Wearable technology to inform the prediction and diagnosis of cardiorespiratory events: a scoping review.
The need for health systems that allow for continuous monitoring and early adverse event detection in individuals outside of the acute care setting has been highlighted by the global rise in chronic cardiorespiratory diseases and the recent COVID-19 pandemic. Currently, it is unclear what type of evidence exists concerning the use of physiological data collected from commercially available wrist and textile wearables to assist in clinical decision making. The aim of this review was therefore to systematically map and summarize the scientific literature surrounding the use of these wearables in clinical decision making as well as identify knowledge gaps to inform further research. Six electronic bibliographic databases were systematically searched (Ovid MEDLINE, EMBASE, CINAHL, PubMed, Scopus, and SportsDiscus). Publications from database inception to May 6, 2020 were reviewed for inclusion. Non-indexed literature relevant to this review was also searched systematically. Results were then collated, summarized and reported. A total of 107 citations were retrieved and assessed for eligibility with 31 citations included in the final analysis. A review of the 31 papers revealed three major study designs which included (1) observational studies (n = 19), (2) case control series and reports (n = 8), and (3) reviews (n = 2). All papers examined the use of wearable monitoring devices for clinical decisions in the cardiovascular domain, with cardiac arrhythmias being the most studied. When compared to electrocardiogram (ECG) the performance of the wearables in facilitating clinical decisions varied depending upon the type of wearable, user's activity levels and setting in which they were employed. Observational studies collecting data in the inpatient and outpatient settings were equally represented. Eight case control series and reports were identified which reported on the use of wrist wearables in patients presenting to an emergency department or clinic to aid in the clinical diagnosis of a cardiovascular event. Two narrative reviews were identified which examined the impact of wearable devices in monitoring cardiovascular disease as well as potential challenges they may pose in the future. To date, studies employing wearables to facilitate clinical decisions have largely focused upon the cardiovascular domain. Despite the ability of some wearables to collect physiological data accurately, there remains a need for a specialist physician to retrospectively review the raw data to make a definitive diagnosis. Analysis of the results has also highlighted gaps in the literature such as the absence of studies employing wearables to facilitate clinical decisions in the respiratory domain. The disproportionate study of wearables in atrial fibrillation detection in comparison to other cardiac arrhythmias and conditions, as well as the lack of diversity in the sample populations used prevents the generalizability of results.


Natriuretic peptide-guided therapy in chronic heart failure: a meta-analysis of 2,686 patients in 12 randomized trials.
The role of cardiac natriuretic peptides in the management of patients with chronic heart failure (HF) remains uncertain. The purpose of this study was to evaluate whether natriuretic peptide-guided therapy, compared to clinically-guided therapy, improves mortality and hospitalization rate in patients with chronic HF. MEDLINE, Cochrane, ISI Web of Science and SCOPUS databases were searched for articles reporting natriuretic peptide-guided therapy in HF until August 2012. All randomized trials reporting clinical end-points (all-cause mortality and/or HF-related hospitalization and/or all-cause hospitalization) were included. Meta-analysis was performed to assess the influence of treatment on outcomes. Sensitivity analysis was performed to test the influence of potential effect modifiers and of each trial included in meta-analysis on results. Twelve trials enrolling 2,686 participants were included. Natriuretic peptide-guided therapy (either B-type natriuretic peptide [BNP]- or N-terminal pro-B-type natriuretic peptide [NT-proBNP]-guided therapy) significantly reduced all-cause mortality (Odds Ratio [OR]:0.738; 95% Confidence Interval [CI]:0.596 to 0.913; p = 0.005) and HF-related hospitalization (OR:0.554; CI:0.399 to 0.769; p = 0.000), but not all-cause hospitalization (OR:0.803; CI:0.629 to 1.024; p = 0.077). When separately assessed, NT-proBNP-guided therapy significantly reduced all-cause mortality (OR:0.717; CI:0.563 to 0.914; p = 0.007) and HF-related hospitalization (OR:0.531; CI:0.347 to 0.811; p = 0.003), but not all-cause hospitalization (OR:0.779; CI:0.414 to 1.465; p = 0.438), whereas BNP-guided therapy did not significantly reduce all-cause mortality (OR:0.814; CI:0.518 to 1.279; p = 0.371), HF-related hospitalization (OR:0.599; CI:0.303 to 1.187; p = 0.142) or all-cause hospitalization (OR:0.726; CI:0.509 to 1.035; p = 0.077). [corrected]. Use of cardiac peptides to guide pharmacologic therapy significantly reduces mortality and HF related hospitalization in patients with chronic HF. In particular, NT-proBNP-guided therapy reduced all-cause mortality and HF-related hospitalization but not all-cause hospitalization, whereas BNP-guided therapy did not significantly reduce both mortality and morbidity.


An adaptive socket with auto-adjusting air bladders for interfacing transhumeral prosthesis: A pilot study.
Comfort is a critical aspect in the application of wearable device, such as rehabilitation robots and upper limb prostheses. As a physical interface between human body and prosthetic limb, the socket and its comfort largely contribute to the user's acceptance. Traditional sockets are static, lacking dynamic adjustment mechanism for the contact pressure. To ensure a reliable suspension during daily activities, the socket is usually designed to be tightly attached, with a large stress, on the residual limb, which may introduce considerable discomfort during long-term use. In this article, we present a novel adaptive transhumeral socket, in which we employ four independent bladders contacting with the stump. Not only can these bladders provide a necessary suspension for the device but also form an air cushion (soft body) that helps relieve the pressure concentration between the biological body and physical prosthesis. In real time, this adaptive socket continuously monitors the limb posture, the operating load, and the contacting pressure between the socket and the limb, and then dynamically adjusts the clamping force to ensure a reliable attachment during various daily activities. Since well adapting to the contours of the stump, the bladders can effectively accommodate the volume change of the stump, making a balanced load distribution on load-tolerant areas. Through modeling and numerical analysis, we established a dynamic strategy for estimating the external load and an automatic scheme for adjusting the bladders' air pressure. Finally, a close-loop control was constructed based on the contact pressure measured by our self-developed force sensors. Our preliminary experiments on one normal (i.e. non-amputee) subject verified the effectiveness of the proposed method, showing that the adaptive socket can considerably reduce the socket-limb contact pressure while sustaining a secure suspension on the upper arm.


Streptomyces roietensis sp. nov., an endophytic actinobacterium isolated from the surface-sterilized stem of jasmine rice, Oryza sativa KDML 105.
An endophytic actinobacterium, strain WES2T, was isolated from the stem of a jasmine rice plant collected from a paddy field in Thung Gura Rong Hai, Roi Et province, Thailand. As a result of a polyphasic study, this strain was identified as representing a novel member of the genus Streptomyces. This strain was a Gram-stain-positive, aerobic actinobacterium with well-developed substrate mycelia and forming chains of looped spores. The closest phylogenetic relations, which shared the highest 16S rRNA gene sequence similarity, were Streptomyces nogalater JCM 4799T and Streptomyces lavenduligriseus NRRL-ISP 5487T at 99.1 and 99.0 %, respectively. Chemotaxonomic data, including major fatty acids, cell wall components and major menaquinones, confirmed the affiliation of WES2T to the genus Streptomyces. The data from the phylogenetic analysis, including physiological and biochemical studies and DNA-DNA hybridization, revealed the genotypic and phenotypic differentiation of WES2T from the most closely related species with validly published names. The name proposed for the novel species is Streptomycesroietensis sp. nov. The type strain is WES2T (=DSM 101729=NRRL B-65344).


Alcohol abuse disorders among U.S. service members with mild traumatic brain injury.
Traumatic brain injury (TBI) has emerged as a preeminent injury in Iraq and Afghanistan. The relationship between TBI and post-injury alcohol use in military personnel has not been clearly defined. The aim of this study was to examine the prevalence of alcohol abuse disorders among combat-injured service members with mild TBI (MTBI). Male U.S. service members with combat injuries were identified from the Expeditionary Medical Encounter Database (n = 3,123). Diagnoses of alcohol abuse disorders were collected from the standard inpatient and ambulatory data records. Overall, a slightly higher proportion of service members with MTBI were diagnosed with an alcohol abuse disorder compared to those with other injury (6.1% vs. 4.9%). In a multivariate analysis, however, it was found that MTBI was not associated with higher levels of alcohol abuse (odds ratio, 1.24; 95% confidence interval, 0.90, 1.70). To better define the consequences of MTBI, future research should include other alcohol dependency measures along with comorbid mental health disorders.


Centella asiatica increases hippocampal synaptic density and improves memory and executive function in aged mice.
Centella asiatica is a plant used for centuries to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) attenuates age-related spatial memory deficits in mice and improves neuronal health. Yet the effect of CAW on other cognitive domains remains unexplored as does its mechanism of improving age-related cognitive impairment. This study investigates the effects of CAW on a variety of cognitive tasks as well as on synaptic density and mitochondrial and antioxidant pathways. Twenty-month-old CB6F1 mice were treated with CAW (2 mg/ml) in their drinking water for 2 weeks prior to behavioral testing. Learning, memory, and executive function were assessed using the novel object recognition task (NORT), object location memory task (OLM), and odor discrimination reversal learning (ODRL) test. Tissue was collected for Golgi analysis of spine density as well as assessment of mitochondrial, antioxidant, and synaptic proteins. CAW improved performance in all behavioral tests suggesting effects on hippocampal and cortical dependent memory as well as on prefrontal cortex mediated executive function. There was also an increase in synaptic density in the treated animals, which was accompanied by increased expression of the antioxidant response gene NRF2 as well as the mitochondrial marker porin. These data show that CAW can increase synaptic density as well as antioxidant and mitochondrial proteins and improve multiple facets of age-related cognitive impairment. Because mitochondrial dysfunction and oxidative stress also accompany cognitive impairment in many pathological conditions this suggests a broad therapeutic utility of CAW.


