens chromosome. Heterologous expression of CYP116B5 in Escherichia coli BL21, together with the A. radioresistens Baeyer-Villiger monooxygenase, allowed the recombinant bacteria to grow on long- and medium-chain alkanes, showing that CYP116B5 is involved in the first step of terminal oxidation of medium-chain alkanes overlapping AlkB and in the first step of sub-terminal oxidation of long-chain alkanes. It was also demonstrated that CYP116B5 is a self-sufficient cytochrome P450 consisting of a heme domain (aa 1-392) involved in the oxidation step of n-alkanes degradation, and its reductase domain (aa 444-758) comprising the NADPH-, FMN- and [2Fe2S]-binding sites. To our knowledge, CYP116B5 is the first member of this class to have its natural substrate and function identified.


PDE4-Mediated cAMP Signalling.
cAMP is the archetypal and ubiquitous second messenger utilised for the fine control of many cardiovascular cell signalling systems. The ability of cAMP to elicit cell surface receptor-specific responses relies on its compartmentalisation by cAMP hydrolysing enzymes known as phosphodiesterases. One family of these enzymes, PDE4, is particularly important in the cardiovascular system, where it has been extensively studied and shown to orchestrate complex, localised signalling that underpins many crucial functions of the heart. In the cardiac myocyte, cAMP activates PKA, which phosphorylates a small subset of mostly sarcoplasmic substrate proteins that drive β-adrenergic enhancement of cardiac function. The phosphorylation of these substrates, many of which are involved in cardiac excitation-contraction coupling, has been shown to be tightly regulated by highly localised pools of individual PDE4 isoforms. The spatial and temporal regulation of cardiac signalling is made possible by the formation of macromolecular "signalosomes", which often include a cAMP effector, such as PKA, its substrate, PDE4 and an anchoring protein such as an AKAP. Studies described in the present review highlight the importance of this relationship for individual cardiac PKA substrates and we provide an overview of how this signalling paradigm is coordinated to promote efficient adrenergic enhancement of cardiac function. The role of PDE4 also extends to the vascular endothelium, where it regulates vascular permeability and barrier function. In this distinct location, PDE4 interacts with adherens junctions to regulate their stability. These highly specific, non-redundant roles for PDE4 isoforms have far reaching therapeutic potential. PDE inhibitors in the clinic have been plagued with problems due to the active site-directed nature of the compounds which concomitantly attenuate PDE activity in all highly localised "signalosomes".


Technical Skills Training for Veterinary Students: A Comparison of Simulators and Video for Teaching Standardized Cardiac Dissection.
The goal of the study was to evaluate alternative student-centered approaches that could replace autopsy sessions and live demonstration and to explore refinements in assessment procedures for standardized cardiac dissection. Simulators and videos were identified as feasible, economical, student-centered teaching methods for technical skills training in medical contexts, and a direct comparison was undertaken. A low-fidelity anatomically correct simulator approximately the size of a horse's heart with embedded dissection pathways was constructed and used with a series of laminated photographs of standardized cardiac dissection. A video of a standardized cardiac dissection of a normal horse's heart was recorded and presented with audio commentary. Students were allowed to nominate a preference for learning method, and students who indicated no preference were randomly allocated to keep group numbers even. Objective performance data from an objective structure assessment criterion and student perception data on confidence and competency from surveys showed both innovations were similarly effective. Evaluator reflections as well as usage logs to track patterns of student use were both recorded. A strong selection preference was identified for kinesthetic learners choosing the simulator and visual learners choosing the video. Students in the video cohort were better at articulating the reasons for dissection procedures and sequence due to the audio commentary, and student satisfaction was higher with the video. The major conclusion of this study was that both methods are effective tools for technical skills training, but consideration should be given to the preferred learning style of adult learners to maximize educational outcomes.