The mouse RACK1 gene is regulated by nuclear factor-kappa B and contributes to cell survival.
Receptor for activated C kinase 1 (RACK1) is a multifunctional, WD motif-containing protein important in regulating several cell surface receptors and intracellular protein kinases. To better understand its function, we cloned the mouse RACK1 gene and found it contains eight exons and seven introns, and maps to mouse chromosome 11B1.2-1.3. Promoter analysis identified NF-kappaB as an important transcription factor for promoter activity. In PC-12 cells, nerve growth factor (NGF), which activates nuclear factor-kappaB (NF-kappaB), maintained RACK1 levels and promoted cell survival in serum-free medium. Inhibitors of NF-kappaB activation blocked NGF-stimulated survival and RACK1 expression, whereas transgenic expression of RACK1 promoted survival in cells deprived of serum and NGF. Thus, RACK1 gene expression is induced by NF-kappaB and RACK1 contributes to NF-kappaB-mediated cell survival.


Racial Disparities in the Presentation and Treatment of Colorectal Cancer: A Statewide Cross-sectional Study.
Non-Hispanic blacks (NHB) and Hispanics often present with advanced colorectal cancer (CRC). The aim of the study was to characterize CRC differences among Hispanics, NHB, and non-Hispanic whites (NHW). A cross-sectional analysis and logistic regression of 2009 Florida Agency for Healthcare Administration Hospital Admission Database data for CRC using the International Classification of Diseases, 9th Revision, Clinical Modification codes was performed. Outcomes included CRC location, frequency of metastasis and colectomy rates. Each minority group was compared with NHW. A total of 34,577 patients were NHW, 5190 were NHB, and 5033 were Hispanic. NHB had more proximal CRC [odds ratio (OR), 1.17; 95% confidence interval (CI), 1.09-1.25; P<0.0001]; Hispanics had more distal CRC (OR, 0.90; 95% CI, 0.83-0.96; P=0.0024). Hispanics had increased metastases (OR, 1.11; 95% CI, 1.02-1.22; P=0.04). NHB and Hispanics underwent fewer colectomies [(OR, 0.93; 95% CI, 0.86-0.99; P=0.03) and (OR, 0.9; 95% CI, 0.84-0.97; P=0.001), respectively]. Disparities in CRC metastases and colectomy rates exist among these racial groups in Florida. This work should serve as a foundation to study potential causes and to design culture-specific interventions.


Expression of syntaxins in rat kidney.
Previously, we demonstrated that a putative vesicle-targeting protein, syntaxin-4, is expressed in renal collecting duct principal cells and is localized to the apical plasma membrane, suggesting a role in targeting aquaporin-2-containing vesicles to the apical plasma membrane. To investigate whether other syntaxin isoforms are present in the renal collecting duct, we determined the intrarenal localization of syntaxin-2 and -3. Reverse transcription-polymerase chain reaction (RT-PCR) experiments using total RNA extracted from kidney and various organs revealed that both syntaxin-2 and -3 are expressed in kidney cortex and medulla. RT-PCR experiments using microdissected tubules and vascular structures from the kidney revealed that syntaxin-3 mRNA, but not syntaxin-2, is expressed in collecting duct cells. Syntaxin-3 mRNA was also relatively abundant in the thick ascending limb of Henle's loop and in vasa recta. Syntaxin-2 mRNA was found chiefly in glomeruli. To investigate the localization of syntaxin-3 protein, a peptide-derived polyclonal antibody was raised in rabbits. In immunoblotting experiments, this antibody labeled a 37-kDa protein in inner medulla that was most abundant in plasma membrane-enriched subcellular fractions. Immunoperoxidase labeling of thin cryosections combined with immunogold electron microscopy showed that, in contrast to the labeling seen for syntaxin-4, syntaxin-3 labeling in medullary collecting duct was predominantly in the basolateral plasma membrane of intercalated cells. These results suggest the possibility that syntaxin-3 may be involved in selective targeting of acid-base transporters and/or in basolateral membrane remodeling in response to systemic acid-base perturbations.


Calcium's role in mechanotransduction during muscle development.
Mechanotransduction is a process where cells sense their surroundings and convert the physical forces in their environment into an appropriate response. Calcium plays a crucial role in the translation of such forces to biochemical signals that control various biological processes fundamental in muscle development. The mechanical stimulation of muscle cells may for example result from stretch, electric and magnetic stimulation, shear stress, and altered gravity exposure. The response, mainly involving changes in intracellular calcium concentration then leads to a cascade of events by the activation of downstream signaling pathways. The key calcium-dependent pathways described here include the nuclear factor of activated T cells (NFAT) and mitogen-activated protein kinase (MAPK) activation. The subsequent effects in cellular homeostasis consist of cytoskeletal remodeling, cell cycle progression, growth, differentiation, and apoptosis, all necessary for healthy muscle development, repair, and regeneration. A deregulation from the normal process due to disuse, trauma, or disease can result in a clinical condition such as muscle atrophy, which entails a significant loss of muscle mass. In order to develop therapies against such diseased states, we need to better understand the relevance of calcium signaling and the downstream responses to mechanical forces in skeletal muscle. The purpose of this review is to discuss in detail how diverse mechanical stimuli cause changes in calcium homeostasis by affecting membrane channels and the intracellular stores, which in turn regulate multiple pathways that impart these effects and control the fate of muscle tissue.


Predictive modeling of cardiovascular complications in incident hemodialysis patients.
The administration of hemodialysis (HD) treatment leads to the continuous collection of a vast quantity of medical data. Many variables related to the patient health status, to the treatment, and to dialyzer settings can be recorded and stored at each treatment session. In this study a dataset of 42 variables and 1526 patients extracted from the Fresenius Medical Care database EuCliD was used to develop and apply a random forest predictive model for the prediction of cardiovascular events in the first year of HD treatment. A ridge-lasso logistic regression algorithm was then applied to the subset of variables mostly involved in the prediction model to get insights in the mechanisms underlying the incidence of cardiovascular complications in this high risk population of patients.


Uncovering the morphological differences between SARS-CoV-2 and SARS-CoV based on transmission electron microscopy images.
Comprehending the morphological disparities between SARS-CoV-2 and SARS-CoV viruses can shed light on the underlying mechanisms of infection and facilitate the development of effective diagnostic tools and treatments. Hence, this study aimed to conduct a comprehensive analysis and comparative assessment of the morphology of SARS-CoV-2 and SARS-CoV using transmission electron microscopy (TEM) images. The dataset encompassed 519 isolated SARS-CoV-2 images obtained from patients in Italy (INMI) and 248 isolated SARS-CoV images from patients in Germany (Frankfurt). In this paper, we employed TEM images to scrutinize morphological features, and the outcomes were contrasted with those of SARS-CoV viruses. The findings reveal disparities in the characteristics of SARS-CoV-2 and SARS-CoV, such as envelope protein (E) 98.6 and 102.2 nm, length of spike protein (S) 10.11 and 9.50 nm, roundness 0.86 and 0.88, circularity 0.78 and 0.76, and area sizes 25145.54 and 38591.35 pixels, respectively. In conclusion, these results will augment the identification of virus subtypes, aid in the study of antiviral medications, and enhance our understanding of disease progression and the virus life cycle. Moreover, these findings have the potential to assist in the development of more accurate epidemiological prediction models for COVID-19, leading to better outbreak management and saving lives.


Inhibition of Endothelin system during the postnatal nephrogenic period in the rat. Its relationship with hypertension and renal disease in adulthood.
The aim of this work was to study the effect of a high sodium (HS) diet on blood pressure and renal function in male adult rats that have been treated with a dual Endothelin receptor antagonist (ERA) during their early postnatal period (day 1 to 20 of life). Male Sprague-Dawley rats were divided in four groups: CNS: control rats with normosodic diet; ERANS: ERA-treated rats with normosodic diet; CHS: control rats with high sodium diet; ERAHS: ERA-treated rats with HS diet. Systolic blood pressure (SBP) was recorded before and after the diet and 24-hour metabolic cage studies were performed. AQP2 and α-ENac expressions were measured by western blot and real time PCR in the renal medulla. Vasopressin (AVP) pathway was evaluated by measuring V2 receptor and adenylyl cyclase 6 (AC6) expression and cAMP production in the renal medulla. Pre-pro ET-1mRNA was also evaluated in the renal medulla. Only rats that had been treated with an ERA during their postnatal period increased their SBP after consumption of a HS diet, showing an impaired capacity to excrete sodium and water, i.e. developing salt sensitivity. This salt sensitivity would be mediated by an increase in renomedullary expression and activity of AQP2 and α-ENaC as a consequence of increased AC6 expression and cAMP production and/or a decreased ET-1 production in the renal medulla. The knowledge of the molecular mechanisms underlying the perinatal programming of salt sensitive hypertension will allow the development of reprogramming strategies in order to avoid this pathology.