Seroprevalence of Sparganosis in Rural Communities of Northern Tanzania.
In this study, the seroprevalence of sparganosis and its relationship with sociodemographic factors in northern Tanzania have been assessed. A total of 216 serum samples from two rural districts, Monduli and Babati, were tested for sparganosis using an enzyme-linked immunosorbent assay. The seroprevalence of anti-sparganum IgG antibodies was 62.5% (95% confidence interval [CI] = 56.1-68.9) in all age groups. There were significant associations between district (relative risk [RR] = 1.95, 95% CI = 1.42-2.69), education (RR = 1.40, 95% CI = 1.15-1.70), and pet ownership with seropositivity (RR = 1.48, 95% CI = 1.02-2.16) based on univariate analysis. However, only the district was significantly associated with seropositivity (odds ratio = 4.20, 95% CI = 1.89-9.32) in binary logistic regression analysis. Providing health education to people residing in sparganosis-endemic areas is likely to improve the efficacy of preventative measures and reduce human disease burden.


Accuracy of a polymerase chain reaction-based assay for detection of pneumococcal bacteremia in children.
To evaluate the utility of a polymerase chain reaction (PCR)-based assay for identifying pneumococcal DNA in the blood of pediatric patients with suspected bacteremia. Children evaluated at the Children's Hospital of Pittsburgh who were having blood drawn for culture had an additional 2 to 3 mL of blood (from the same sampling) obtained and placed in a sodium citrate tube for PCR processing (study group). The control group for this study consisted of children having blood drawn for biochemical analysis who were afebrile, well-appearing, and had no recent illnesses. Specimens were frozen at -70 degrees C and then batch-processed for PCR-based analyses with the JM201/202-204 primer/probe set. Amplified products were detected after liquid hybridization format wherein a 32P end-labeled probe was annealed to the amplified DNA and visualized by autoradiographic analysis after gel retardation. Four hundred eighty study group patients and 103 controls had specimens tested by both PCR and blood culture. Twenty-six (5%) patients had a positive blood culture for a pathogenic organism (21 of which were Streptococcus pneumoniae). Twelve (57%) of the 21 patients with blood cultures positive for S pneumoniae also were positive by PCR. In addition, 206 study group patients and 16 controls with negative blood cultures had positive PCR results. A greater proportion of study group patients were PCR-positive/culture-negative than were controls (206/459 vs 16/103). Although this assay currently lacks adequate sensitivity and specificity for clinical use, the high frequency of PCR-positive cases in patients with suspected bacteremia may indicate a greater role for S pneumoniae than had previously been appreciated. Further refinement of this assay as well as the development of a rapid PCR-based assay appears warranted.


Reproductive tissue activity in hypothyroid or heat stressed hens.
The ability of the reproductive tract of the White Leghorn hen under heat stress or methimazole thyroid blockage to assimilate 32P was examined. Both treatments increase the uptake of 32P by the shell gland and egg shell but only heal stress increases 32P uptake by the ovaries and reduces shell thickness. The greater shell thinness under the heat stress is related to an increased deposition of phosphate in the shell. Gilbert (1967) has reported an increased serum calcium, due to calcification inhibitions by phosphate, leading to an increased gonadotropin secretion. Thyroid blockage appears to stimulate TSH and gonadotropin LH secretion but in the absence of phosphate inhibition of calcification shell thickness is not affected. It is also speculated that hypothyroidism does not stimulate FSH secretion and therefore ovarian tissues is not activated by this condition.


Clinical features, causes, treatments, and outcomes of peristomal pyoderma gangrenosum (PPG) in 44 patients: The Mayo Clinic experience, 1996 through 2013.
There are limited large case series of peristomal pyoderma gangrenosum (PPG), an uncommon cause of recalcitrant peristomal ulceration. We sought to further characterize the clinical features, causes, treatments, and outcomes of PPG. We conducted a retrospective chart review of patients with PPG seen at Mayo Clinic from January 1996 to July 2013. A total of 44 patients had PPG (mean age, 46 years; 32 women [73%]); 41 (93%) had inflammatory bowel disease. Mean time to PPG onset after stoma surgery was 5.2 months (excluding 1 outlier). Systemic therapies included corticosteroids (66%), immunosuppressants (41%), biologics (36%), and a combination of systemic treatments (36%). Mean time to reach a complete response was 10.7 weeks. Stoma closure had the greatest complete response (4 of 4 patients, no recurrences). Recurrence after any treatment was documented in 23 of 38 (61%) patients. Stoma relocation/revision recurred in 10 of 15 (67%) patients. Remission occurred in 29 of 31 (94%) patients. Small sample size and retrospective study design are limitations. PPG is strongly associated with inflammatory bowel disease, is predominant in women, and has a prolonged time to onset and high recurrence rate. Systemic corticosteroid or combination therapies and surgical closure can be effective treatments. Timely recognition and management are paramount to achieving early remission.


Independent analysis of a clinical predictive algorithm to identify methicillin-resistant Staphylococcus aureus osteomyelitis in children.
The number of serious, life-threatening musculoskeletal infections in children due to methicillin-resistant Staphylococcus aureus (MRSA) infections is increasing. The early identification of the bacteria causing osteomyelitis is critical to determine the appropriate antibiotic treatment. A recent study proposed a clinical algorithm to predict which infections were caused by MRSA by stratifying basic clinical values at the time of admission for children with osteomyelitis. The purpose of this study is to apply that predictive algorithm on an independent patient population to determine its wider applicability. This was a retrospective chart review at a tertiary care children's hospital. All children who were treated for a culture-positive osteomyelitis were identified over a 3-year period. The previously reported predictors, determined by multivariate regression analysis, of MRSA infection (temperature >38°C, hematocrit <34%, white blood cell count >12,000/µL, and C-reactive protein >13 mg/L) were determined for each patient. The number of positive predictors was then correlated with the percentage of cases that were MRSA positive. A total of 58 patients with culture-positive osteomyelitis were identified from 2008 to 2010. Sixteen of the infections were caused by MRSA (overall 26%). The percentage of patients with MRSA osteomyelitis according to the number of risk factors were as follows: all 4 risk factors, 50% (1 out of 2 patients); 3 risk factors, 42% (5 out of 12 patients); 2 risk factors, 21% (4 out of 19 patients); 1 risk factor, 50% (6 out of 12 patients); and 0 risk factor, 0% (0 out of 13 patients). The previously reported clinical predictive algorithm had a relatively poor diagnostic performance in this independent patient population. Specifically, the percentages of MRSA were the same for 1 risk factor compared with 4 (50%). Differences in bacteria strain, host responses, and a variety of other confounding variables could be responsible for these differences. Specific genetic markers may be the best early test to identify MRSA infections in the future. Level III-case-control series.


Warm-needling acupuncture and medicinal cake-separated moxibustion for hyperlipidemia: study protocol for a randomized controlled trial.
Acupuncture and moxibustion has been widely applied to hyperlipidemia treatment in clinical practice in China, serving as an alternative treatment to statins. Warm-needling acupuncture and medicinal cake-separated moxibustion have been separately reported with potential therapeutic effects on hyperlipidemia treatment in several studies but with limitations in study methodology. Combining these two modalities may provide a more advantageous strategy in treating hyperlipidemia. Therefore, a strict evaluation through well-designed randomized controlled trials (RCT) is necessary to determine their efficacy and safety on hyperlipidemia. The study a multicenter, open-label, randomized, stratified, active-controlled, noninferiority trial with two parallel groups. Subjects with hyperlipidemia will be stratified into different groups by risk levels of heart diseases. They then will be instructed to the Therapeutic Lifestyle Change (TLC) diet. Those who have not reached the target lipid level will be randomly assigned to the treatments of either acupuncture and moxibustion or simvastatin with a 1:1 allocation. One hundred and thirty subjects are aimed to be recruited. The duration of intervention for this study will be 12 weeks, followed by another 4 weeks for post-treatment assessment. The primary outcome is percentage change from baseline to the end of the study in low-density lipoprotein cholesterol (LDL-C). Other indicators in lipid change, safety and adherence will also be assessed secondarily. The repeated measures, linear mixed-effects model will be applied to the analysis. Acupuncture and moxibustion could be a potentially effective treatment alternative for hyperlipidemia. A study with careful design is developed to evaluate the efficacy and safety of combined acupuncture and moxibustion, by integrating the traditional Chinese Medicine (TCM) regimens with the standardized Western medicine appraisal approach. ClinicalTrials.gov, NCT02269046 . Registered on 26 September 2014.