Isolation and regional localization of DNA segments revealing polymorphic loci from human chromosome 13.
A recombinant DNA library enriched for portions of human chromosome 13 has been constructed from a hamster-human somatic cell hybrid that contained human chromosomes 13, 12, and 6p. A total of 733 phages were identified that contain human DNA inserts, and 46 single-copy subfragments have been derived and used as probes on Southern transfers of genomic DNA isolated from unrelated individuals. From this set, nine fragments revealing polymorphic loci (RFLP) in Msp I- or Taq I-digested DNA have been identified, of which three are polymorphic with both enzymes. Six of these probes have been shown to segregate concordantly with human chromosome 13 in a somatic cell hybrid mapping panel, and the RFLPs at these loci have been shown to behave as codominant Mendelian alleles. Additionally, hybridization to DNA isolated from cells containing various deletions of chromosome 13 has allowed regional localization. This recombinant DNA library will be useful in the study of retinoblastoma as well as in the study of the mechanisms responsible for abnormalities of this autosome.


Assessment of leukotriene B4 synthesis in human lymphocytes by using high performance liquid chromatography and radioimmunoassay methods.
Leukotrienes (LT), mainly LTB4, have been shown recently to affect several functions of human lymphocytes in vitro, and they are regarded as putative modulators of the immune response. Although it is recognized that human neutrophils, eosinophils, monocyte-macrophages, and mast cells can generate LTs, the synthesis of 5-lipoxygenase products by lymphocytes is still the subject of a controversy. Human peripheral blood mononuclear leukocytes, nylon wool-purified lymphocytes, CD4+, CD4- T cells, large granular lymphocytes, and various fractions of pure lymphocyte preparations obtained by counter flow centrifugal elutriation were stimulated for 10 min to 24 hr with ionophore A23187, phytohemagglutinin, concanavalin A, or lipopolysaccharide with or without exogenous arachidonic acid (AA); supernatants were analyzed by reverse-phase high performance liquid chromatography (HPLC) coupled with radioimmunoassay (RIA) methods for the presence of LTB4. Pure human lymphocyte preparations, which were shown to be free of monocytes, did not release any detectable amount of LTB4. Increasing percentage of contaminating monocytes was clearly paralleled by increasing amounts of LTB4. Murine thymocytes, interleukin 2-dependent CTLL2 cytotoxic lymphocytes, EL4 thymoma cells, and human Jurkatt cells were also found to be unable to generate detectable amounts of LTB4 after stimulation with ionophore A23187, phytohemagglutinin, phorbol myristate acetate, recombinant interleukin 1, or interleukin 2 with or without exogenous AA. The addition of increasing numbers of adherence-purified monocytes to Jurkatt cells was followed by increased synthesis of LTB4. In conclusion, the present study indicates that the synthesis of LTB4 by pure human lymphocyte preparations or some human and animal lymphoid cell lines is not detectable by combined HPLC-RIA methods in any of the conditions used.


Intestinal transport of fructose and glycine in Ophiocephalus punctatus.
The regional variations in the absorption of fructose and glycine have been studied in the intestine and pyloric caeca of the fish, Ophiocephalus punctatus in vivo, by preparing intestinal sacs. Diffusion of amino acids out of the intracellular compartment of the intestine was observed in all the portions of the intestine. The pyloric caeca showed maximum transport of fructose. Absorption of fructose was slightly more in the posterior intestine than in the anterior intestinal sac. Maximum transport of glycine took place in the anterior intestinal sac. Pyloric caeca adsorbed more glycine than did the posterior sac. For both nutrients, the rate of uptake did not differ significantly in the upper and the lower portion of the intestine. In all the portions, the transport of fructose was more rapid than that of glycine. The experiments revealed that though the nutrients are absorbed in the entire length of the intestine, the quantity absorbed varies from one portion to another and is dependent on the nature of the compound absorbed.


High-Reliability Perovskite Quantum Dots Using Atomic Layer Deposition Passivation for Novel Photonic Applications.
In this study, we propose highly stable perovskite quantum dots (PQDs) coated with Al2O3 using atomic layer deposition (ALD) passivation technology. This passivation layer effectively protects the QDs from moisture infiltration and oxidation as well as from high temperatures and any changes in the material characteristics. They exhibit excellent wavelength stability and reliability in terms of current variation tests, long-term light aging tests, and temperature/humidity tests (60°/90%). A white-light system has been fabricated by integrating a micro-LED and red phosphor exhibiting a high data transmission rate of 1 Gbit/s. These results suggest that PeQDs treated with ALD passivation protection offer promising prospects in full-color micro-displays and high-speed visible-light communication (VLC) applications.


[The clinico-epidemiological and laboratory characteristics of the early period of Lyme borreliosis in Kirov Province].
Tick borreliosis is widespread in the Kirov Province of Russia due to its specific climatic and geographical conditions. Early tick borreliosis was studied in 191 patients in the city of Kirov in 1995-1996. The diagnosis was verified by the epidemiological history, clinical symptoms (chronic erythema migrans), and/or positive serological assays. Tick erythema migrans was detected in 165 (86%) patients. Specific antibodies to Borrelia afcelii antigen were revealed in 128 (67%) patients. The serological tests were false-negative in early infection or just after initiation of treatment. Only 84 (44%) patients with borrelial erythema migrans had specific antibodies to B. afcelii antigen. Mixed tick infection was detected in 6 (3%) patients who showed antibodies to B. afcelii antigen and to tick encephalitis virus. All the patients benefited from wide spectrum antibiotics just within the first days of the disease.


Potential alterations in gene expression associated with carcinogen exposure in Mya arenaria.
Gonadal cancers in soft-shell clams (Mya arenaria) have been found at high prevalences (20-40%) in populations in eastern Maine. The aetiology of these tumours is unknown. We hypothesized that gene expression would be altered in gonadal tumours and that examination of gene expression patterns would provide some information as to the mechanism of tumour development. To investigate this hypothesis, we initiated a broad search for differentially expressed genes using differential display polymerase chain reaction (dd-PCR) to compare RNA from tumour and normal gonadal tissue. We identified two classes of genes whose expression may be altered in the gonadal tumours: genes involved in biosynthetic processes and genes with possible roles in signal transduction. We also investigated the hypothesis that environmental contaminants, such as tetrachlorodibenzo-p-dioxin (TCDD), may play a role in the development of these tumours. To investigate this hypothesis, we performed a short-term exposure of M. arenaria to [(3)H]TCDD. Tissues were sampled up to 2 weeks after a 24-h exposure to 10 pptr or 2000 pptr of [(3)H]TCDD in the water. Using dd-PCR, we identified potential alterations in expression of genes associated with cell proliferation: heparan sulphate proteoglycan, E3 ubiquitinating enzyme and p68 RNAhelicase/initiation factor eIEF-4A. There were no observable histopathological alterations in gonadal or gill tissue from exposed animals. These results suggest possible early changes in gene expression indicative of environmental exposures.


Expression of FlHMA3, a P1B2-ATPase from Festulolium loliaceum, correlates with response to cadmium stress.
Heavy metal ATPase 3 (HMA3), a P1B2-ATPase, is a key tonoplast transporter involved in mediating the vacuolar sequestration of cadmium (Cd) to detoxify the intake of this element by plants. HMA3 expression in response to Cd stress has not been previously examined in the grass hybrid species Festulolium loliaceum (Huds.) P. Fourn. In this study, FlHMA3 isolated from F. loliaceum was found to comprise 833 amino acid residues with 77% homology to the rice OsHMA3. Transient expression of FlHMA3 fused to enhanced green fluorescent protein in Arabidopsis protoplasts suggested its localization to vacuolar membranes. Quantitative real-time RT-PCR analysis of F. loliaceum revealed that FlHMA3 is expressed predominantly within roots and up-regulated by excess Cd. Over the 168 h treatment, Cd content of F. loliaceum roots was significantly higher than that of shoots, regardless of external CdCl2 concentrations. A significant positive correlation was found between FlHMA3 expression and Cd accumulation in roots of F. loliaceum seedlings subjected to 10-100 mg L-1 CdCl2 for 168 h or, in a separate experiment, to 25 or 100 mg L-1 CdCl2 for the same duration. These findings provide evidence that FlHMA3 encodes a vacuolar P1B2-ATPase that may play an important role in Cd2+ sequestration into root cell vacuoles, thereby limiting the entry of Cd2+ into the cytoplasm and reducing Cd2+ toxicity.


Amoeboid Microglial Cells and not Astrocytes Synthesize TNF-alpha in Swiss Mouse Brain Cell Cultures.
The role of tumour necrosis factor (TNF-alpha) in brain physiology and pathology has been the focus of several studies. However, the source of this lymphokine in the central nervous system and the regulation of its synthesis is still poorly understood. We have therefore used purified astrocytes and brain macrophages in culture to compare the abilities of these two cell types to synthesize TNF-alpha and its mRNA. We find that, in the Swiss mouse, no significant TNF activity or TNF-alpha mRNA are produced by astrocytes, even following activation with lipopolysaccharides (LPS). On the other hand, purified microglial cells express a cytotoxic activity able to kill TNF-sensitive LM cells. Part of this activity is released into the culture medium and part remains bound to the membrane after mild paraformaldehyde treatment, demonstrating the existence in the culture of the soluble and membrane-bound forms of TNF activity. The fact that amoeboid microglial cells, and not astrocytes, are the actual source of TNF in brain cultures was further demonstrated by Northern blot analysis and in situ hybridization using a TNF-alpha specific oligonucleotide probe. The definition of the cell type which, in the CNS, is responsible for TNF synthesis will allow the regulation of this lymphokine to be analysed and opens the way for a better understanding of the interactions between amoeboid microglial cells and the other cell types which make up the nervous system.