Negative regulatory domains in a trophoblast interferon promoter.
A bovine trophoblast interferon (IFN-tau) gene promoter sequence (-450 to +26 bp relative to the transcription start site) led to expression of reporter gene (CAT) constructs transfected into L929 (murine fibroblast) or JAR (human choriocarcinoma) cells. Expression depended on the presence of an exogenous (SV40) enhancer. Poly(I)(C) activated endogenous IFN production in L929 and JAR cells but had no consistent effect on CAT expression. Similar results were obtained in L929 cells with inactivated Newcastle disease virus. There was no 'priming' effect of exogenous Type I IFN. Deletion mutants revealed sites exerting negative control on expression between - 338 and - 247 bp, and between - 150 and - 71 bp; these regions contained sequences resembling previously identified negative regulatory domains. In the absence of viral inducibility it is proposed that negative regulation contributes towards the stringent control of expression characteristic of IFN-tau genes.


Regulation of PLK1 through competition between hnRNPK, miR-149-3p and miR-193b-5p.
Polo-like kinase 1 (PLK1) is a critical regulator of cell cycle progression and apoptosis. However, its regulation remains poorly understood. In the present study, we investigated the molecular mechanism underlying the post-transcriptional regulation of PLK1. We observed that heterogeneous nuclear ribonucleoprotein K (hnRNPK) and PLK1 were positively associated in several different cancers and high expression levels of them correlated with poor prognosis in patients with cancer. Knockdown of hnRNPK resulted in reduced expression of PLK1, whereas conversely, PLK1 expression was increased in hnRNPK-overexpressing cells. We found that hnRNPK regulated PLK1 expression through KH1- and KH2-dependent interactions with the 3'UTR of PLK1 mRNA. In addition, microRNA-149-3p (miR-149-3p) and miR-193b-5p suppressed PLK1 expression by targeting the 3'UTR of PLK1 mRNA. MicroRNA-elicited enrichment of PLK1 mRNA in Ago2 immunoprecipitation was altered by the presence or absence of hnRNPK. Furthermore, the deletion of the cytosine (C)-rich sequences of the 3'UTR of PLK1 mRNA abolished the decreased PLK1 expression observed via hnRNPK silencing and administration of miRNAs, a finding that suggests that hnRNPK shares this C-rich motif with miR-149-3p and miR-193b-5p. We also found that downregulation of PLK1 by either silencing hnRNPK or overexpression of miR-149-3p and miR-193b-5p decreased clonogenicity and induced apoptosis. Our findings from this study demonstrate that hnRNPK regulates PLK1 expression by competing with the PLK1-targeting miRNAs, miR-149-3p and miR-193b-5p.


Using the MEROPS Database for Proteolytic Enzymes and Their Inhibitors and Substrates.
MEROPS is a database of proteolytic enzymes as well as their inhibitors and substrates. Proteolytic enzymes and protein inhibitors are organized into protein domain families. In turn, families are organized into clans. Each peptidase, inhibitor, family, and clan has associated annotation, a multiple sequence alignment, a phylogenetic tree, literature references, and links to other databases. Interactions between proteolytic enzymes and inhibitors and between proteolytic enzymes and substrates are also presented. The entries in MEROPS are available via the World Wide Web. This unit contains detailed information on how to access and utilize the information present in the MEROPS database. Details on running MEROPS both remotely and locally are presented.


Novel assembly properties of recombinant spider dragline silk proteins.
Spider dragline silk, which exhibits extraordinary strength and toughness, is primarily composed of two related proteins that largely consist of repetitive sequences. In most spiders, the repetitive region of one of these proteins is rich in prolines, which are not present in the repetitive region of the other. The absence of prolines in one component was previously speculated to be essential for the thread structure. Here, we analyzed dragline proteins of the garden spider Araneus diadematus, ADF-3 and ADF-4, which are both proline rich, by employing the baculovirus expression system. Whereas ADF-3 represented an intrinsically soluble protein, ADF-4 was insoluble in vitro and self-assembled into filaments in the cytosol of the host insect cells. These ADF-4 filaments displayed the exceptional chemical stability of authentic silk threads. We provide evidence that the observed properties of ADF-3 and ADF-4 strongly depend on intrinsic characteristics such as hydropathicity, which differs dramatically between the two proteins, as in most other pairs of dragline silk proteins from other Araneoidea species, but not on their proline content. Our findings shed new light on the structural components of spider dragline silk, allowing further elucidation of their assembly properties, which may open the door for commercial applications.