Sensitivity Enhanced Vital Sign Detection Based on Antenna Reflection Coefficient Variation.
This paper presents a vital sign detection sensor based on reflection coefficient variance from an antenna used in wireless communication devices. The near-field effect is estimated by performing 3D full-wave simulations using a dipole antenna and the magnitude variation of the reflection coefficient induced by human thorax movement due to heart and lungs is observed. The results support the possibility of vital sign detection based on the magnitude variation of the reflection coefficient from an antenna, which can be explained as a narrowband modulation scheme. In particular, a sensitivity enhancement method is proposed and analyzed, and experiments are carried out for heartbeat detection using a dipole antenna with the proposed system. Experimental results are compared between the direct detection and sensitivity enhancement detection schemes. FM signal is also applied to confirm that the proposed sensor works properly in conjunction with an existing communication system. The proposed cardiopulmonary detection sensor is implemented with off-the-shelf components at 2.4 GHz and excellent performance is obtained.


Superstripes and the excitation spectrum of a spin-orbit-coupled Bose-Einstein condensate.
Using Bogoliubov theory we calculate the excitation spectrum of a spinor Bose-Einstein condensed gas with an equal Rashba and Dresselhaus spin-orbit coupling in the stripe phase. The emergence of a double gapless band structure is pointed out as a key signature of Bose-Einstein condensation and of the spontaneous breaking of translational invariance symmetry. In the long wavelength limit the lower and upper branches exhibit, respectively, a clear spin and density nature. For wave vectors close to the first Brillouin zone, the lower branch acquires an important density character responsible for the divergent behavior of the structure factor and of the static response function, reflecting the occurrence of crystalline order. The sound velocities are calculated as functions of the Raman coupling for excitations propagating orthogonal and parallel to the stripes. Our predictions provide new perspectives for the identification of supersolid phenomena in ultracold atomic gases.


Hypothalamic obesity: multiple routes mediated by loss of function in medial cell groups.
Cell groups of the medial hypothalamus are key to the regulation of energy balance. Functional disruption by colchicine injected in the hypothalamic arcuate (ARC), paraventricular (PVN), and ventromedial (VMN) cell groups produced increased food intake and obesity; disruption of the dorsomedial nuclei (DMN) produced decreased food intake. Colchicine in ARC or PVN increased food intake during both light and dark periods and increased cumulative food intake. By contrast, colchicine in VMN increased food intake only during the light, and cumulative food intake was not increased. Both leptin and insulin were elevated in the obese rats. Compared with sham, the slope of regression of leptin on insulin was increased by disruption of PVN and DMN but was not altered by disruption of VMN. ARC disruption abolished the relationship between leptin and insulin. Colchicine injected in the DMN did not cause obesity but altered feeding and the normal relationship between leptin, fat, and insulin, suggesting that blockade of signals, for example, from the lateral hypothalamus to DMN may disinhibit the normal medial hypothalamic drive to decrease energy stores. Changes in caloric efficiency with time after colchicine injections suggest that rats with both ARC and PVN disruption respond to signals of obesity, whereas rats with VMN disruption do not. These studies distinguish among functions in the four medial hypothalamic nuclei and suggest that interactions among them normally serve to regulate energy balance through alterations in food acquisition and storage.


[Sucking effect of diaphragm and its significance in drainage of abdominal cavity during hepatic surgery].
Investigation of the value of the sucking effect of the diaphragm in 44 patients was carried out. The first group consisted of 28 patients who have not undergone hepatic resection. The second group included patients after hepatic resections of various volume in local pathology. The balloon method in modification of this clinic was used for measurement of the value of the sucking effect. In patients of the first group the value of sucking effect was almost two times more under the right cupula of the diaphragm (130.33 + 4.78 mm of water column) in comparison with the left infradiaphragmatic space. It is responsible for presence of the slot between the right half of the liver and the diaphragm, which aggravates the sucking effect. In the second group of patients the value of the sucking effect under the right diaphragmatic cupula was practically the same as in patients of the first group. After right-sided hemihepatectomy the value of the sucking effect under right cupula of the diaphragm has significantly diminished. After resection of the right lobe of the liver as well as after left-sided hemihepatectomy, or without them, the value of sucking effect under left cupula of the diaphragm did not significantly differ. The investigations showed that vacuum-aspiration with vacuum of not less than 150 mm water column should be used for effective drainage of infradiaphragmatic space.


Melatonin ameliorates nonalcoholic fatty liver induced by high-fat diet in rats.
Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized condition that may progress to end-stage liver disease, which ranges from simple steatosis to steatohepatitis, advanced fibrosis, and cirrhosis. Oxidative stress and lipid peroxidation are key pathophysiological mechanisms in NAFLD. We investigate the preventive effects of intraperitoneal administration of melatonin (2.5, 5, 10 mg/kg, daily, respectively) in NAFLD rats induced by high-fat diets for 12 wk. Liver damage was evaluated by serological analysis, serum and hepatic lipid assay as well as hematoxylin-eosin staining in liver sections. Oxidative stress and lipid peroxidation were assessed by measuring malondialdehyde (MDA) levels and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in liver. The results showed that high-fat diet induced oxidative stress with extensive liver steatosis in rats. Melatonin (5 or 10 mg/kg) was effective in reducing hepatic steatosis and inflammation with lowering serum alanine aminotransferase, aspartate aminotransferase, and levels liver total cholesterol and triglycerides in high-fat diet rats. Moreover, melatonin (2.5, 5, 10 mg/kg) increased SOD and GSH-Px activities and the 10 mg/kg dose of melatonin reduced MDA levels in liver. This study shows that melatonin exerts protective effects against fatty liver in rats induced by high-fat diet possibly through its antioxidant actions.


SM22alpha modulates vascular smooth muscle cell phenotype during atherogenesis.
The function of cytoskeletal proteins in the modulation of vascular smooth muscle cell (SMC) phenotype during vascular disease is poorly understood. In this report, we used a combination of gene targeting and Cre/lox-mediated cell fate mapping in mice to investigate the role of SM22alpha, an SMC-specific cytoskeletal protein of unknown function, in the development of atherosclerosis. In hypercholesterolemic ApoE-deficient mice, genetic ablation of SM22alpha resulted in increased atherosclerotic lesion area and a higher proportion of proliferating SMC-derived plaque cells. These results identify a role for SM22alpha in the regulation of SMC phenotype during atherogenesis.


Heterogeneity and hierarchy of hematopoietic stem cells.
Hematopoietic stem cells (HSCs) are a more heterogeneous population than previously thought. Extensive analysis of reconstitution kinetics after transplantation allows a new classifications of HSCs based on lineage balance. Previously unrecognized classes of HSCs, such as myeloid- and lymphoid-biased HSCs, have emerged. However, varying nomenclature has been used to describe these cells, promoting confusion in the field. To establish a common nomenclature, we propose a reclassification of short-, intermediate-, and long-term (ST, IT, and LT) HSCs defined as: ST < 6 months, IT > 6 months, and LT > 12. We observe that myeloid-biased HSCs or α cells overlap with LT-HSCs, whereas lymphoid-biased HSCs or γ/δ cells overlap with ST-HSCs, suggesting that HSC lifespan is linked to cell differentiation. We also suggest that HSC heterogeneity prompts reconsideration of long-term (>4 months) multilineage reconstitution as the gold standard for HSC detection. In this review, we discuss relationships among ST-, IT-, and LT-HSCs relevant to stem cell heterogeneity, hierarchical organization, and differentiation pathways.


Acute A4 Pulley Reconstruction with a First Extensor Compartment Onlay Graft.
The integrity of the flexor tendon pulley apparatus is crucial for unimpaired function of the digits. Although secondary reconstruction is an established procedure in multi-pulley injuries, acute reconstruction of isolated, closed pulley ruptures is a rare occurrence. There are 3 factors influencing the functional outcome of a reconstruction: gapping distance between tendon and bone (E-space), bulkiness of the reconstruction, and stability. As direct repair is rarely done, grafts are used to reinforce the pulley. An advantage of the first extensor retinaculum graft is the synovial coating providing the possibility to be used both as a direct graft with synovial coating or as an onlay graft after removal of the synovia when the native synovial layer is present. A graft from the first dorsal extensor compartment is used as an onlay graft to reinforce the sutured A4 pulley. This technique allows reconstruction of the original dimensions of the pulley system while stability is ensured by anchoring the onlay graft to the bony insertions of the pulley. Anatomical reconstruction can be achieved with this method. The measured E-space remained 0 mm throughout the recovery, while the graft incorporated as a slim reinforcement of the pulley, displaying no bulkiness. The ideal reconstruction should provide synovial coating and sufficient strength with minimal bulk. Early reconstruction using an onlay graft offers these options. The native synovial lining is preserved and the graft is used to reinforce the pulley.


Diverse Chemical Compounds Target Plasmodium falciparum Plasma Membrane Lipid Homeostasis.
Lipid homeostasis is essential to the maintenance of life. We previously reported that disruptions of the parasite Na+ homeostasis via inhibition of PfATP4 resulted in elevated cholesterol within the parasite plasma membrane as assessed by saponin sensitivity. A large number of compounds have been shown to target the parasite Na+ homeostasis. We screened 800 compounds from the Malaria and Pathogen Boxes to identify chemotypes that disrupted the parasite plasma membrane lipid homeostasis. Here, we show that the compounds disrupting parasite Na+ homeostasis also induced saponin sensitivity, an indication of parasite lipid homeostasis disruption. Remarkably, 13 compounds were identified that altered the plasma membrane lipid composition independently of the Na+ homeostasis disruption. Further studies suggest that these compounds target the Plasmodium falciparum Niemann-Pick type C1-related (PfNCR1) protein, which is hypothesized to be involved in maintaining plasma membrane lipid composition. PfNCR1, like PfATP4, appears to be targeted by multiple chemotypes with the potential for drug discovery.