A new iridoid diglucoside from Antirrhinum siculum.
A new iridoid diglucoside has been isolated from an ethanolic extract of Antirrhinum siculum, together with five-known compounds. Its structure has been assigned as 5-O-glucopyranosyl-7α-hydroxyharpagide by spectroscopic means.


[The problem of hemoperfusion in poisonings: ineffectiveness in maprotiline poisoning].
A case of self-poisoning with maprotiline presenting with coma stage III was treated by resin hemoperfusion for 9 hours using an XAD-4 resin cartridge. Plasma levels of about 800 ng/ml maprotilin were initially found. After 5 hours of hemoperfusion progredient clinical improvement was noticed without decreasing tendency of the blood drug levels. The theoretical extraction efficiency calculated from the maprotiline blood levels and the perfusion rate yielded 50 mg for maprotiline and 16 mg for desmethylmaprotiline and was in good agreement with 60.5 mg of maprotiline and 17.3 mg of desmethylmaprotiline recovered from the resin cartridge at the end of the hemoperfusion. The in vitro binding capacity for maprotiline was estimated to be 230 mg per g of resin. These results demonstrate that XAD-4 resin efficiently binds maprotiline. However, because of the very low blood concentrations due to the large volume of distribution, whole body concentrations are minimally affected by resin hemoperfusion. Main complications consisted in thrombocytopenia extending over 24 hours after stopping hemoperfusion, anemia, a short initial decrease of blood pressure and an episode of premature ventricular beats.


Clinical Guidelines of the Egyptian Psychiatric Association for the Management of Treatment-Resistant Unipolar Depression in Egypt.
Major depressive disorder (MDD) is a public health burden that creates a strain not only on individuals, but also on the economy. Treatment-resistant depression in the course of major depressive disorder represents a clinically challenging condition that is defined as insufficient response to two or more antidepressant trails with antidepressants of the same or different classes that were administered at adequate daily doses for at least 4 weeks. To develop a treatment guideline for Treatment Resistant Depression (TRD). Experts in the field gathered and reviewed the available evidence about the subject. Then, a series of meetings were held to create recommendations that can be utilized by Egyptian psychiatrists. The guidelines provide recommendations in various clinical settings. It evaluates different situations, such as patients at risk of resistance, those with resistance and recommends strategies to resolve the clinical case. The consensus guidelines will improve the outcomes of patients, as they provide recommendations across various domains that are of concern for the practicing psychiatrist.


A Single-blind, Split-face, Randomized, Pilot Study Comparing the Effects of Intradermal and Intramuscular Injection of Two Commercially Available Botulinum Toxin A Formulas to Reduce Signs of Facial Aging.
Objective: To examine the effectiveness of intradermal botulinum toxin type A injection in improving skin texture and midface lift while reducing pore size and sebum production, as well as investigate the differences in effectiveness between onabotulinumtoxinA and abobotulinumtoxinA using intradermal and intramuscular injection methods. Design: A 16-week, single-blind, split-face, randomized study. Each patient served as their own control, receiving onabotulinumtoxinA and abobotulinumtoxinA randomized to either the left or right side of the face. Patients received intradermal botulinum toxin type A injections at Week 0 and intramuscular botulinum toxin type A injections at Week 2. Participants: Ten women aged 35 to 65 years who exhibited static rhytids in the glabellar and periorbital area. Measurements: The primary endpoint was efficacy of split-face treatment of intradermal and intramuscular onabotulinumtoxinA and abobotulinumtoxinA as assessed by a blinded evaluator using baseline and post-treatment photographs. The secondary endpoints included safety as assessed by adverse events and patient satisfaction measured by questionnaires completed at baseline and post-treatment. Results: Intradermal injection of botulinum toxin type A led to a statistically significant improvement in skin texture (p=0.004) while also resulting in mild midface lift (p=0.024), but did not provide a significant reduction of pore size and sebum production. There was no statistically significant difference between onabotulinumtoxinA and abobotulinumtoxinA when injected intradermally or intramuscularly. Conclusion: Intradermal injection of botulinum toxin type A appears to be a safe and effective therapy that provides an improvement in facial skin texture and midface lift. Registry: clinicaltrials.gov (ID#: NCT02907268).