Predicting pathological complete response to neoadjuvant systemic therapy for triple-negative breast cancers using deep learning on multiparametric MRIs.
We trained and validated a deep learning model that can predict the treatment response to neoadjuvant systemic therapy (NAST) for patients with triple negative breast cancer (TNBC). Dynamic contrast enhanced (DCE) MRI and diffusion-weighted imaging (DWI) of the pre-treatment (baseline) and after four cycles (C4) of doxorubicin/cyclophosphamide treatment were used as inputs to the model for prediction of pathologic complete response (pCR). Based on the standard pCR definition that includes disease status in either breast or axilla, the model achieved areas under the receiver operating characteristic curves (AUCs) of 0.96 ± 0.05, 0.78 ± 0.09, 0.88 ± 0.02, and 0.76 ± 0.03, for the training, validation, testing, and prospective testing groups, respectively. For the pCR status of breast only, the retrained model achieved prediction AUCs of 0.97 ± 0.04, 0.82 ± 0.10, 0.86 ± 0.03, and 0.83 ± 0.02, for the training, validation, testing, and prospective testing groups, respectively. Thus, the developed deep learning model is highly promising for predicting the treatment response to NAST of TNBC.Clinical Relevance- Deep learning based on serial and multiparametric MRIs can potentially distinguish TNBC patients with pCR from non-pCR at the early stage of neoadjuvant systemic therapy, potentially enabling more personalized treatment of TNBC patients.


A mouse model of familial oligoasthenoteratozoospermia.
Hrb is an HIV-1 Rev-binding/interacting protein and is a cofactor for Rev export pathway. Hrb interacts with Eps15 homology (EH) domain-containing proteins and is a component of EH network and functions in vesicle sorting. Earlier, we reported that Hrb-deficient male mice are infertile and that they show oligozoospermia. Their sperm lack acrosomes and present globozoospermia. The aim of this study was: (i) to investigate the additional defects in spermatogenesis in Hrb-deficient mice; and (ii) to investigate the effect of acrosomelessness on spermatid differentiation in Hrb-deficient mice. Hrb(-/-) testes, epididymides, spermatids and sperm were analyzed by histology and electron microscopy. Centrioles were analyzed in spermatids and sperm by indirect immunofluorescence technique. Hrb(-/-) male mice exhibited multiple anomalies during meiosis and spermiogenesis that produced developmentally impaired sperm with unshaped or deformed nuclei, loss in cell polarity, intracellular flagellar coiling, multinucleation, supernumerary centrioles and multiflagellation. A total of 13.0% Hrb(-/-) sperm showed macrocephaly. The Hrb(-/-) sperm exhibited variation in head size and shape, disarranged cellular organelles, nuclear and cytoplasmic vacuolization, mitochondrial loss or scattering and no forward motility. These aberrations, in Hrb(-/-) mouse spermatids and sperm, are reminiscent of human familial male infertility with oligoasthenoteratozoospermia syndrome. The Hrb-deficient mouse may be useful in understanding familial oligoasthenoteratozoospermia syndrome.


A Phase 2 Trial of CD24Fc for Prevention of Graft-vs-Host Disease.
Patients who undergo human leukocyte antigen-matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning for hematologic malignancies often develop acute graft-vs-host disease (GVHD) despite standard calcineurin inhibitor-based prophylaxis in combination with methotrexate. This trial evaluated a novel human CD24 fusion protein (CD24Fc/MK-7110) that selectively targets and mitigates inflammation due to damage-associated molecular patterns underlying acute GVHD while preserving protective immunity after myeloablative conditioning. This Phase 2a, multicenter study evaluated the pharmacokinetics, safety, and efficacy of CD24Fc in combination with tacrolimus and methotrexate in preventing acute GVHD in adults undergoing MUD HSCT for hematologic malignancies. A double-blind, placebo-controlled, dose-escalation phase to identify a recommended dose was followed by an open-label expansion phase with matched controls to further evaluate the efficacy and safety of CD24Fc in preventing acute GVHD. A multidose regimen of CD24Fc produced sustained drug exposure with similar safety outcomes when compared with single-dose regimens. Grade 3 to 4 acute GVHD-free survival at Day 180 was 96.2% (95% confidence interval [CI], 75.7-99.4) in the CD24Fc expansion cohort (CD24Fc multidose), compared with 73.6% (95% CI, 63.2-81.4) in matched controls (hazard ratio, 0.1 [95% CI, 0.0-0.6]; log-rank test, P=0.03). No participants in the CD24Fc escalation or expansion phases experienced dose-limiting toxicities (DLTs). The multidose regimen of CD24Fc was well tolerated with no DLTs and was associated with high rates of severe acute GVHD-free survival after myeloablative MUD HSCT. This trial was registered at ClinicalTrials.gov as NCT02663622.


Radiocarpal fusion and midcarpal resection interposition arthroplasty: long-term results in severely destroyed rheumatoid wrists.
The aim of this retrospective study is to evaluate distal resection interposition arthroplasty of the wrist as a tool to restore mobility as well as to restore stability in severely destroyed wrist joints. Thirty-four wrists in 28 rheumatoid arthritis patients were included. The mean follow-up time was 9 years after surgical treatment with clinical and radiological examination. The results were accessed based on a modification of Clayton ́s scoring system as well as a functional questionnaire. 71% patients were satisfied with pain, function and activities of daily life. Better results were reported by patients with a young age, early surgical intervention, a shorter duration of the disease, and lesser involvement of other joints. The results for radiocarpal arthrodesis were comparable to those of synovectomy or arthrodesis of the wrist. The results after total wrist joint arthroplasty varies probably as the result of different patient groups, implant types and evolution of prosthetic designs, and are not comparable with the present study.


Evaluation of the effectiveness and usability of an educational portion size tool, ServARpreg, for pregnant women.
Elevated blood glucose levels in pregnancy increases the risk of adverse pregnancy outcomes. Modifying consumption of carbohydrate-rich foods is important for blood glucose regulation; however, the tools commonly used to assist in guiding portion control are impractical. The present study aimed to evaluate usability of ServARpreg, a mobile phone-based nutrition tool, and its effectiveness with respect to improving carbohydrate and standard serve size knowledge in pregnant women. A baseline survey assessed knowledge of carbohydrates and standard serve sizes of pregnant women. A subset of women living in Newcastle were invited to use ServARpreg, containing pregnancy nutrition information and augmented reality guidance on portion control. A follow-up survey was sent to all women 4 weeks after baseline and women who received ServARpreg also received a process evaluation survey after 10 weeks. Responses were received from 186 pregnant women for the baseline survey, with 97 completing the follow-up (52.2%). Of the 56 women eligible to receive ServARpreg in the sub-study, 47 accepted (83.9%) and, of these, 40 completed the process evaluation survey (85.1%). At follow-up, there was a significant group × time interaction in favour of the ServARpreg group for carbohydrate quantification knowledge (F1,279 = 9.705, P = 0.002). Standard serve size knowledge did not change between groups. In the process evaluation survey, 80% strongly agreed/agreed that ServARpreg made them more aware of how much they ate and 72.5% found ServARpreg easy to use. ServARpreg has shown potential to educate pregnant women about carbohydrate quantification and increase portion size awareness. Further refinement of the tool and evaluation is needed to improve standard serve size knowledge.


Importance of hypovolaemic shock and endoscopic signs in predicting recurrent haemorrhage from peptic ulceration: a prospective evaluation.
The incidence of rebleeding was studied prospectively in 177 patients with acute gastrointestinal haemorrhage from peptic ulceration with reference to the degree of haemodynamic insult on admission and the presence of endoscopic signs of recent haemorrhage on initial endoscopy. Rebleeding occurred in two (2%) of 114 patients without shock, in seven (18%) of 38 with tachycardia (pulse rate greater than 100 beats/min, systolic blood pressure greater than 100 mm Hg), and in 12 (48%) of 25 with shock (systolic blood pressure less than 100 mm Hg). A similar gradient was noted with the presence of endoscopic signs alone. Rebleeding occurred in four (5%) of 79 patients with no endoscopic signs, in none of 40 with black spot only, in 11 (23%) of 48 with a clot, and in five (50%) of 10 with a visible vessel on endoscopy. When the incidence of rebleeding was assessed in shocked patients, however, it was significantly higher in those with important signs (clot or visible vessel), in 11 (79%) out of 14 patients, than in those with no signs, in one (9%) out of 11 (p less than 0.001). These data suggest that the association of shock with important endoscopic signs is a stronger predictor of rebleeding than either shock or important signs alone. More aggressive treatment may be warranted in this small group of patients.


Differential polymer structure tunes mechanism of cellular uptake and transfection routes of poly(β-amino ester) polyplexes in human breast cancer cells.
Successful gene delivery with nonviral particles has several barriers, including cellular uptake, endosomal escape, and nuclear transport. Understanding the mechanisms behind these steps is critical to enhancing the effectiveness of gene delivery. Polyplexes formed with poly(β-amino ester)s (PBAEs) have been shown to effectively transfer DNA to various cell types, but the mechanism of their cellular uptake has not been identified. This is the first study to evaluate the uptake mechanism of PBAE polyplexes and the dependence of cellular uptake on the end group and molecular weight of the polymer. We synthesized three different analogues of PBAEs with the same base polymer poly(1,4-butanediol diacrylate-co-4-amino-1-butanol) (B4S4) but with small changes in the end group or molecular weight. We quantified the uptake and transfection efficiencies of the pDNA polyplexes formulated from these polymers in hard-to-transfect triple negative human breast cancer cells (MDA-MB 231). All polymers formed positively charged (10-17 mV) nanoparticles of ∼200 nm in size. Cellular internalization of all three formulations was inhibited the most (60-90% decrease in cellular uptake) by blocking caveolae-mediated endocytosis. Greater inhibition was shown with polymers that had a 1-(3-aminopropyl)-4-methylpiperazine end group (E7) than the others with a 2-(3-aminopropylamino)-ethanol end group (E6) or higher molecular weight. However, caveolae-mediated endocytosis was generally not as efficient as clathrin-mediated endocytosis in leading to transfection. These findings indicate that PBAE polyplexes can be used to transfect triple negative human breast cancer cells and that small changes to the same base polymer can modulate their cellular uptake and transfection routes.