Tuning Paramagnetic Spin Excitations of Single Adatoms.
We predict the existence of paramagnetic spin excitations (PSE) in nonmagnetic single adatoms. Our calculations demonstrate that PSE develop a well-defined structure in the meV region when the adatom's Stoner criterion for magnetism is close to the critical point. We further reveal a subtle tunability and enhancement of PSE by external magnetic fields. Finally, we show how PSE can be detected as moving steps in the dI/dV signal of inelastic scanning tunneling spectroscopy, opening a potential route for experimentally accessing electronic properties of nonmagnetic adatoms, such as the Stoner parameter.


BNDF heterozygosity is associated with memory deficits and alterations in cortical and hippocampal EEG power.
Brain derived neurotrophic factor (BDNF) plays a pivotal role in structural plasticity, learning, and memory. Electroencephalogram (EEG) spectral power in the cortex and hippocampus has also been correlated with learning and memory. In this study, we investigated the effect of globally reduced BDNF levels on learning behavior and EEG power via BDNF heterozygous (KO) rats. We employed several behavioral tests that are thought to depend on cortical and hippocampal plasticity to varying degrees: novel object recognition, a test that is reliant on a variety of cognitive systems; contextual fear, which is highly hippocampal-dependent; and cued fear, which has been shown to be amygdala-dependent. We also examined the effects of BDNF reduction on cortical and hippocampal EEG spectral power via chronically implanted electrodes in the motor cortex and dorsal hippocampus. We found that BDNF KO rats were impaired in novelty recognition and fear memory retention, while hippocampal EEG power was decreased in slow waves and increased in fast waves. Interestingly, our results, for the first time, show sexual dimorphism in each of our tests. These results support the hypothesis that BDNF drives both cognitive plasticity and coordinates EEG activity patterns, potentially serving as a link between the two.


Safety and efficacy of pulsed low-dose rate radiotherapy for local recurrent esophageal squamous cell carcinoma after radiotherapy: Study protocol for a prospective multi-center phase II trial.
Re-irradiation after radiotherapy is a common treatment for locally recurrent esophageal cancer. However, the side effects of re-irradiation are serious. The most serious adverse reactions of re-irradiation include esophageal perforation and hemorrhage caused by esophageal perforation. Studies have shown that pulsed low-dose rate radiotherapy (PLDR) induces a hypersensitivity effect on tumor tissue and a hyper-repair effect on normal tissue, which can simultaneously reduce damage on the normal tissue and increase the therapeutic effect on the tumor. The objective of this study is to explore whether PLDR can reduce rate of esophageal perforation and improve efficacy in patients with recurrent esophageal squamous cell carcinoma (ESCC) after radiotherapy. This study is a prospective, multi-center, open, single-arm clinical trial designed to enroll 27 patients with locally recurrent ESCC after radiotherapy with or without chemotherapy. Re-irradiation will be performed using intensity modulated radiation therapy in 50 Gy/25 fractions. The strategy of PLDR includes dividing 2 Gy into 10 fractions, and administering each irradiating dose of 20 cGy at an interval of 3 minutes before the next low-dose irradiation. The actual dose rate of administration each time will be 16.67 cGy /minute. The primary endpoint in this study is the rate of esophageal perforation. The secondary endpoints are the objective remission rate, the palliative effect on quality of life and pain, and the time of disease progression. The observation time is 2 years after the end of the study. Clinical trial number: ChiCTR1900020609.