Epinephrine produces a beta-adrenergic receptor-mediated mechanical hyperalgesia and in vitro sensitization of rat nociceptors.
Hyperalgesic and nociceptor sensitizing effects mediated by the beta-adrenergic receptor were evaluated in the rat. Intradermal injection of epinephrine, the major endogenous ligand for the beta-adrenergic receptor, into the dorsum of the hindpaw of the rat produced a dose-dependent mechanical hyperalgesia, quantified by the Randall-Selitto paw-withdrawal test. Epinephrine-induced hyperalgesia was attenuated significantly by intradermal pretreatment with propranolol, a beta-adrenergic receptor antagonist, but not by phentolamine, an alpha-adrenergic receptor antagonist. Epinephrine-induced hyperalgesia developed rapidly; it was statistically significant by 2 min after injection, reached a maximum effect within 5 min, and lasted 2 h. Injection of a more beta-adrenergic receptor-selective agonist, isoproterenol, also produced dose-dependent hyperalgesia, which was attenuated by propranolol but not phentolamine. Epinephrine-induced hyperalgesia was not affected by indomethacin, an inhibitor of cyclo-oxygenase, or by surgical sympathectomy. It was attenuated significantly by inhibitors of the adenosine 3',5'-cyclic monophosphate signaling pathway (the adenylyl cyclase inhibitor, SQ 22536, and the protein kinase A inhibitors, Rp-adenosine 3',5'-cyclic monophosphate and WIPTIDE), inhibitors of the protein kinase C signaling pathway (chelerythrine and bisindolylmaleimide) and a mu-opioid receptor agonist DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin). Consistent with the hypothesis that epinephrine produces hyperalgesia by a direct action on primary afferent nociceptors, it was found to sensitize small-diameter dorsal root ganglion neurons in culture, i. e., to produce an increase in number of spikes and a decrease in latency to firing during a ramped depolarizing stimulus. These effects were blocked by propranolol. Furthermore epinephrine, like several other direct-acting hyperalgesic agents, caused a potentiation of tetrodotoxin-resistant sodium current, an effect that was abolished by Rp-adenosine 3',5'-cyclic monophosphate and significantly attenuated by bisindolylmaleimide. Isoproterenol also potentiated tetrodotoxin-resistant sodium current. In conclusion, epinephrine produces cutaneous mechanical hyperalgesia and sensitizes cultured dorsal root ganglion neurons in the absence of nerve injury via an action at a beta-adrenergic receptor. These effects of epinephrine are mediated by both the protein kinase A and protein kinase C second-messenger pathways.


An in vitro comparison of the marginal fit of provisional crowns using the virtual tooth preparation workflow against the traditional technique.
This study investigates the effectiveness of an innovative virtual tooth preparation workflow for the fabrication of dental crowns using cone-beam computed tomography (CBCT) and intraoral scanners (IOSs) with conventional workflow using extraoral/laboratory scanners. This in vitro experimental study was conducted in the laboratory of a university in Chennai, India. The dental laboratory and research facilities at the institution were utilized for the fabrication of the temporary crowns and the data acquisition process. Institutional approval was obtained from the university. It was basically a comparison between the virtual prep technique using CBCT and IOS and the conventional digital technique using extra oral scanners (EOS) for temporary crown fabrication. The sample size was estimated using an effect size of 1.5004, assuming a normal distribution, a significance level of 0.05, and a power of 0.95 in G power software. Based on this calculation, an extracted second lower molar was used to fabricate 10 samples in each group. The samples were divided into three groups: the CBCT (Group 1), the IOS (Group 2), and laboratory scanner (Group 3 as control) groups. The vertical marginal gap of all the surfaces of the crown was evaluated using a scanning electron microscope. Data were analyzed using one-way ANOVA using the SPSS software version 26.0, IBM, Armonk, NY, USA. Acceptable marginal discrepancy values were obtained in all three groups. There was no significant difference in the marginal discrepancy recorded (P = 0.113). Virtual tooth preparation using CBCT and IOSs can be used as an alternative to the conventional workflow for provisional crown and bridge fabrication.


Effectiveness of four dynamic treatment strategies in patients with anticitrullinated protein antibody-negative rheumatoid arthritis: a randomised trial.
To determine the most effective treatment strategy among anticitrullinated protein antibodies (ACPA)-negative patients with early rheumatoid arthritis. In the BeSt study, 184 ACPA-negative patients were randomised to: (1) sequential monotherapy, (2) step-up therapy, (3) initial combination including prednisone, (4) initial combination including infliximab. Treatment was targeted at the disease activity score (DAS) ≤2.4. Early response and 10-year outcomes were compared between the four strategy-arms in ACPA-negative patients. ACPA-negative patients achieved more short-term functional improvement from initial combination therapy than when on monotherapy (at month 3, mean Health Assessment Questionnaire (HAQ) 0.71 vs 0.98, p=0.006; at month 6, 0.59 vs 0.87, p=0.004). Functional ability over time was comparable between the strategy-arms (p=0.551) with a mean HAQ of 0.6 at year 10 (p=0.580 for comparison across the strategy-arms). 10-year radiographic progression was negligible (median 0.5) and comparable between the 4 strategy-arms (p=0.082). At year 10, remission was achieved by 11/40 (28%), 9/45 (20%), 17/56 (30%) and 17/43 patients (40%) in strategy-arms 1-4, respectively (p=0.434). Over time, similar remission percentages were achieved in all strategy-arms (p=0.815). 18%, 16%, 20% and 21% in strategy-arms 1 to 4 (p=0.742) were in drug-free remission at year 10, with a median duration of 60 months across the arms. Initial combination therapy with methotrexate, sulfasalazine and prednisone, or methotrexate and infliximab, is the most effective treatment strategy for ACPA-negative patients, resulting in earlier functional improvement than when on initial methotrexate monotherapy. After 10 years of targeted treatment, in all strategy-arms favourable clinical outcomes were achieved and radiographic progression was limited. NTR262, NTR265.


Cardiovascular effect of 7.5% sodium chloride-dextran infusion after thermal injury.
Clinical study can help determine the safety and cardiovascular and systemic effects of an early infusion of 7.5% sodium chloride in 6% dextran-70 (hypertonic saline-dextran-70 [HSD]) given as an adjuvant to a standard resuscitation with lactated Ringer (RL) solution following severe thermal injury. Prospective clinical study. Intensive care unit of tertiary referral burn care center. Eighteen patients with thermal injury over more than 35% of the total body surface area (TBSA) (range, 36%-71%) were studied. Eight patients (mean +/- SEM, 48.2% +/- 2% TBSA) received a 4-mL/kg HSD infusion approximately 3.5 hours (range, 1.5-5.0 hours) after thermal injury in addition to routine RL resuscitation. Ten patients (46.0% +/- 6% TBSA) received RL resuscitation alone. Pulmonary artery catheters were employed to monitor cardiac function, while hemodynamic, metabolic, and biochemical measurements were taken for 24 hours. Serum troponin I levels, while detectable in all patients, were significantly lower after HSD compared with RL alone (mean +/- SEM, 0.45 +/- 0.32 vs 1.35 +/- 0.35 microg/L at 8 hours, 0.88 +/- 0.55 vs 2.21 +/- 0.35 microg/L at 12 hours). While cardiac output increased proportionately between 4 and 24 hours in both groups (from 5.79 +/- 0.8 to 9.45 +/- 1.1 L/min [mean +/- SEM] for HSD vs from 5.4 +/- 0.4 to 9.46 +/- 1.22 L/min for RL), filling pressure (central venous pressure and pulmonary capillary wedge pressure) remained low for 12 hours after HSD infusion (P = .048). Total fluid requirements at 8 hours (2.76 +/- 0.7 mL/kg per each 1% TBSA burned [mean +/- SEM] for HSD vs 2.67 +/- 0.24 mL/kg per each 1% TBSA burned for RL) and 24 hours (6.11 +/- 4.4 vs 6.76 +/- 0.75 mL/kg per each 1% TBSA burned) were similar. Blood pressure remained unchanged, and serum sodium levels did not exceed 150 +/- 2 mmol/L (mean +/- SD) in either group. The absence of deleterious hemodynamic or metabolic side effects following HSD infusion in patients with major thermal injury confirms the safety of this resuscitation strategy. Postburn cardiac dysfunction was demonstrated in all burn patients through the use of cardiospecific serum markers and pulmonary artery catheter monitoring. Early administration of HSD after a severe thermal injury may reduce burn-related cardiac dysfunction, but it had no effect on the volume of resuscitation or serum biochemistry values.


A yellow fever-Zika chimeric virus vaccine candidate protects against Zika infection and congenital malformations in mice.
The recent Zika virus (ZIKV) epidemic in the Americas led to an intense search for therapeutics and vaccines. Here we report the engineering of a chimeric virus vaccine candidate (YF-ZIKprM/E) by replacing the antigenic surface glycoproteins and the capsid anchor of YFV-17D with those of a prototypic Asian lineage ZIKV isolate. By intracellular passaging, a variant with adaptive mutations in the E protein was obtained. Unlike YFV-17D, YF-ZIKprM/E replicates poorly in mosquito cells. Also, YF-ZIKprM/E does not cause disease nor mortality in interferon α/β, and γ receptor KO AG129 mice nor following intracranial inoculation of BALB/c pups. A single dose as low as 1 × 102 PFU results, as early as 7 days post vaccination, in seroconversion to neutralizing antibodies and confers full protection in AG129 mice against stringent challenge with a lethal inoculum (105 LD50) of either homologous or heterologous ZIKV strains. Induction of multi-functional CD4+ and CD8+ T cell responses against ZIKV structural and YFV-17D non-structural proteins indicates that cellular immunity may also contribute to protection. Vaccine immunogenicity and protection was confirmed in other mouse strains, including after temporal blockade of interferon-receptors in wild-type mice to facilitate ZIKV replication. Vaccination of wild-type NMRI dams with YF-ZIKprM/E results in complete protection of foetuses against brain infections and malformations following a stringent intraplacental challenge with an epidemic ZIKV strain. The particular characteristic of YF-ZIKprM/E in terms of efficacy and its marked attenuation in mice warrants further exploration as a vaccine candidate.


Heterotetrameric composition of aquaporin-4 water channels.
Aquaporin (AQP) water channel proteins are tetrameric assemblies of individually active approximately 30 kDa subunits. AQP4 is the predominant water channel protein in brain, but immunoblotting of native tissues has previously yielded multiple poorly resolved bands. AQP4 is known to encode two distinct mRNAs with different translation initiating methionines, M1 or M23. Using SDS-PAGE urea gels and immunoblotting with anti-peptide antibodies, four polypeptides were identified in brain and multiple other rat tissues with the following levels of expression: 32 kDa > 34 kDa > 36 kDa > 38 kDa. The 34 and 38 kDa polypeptides react with an antibody specific for the N-terminus of the M1 isoform, and 32 and 36 kDa correspond to the shorter M23 isoform. Immunogold electron microscopic studies with rat cerebellum cryosections demonstrated that the 34 kDa polypeptide colocalizes in perivascular astrocyte endfeet where the 32 kDa polypeptide is abundantly expressed. Velocity sedimentation, cross-linking, and immunoprecipitation analyses of detergent-solubilized rat brain revealed that the 32 and 34 kDa polypeptides reside within heterotetramers. Immunoprecipitation of AQP4 expressed in Xenopus laevis oocytes demonstrated that heterotetramer formation reflects the relative expression levels of the 32 and 34 kDa polypeptides; however, tetramers containing different compositions of the two polypeptides exhibit similar water permeabilities. These studies demonstrate that AQP4 heterotetramers are formed from two overlapping polypeptides and indicate that the 22-amino acid sequence at the N-terminus of the 34 kDa polypeptide does not influence water permeability but may contribute to membrane trafficking or assembly of arrays.


Wise Information Technology of Med: Human Pose Recognition in Elderly Care.
The growing problem of aging has led to a social concern on how to take care of the elderly living alone. Many traditional methods based on visual cameras have been used in elder monitoring. However, these methods are difficult to be applied in daily life, limited by high storage space with the camera, low-speed information processing, sensitivity to lighting, the blind area in vision, and the possibility of revealing privacy. Therefore, wise information technology of the Med System based on the micro-Doppler effect and Ultra Wide Band (UWB) radar for human pose recognition in the elderly living alone is proposed to effectively identify and classify the human poses in static and moving conditions. In recognition processing, an improved PCA-LSTM approach is proposed by combing with the Principal Component Analysis (PCA) and Long Short Term Memory (LSTM) to integrate the micro-Doppler features and time sequence of the human body to classify and recognize the human postures. Moreover, the classification accuracy with different kernel functions in the Support Vector Machine (SVM) is also studied. In the real experiment, there are two healthy men and one woman (22-26 years old) selected to imitate the movements of the elderly and slowly perform five postures (from sitting to standing, from standing to sitting, walking in place, falling and boxing). The experimental results show that the resolution of the entire system for the five actions reaches 99.1% in the case of using Gaussian kernel function, so the proposed method is effective and the Gaussian kernel function is suitable for human pose recognition.


Distributed optical fiber vibration sensor based on spectrum analysis of Polarization-OTDR system.
A fully distributed optical fiber vibration sensor is demonstrated based on spectrum analysis of Polarization-OTDR system. Without performing any data averaging, vibration disturbances up to 5 kHz is successfully demonstrated in a 1km fiber link with 10m spatial resolution. The FFT is performed at each spatial resolution; the relation of the disturbance at each frequency component versus location allows detection of multiple events simultaneously with different and the same frequency components.


PRC1 and Suv39h specify parental asymmetry at constitutive heterochromatin in early mouse embryos.
In eukaryotes, Suv39h H3K9 trimethyltransferases are required for pericentric heterochromatin formation and function. In early mouse preimplantation embryos, however, paternal pericentric heterochromatin lacks Suv39h-mediated H3K9me3 and downstream marks. Here we demonstrate Ezh2-independent targeting of maternally provided polycomb repressive complex 1 (PRC1) components to paternal heterochromatin. In Suv39h2 maternally deficient zygotes, PRC1 also associates with maternal heterochromatin lacking H3K9me3, thereby revealing hierarchy between repressive pathways. In Rnf2 maternally deficient zygotes, the PRC1 complex is disrupted, and levels of pericentric major satellite transcripts are increased at the paternal but not the maternal genome. We conclude that in early embryos, Suv39h-mediated H3K9me3 constitutes the dominant maternal transgenerational signal for pericentric heterochromatin formation. In absence of this signal, PRC1 functions as the default repressive back-up mechanism. Parental epigenetic asymmetry, also observed along cleavage chromosomes, is resolved by the end of the 8-cell stage--concurrent with blastomere polarization--marking the end of the maternal-to-embryonic transition.


Re-birth after coronary bypass graft surgery: a hermeneutic-phenomenological study.
Although coronary artery bypass graft surgery has significant effects on reducing the symptoms of coronary artery disease, there is not enough knowledge and understanding of lived experience of patients after surgery. Understanding lived experience of this group of patients would be helpful for healthcare staff to provide better services to the patients. The aim of this study was to describe with a deeper understanding, the lived experiences of patients after Coronary Artery Bypass Graft Surgery. Using a hermeneutic phenomenological approach and a Van-Manen analysis method, in-depth semi-structured interviews were conducted with eleven participants who had lived experienced of at least six months post - coronary artery bypass graft surgery. Re-birth was the main theme that emerged in the process of data analysis. This theme was derived from four sub-themes including "feels younger", ''vigorous heart'', ''intrepid life'' and ''oriented to be healthy''. Life after a coronary artery bypass graft surgery is often appreciated as a re-birth by persons with these experiences as surgery did not only provide a feeling of wellness, but also added a sensation of youthfulness and improvement in the quality of life for these participants. In addition, they would actively participate in health promotional activities such as; adherence to medication and diet regimes, changes in lifestyle to maintain their health.


Disturbed anal sphincter function following vaginal delivery.
Recently interest in idiopathic (neurogenic) faecal incontinence has swung from denervation of the external anal sphincter to the internal sphincter. To evaluate the effects of vaginal delivery on the internal sphincter. 1372 mothers were studied antenatally and 1202 were accepted into the study. Sphincter pressures were measured antenatally, in the early postnatal period, and six to 10 weeks later in selected patients. 755 of 1202 subjects assessed antenatally were primiparous women and 447 multiparous women. Some 320 previous spontaneous vaginal deliveries (SVD) (mean 59 mm Hg) and 67 previous forceps deliveries (mean 58 mm Hg) had lower resting pressures than 755 primiparous women (mean 66 mm Hg) (p < 0.01). A total of 493 subjects were reassessed postnatally. There were 372 SVDs, 47 vacuum extractions, 20 forceps, and 54 caesarean deliveries. All vaginal deliveries but not caesarean sections dropped their resting anal pressures from antenatal values (p < 0.001). Some 227 first SVDs had a much greater fall than 145 subsequent SVDs. In 162 subjects who had undergone their first vaginal delivery and who were followed up there was some recovery but the resting pressures were still lowered at six to 10 weeks post partum. The first vaginal delivery causes a permanent lowering of resting anal pressures. The possible reasons for this are discussed.


Simultaneous noninvasive determination of regional myocardial perfusion and oxygen content in rabbits: toward direct measurement of myocardial oxygen consumption at MR imaging.
To determine whether myocardial arterial perfusion and oxygen concentration can be quantified simultaneously from the same images by using spin labeling and the blood oxygenation level-dependent (BOLD) effect with fast spin-echo (SE) imaging. A T2-weighted fast SE pulse sequence was written to image isolated, arrested, blood-perfused rabbit hearts (n = 6) at 4.7 T. Perfusion images with intensity in units of milliliters per minute per gram that covered the entire left ventricle with 0.39 x 0.39 x 3.00-mm resolution were obtained in less than 15 minutes with a 32-fold reduction in imaging time from that of a previous study. Estimates of oxygen concentration were made from the same images acquired for calculation of perfusion images. Estimates of regional myocardial oxygen content could be made from the perfusion images; this demonstrated the feasibility of three-dimensional calculation of regional oxygen consumption, which requires concomitant measurement of both oxygen content and flow. Fast SE imaging was shown to be as sensitive to hemoglobin desaturation as standard SE imaging. Perfusion abnormalities and oxygen deficits were easily identified and verified qualitatively with gadopentetate dimeglumine on both perfusion and BOLD images obtained after coronary arterial ligation. T2-weighted fast SE imaging combined with perfusion-sensitive spin labeling can be used to measure myocardial arterial perfusion and oxygen concentration. This provides the groundwork for calculation of regional myocardial oxygen consumption.


To Dialyse or not to Dialyse - Is that the Question? A Psychosocial Perspective on Dilemmas Concerning Dialysis for People with Dementia.
There is increasing recognition that the organisation of health care into specialist areas of practice can be counterproductive for older people with multiple morbidities and that dementia can raise particular challenges in health care. In the context of treatment for chronic kidney disease, these challenges concern complex decisions about the suitability and efficacy of dialysis and other treatments. This article draws on a literature review to present a psychosocial perspective on these decisions. It considers the value of the concept of 'dementia friendliness' for nephrology practice and suggests how this could provide a valuable frame of reference for the multidisciplinary nephrology team to ensure they are best equipped to work with people living with dementia and their carers and to ensure that the individual patient is truly at the centre of their treatment regime.


The use of marine sponge species as a bioindicator to monitor metal pollution in Red Sea, Saudi Arabia.
The existing data on trace elements of benthic sea organisms is scarce. Yet, the pressing issue of environmental contamination has spurred a surge in the use of organisms as biomonitors. In this study, sediment cores were sampled with the sponges, and metal concentrations were determined in both samples using ICP-MS. The mean concentrations of metals in benthic sediments and sponge species analyzed in this study differed significantly (Sediment > Phorbas species > Negombata magnifica > Callyspongia species > Amphimedon chloros). This could be due to the varying capacity of each sponge species to accumulate a particular metal by different means. Negombata magnifica and Phorbas species appear to be indicators, accumulators, or hyper-accumulators of Cu and Mn, while Callyspongia species is an indicator, accumulator, or hyper-accumulator of Cu only due to bioconcentration factor > 1 for the aforementioned metals. Concentrations of Cu and As in sediment were below the Effects Range Median but above the Effects Range Low threshold, hence the need to give more attention to these metals. This research provides a baseline dataset for designing monitoring strategies on this ecosystem and using sponge species for biomonitoring.


Adolescent propensity for depressed mood and help seeking: race and gender differences.
Studies investigating the correlates of adolescent depression and suicidal tendencies have found that the probability of such tendencies vary by race and gender. However, while there exists evidence that most adolescents suffering from the above problems fail to seek (and obtain) help, the role of race and gender in determining the propensity to seek help for depression remains largely unexplored. The study uses data from the 1996 round of Health Behavior in School-Aged Children' (HBSC), USA, which surveys a representative sample of more than 9000 adolescents enrolled in grades 6-10. Respondents are asked if they suffered from persistent depressed moods (lasting two weeks or more) over the past year, and whether they sought help while suffering from depressed mood, and if so, from whom. Questions are also asked about whether the respondent had self-injury ideation or actually attempted self-injury. Demographic and other information on respondents is also provided. The primary aim is to test whether there are significant differences between genders, and between non-Hispanic whites, non-Hispanic blacks, Hispanics and Asians in the likelihood of seeking help, and from whom, when depressed. Gender and race-ethnicity differences in the likelihood of being depressed are also explored to find if they correspond to results in the extant literature. Multinomial logit models are used to estimate the likelihood of being depressed or at self-injury risk, and help-seeking behavior in event of depressed mood. Models are estimated for the full-sample and sub-samples who report depressed mood or are at self-injury risk. In addition to race and gender, all models control for additional demographic characteristics such as age, family structure, and family socio-economic status. Adolescent females are significantly more likely than adolescent males to suffer from depressed mood. However, adolescent males are less likely to ask for help than females (odds ratio: 0.72). All minority groups are more likely to suffer from depressed mood compared to non-Hispanic whites, but blacks are at lower self-injury risk. Blacks and Asians are especially prone not to ask for help, with the problem being particularly acute in case of black males and Asian males. The lower propensity of adolescent males to seek help for depression compared to females are in keeping with previous research. However, predicted values show that the majority of males and females with depressed mood or at self-injury risk do not seek help from anyone. Certain racial groups are also at greater risk for not asking for help for depression. This may have implications regarding racial differences in suicide rates, as well as racial differences in future life outcomes. The study suffers from the drawback that because the survey is confined to those enrolled in school, adolescents who are institutionalized for mental health problems or who have dropped out of school due to problems related to depression are not represented in it. There have been efforts in the USA to educate the population about the problems of adolescent depression. However, the above results suggest that it may be useful to have additional educational efforts targeted at specific population groups, to educate them about the risks associated with depression, help overcome any stigma associated with depression and encourage help-seeking when suffering from depressed mood. A number of directions of future research are suggested. It would be useful to obtain information on the outcomes of help seeking - whether it actually led to obtaining help. It would also be useful to know the probability of an adolescent being diagnosed with depressed mood (perhaps by a primary care physician) even without actively seeking help. Regarding the racial differences, it would be useful to examine the extent to which such differences arise from immigration status, and also to have more extensive information about attitudes, familial expectations, religiosity, community ties, confidence in the medical system and other factors, so as to analyze further why some races are more prone to depression and averse to seeking help for depression than others. Finally, it would be useful to periodically revisit this topic with more contemporary data to see whether recent efforts at awareness raising has increased the odds of help-seeking among adolescents with depressed mood.


Inhibition by (+)-persenone [corrected] A-related compounds of nitric oxide and superoxide generation from inflammatory leukocytes.
We have previously reported that persenone A, isolated from avocado fruit, is an effective inhibitor of both nitric oxide (NO) and superoxide (O2-) generation in cell culture systems. In this study, we have prepared four persenone A-related compounds and examined their inhibition of NO and O2- generation from inflammatory leukocytes. Some structural importance in persenone A to attenuate free radical generation is discussed.


The emerging importance of cortical spreading depression in migraine headache.
Migraine is a disabling neurovascular disorder with a complex pathophysiology. Functional imaging and magneto encephalographic studies strongly suggest that Cortical Spreading Depression (CSD) constitutes the biological basis for the neurologic aura that precedes headache in one fourth of migrainers. It is likely that the aura is the generator of the headache since experimentally, CSD triggers the activation of the trigeminovascular system, possibly through matrix metalloproteases activation which is associated with an increase in vascular permeability. These data may have therapeutic implications: strategies to block trigeminal activation or its downstream consequences are central to treat the acute headache whereas strategies to block events lying upstream of trigeminal activation would be crucial in prophylaxis.


Clinical characteristics and risk factors of fatal patients with COVID-19: a retrospective cohort study in Wuhan, China.
The coronavirus disease 2019 (COVID-19) has caused a global pandemic, resulting in considerable mortality. The risk factors, clinical treatments, especially comprehensive risk models for COVID-19 death are urgently warranted. In this retrospective study, 281 non-survivors and 712 survivors with propensity score matching by age, sex, and comorbidities were enrolled from January 13, 2020 to March 31, 2020. Higher SOFA, qSOFA, APACHE II and SIRS scores, hypoxia, elevated inflammatory cytokines, multi-organ dysfunction, decreased immune cell subsets, and complications were significantly associated with the higher COVID-19 death risk. In addition to traditional predictors for death risk, including APACHE II (AUC = 0.83), SIRS (AUC = 0.75), SOFA (AUC = 0.70) and qSOFA scores (AUC = 0.61), another four prediction models that included immune cells subsets (AUC = 0.90), multiple organ damage biomarkers (AUC = 0.89), complications (AUC = 0.88) and inflammatory-related indexes (AUC = 0.75) were established. Additionally, the predictive accuracy of combining these risk factors (AUC = 0.950) was also significantly higher than that of each risk group alone, which was significant for early clinical management for COVID-19. The potential risk factors could help to predict the clinical prognosis of COVID-19 patients at an early stage. The combined model might be more suitable for the death risk evaluation of COVID-19.


Surgical-orthodontic retreatment of a severe skeletal Class III malocclusion following an orthodontic camouflage.
Class III malocclusions are some of the most difficult occlusal anomalies to be treated. Some patients with this condition may require orthognathic surgery, while others may be treated with dental camouflage. Proper patient assessment and selection remains critical in order to achieve favorable results. This report outlines the case of an 18-year-old male who sought retreatment for a severe skeletal Class III dentofacial deformity after undergoing orthodontic camouflage treatment involving mandibular arch extractions. A treatment plan comprising dental decompensation and orthognathic surgery was implemented in order to achieve optimal facial and occlusal results. After 28 months of treatment, skeletal and dental correction was achieved and facial features were significantly improved. The orthognathic surgery required a 20-mm sagittal maxillomandibular skeletal correction, combined with a 4-mm correction of the midlines and a 2-mm impaction of the maxilla. Dental compensation may be a risky treatment alternative for severe dentoskeletal discrepancies. In these patients, orthodontics combined with orthognathic surgery is the recommended treatment option.


Investor Outlook: Gene Therapy Picking up Steam; At a Crossroads.
The gene therapy field continues to pick up steam with recent successes in a number of different therapeutic indications that highlight the potential for the platform. As the field continues to make progress, a growing data set of long-term safety and efficacy data will continue to define gene therapy's role, determining ultimately how widely it may be used beyond rare, serious diseases with high unmet needs. New technologies often take unanticipated twists and turns as patient exposure accumulates, and gene therapy may be no exception. That said, with many diseases that have no other treatment options beyond gene therapy and that present considerable morbidity and mortality, the field appears poised to withstand some minor and even major bumps in the road should they emerge.


The influence of drop size of cyclopentolate, phenylephrine and tropicamide on pupil dilatation and systemic side effects in infants.
In this prospective study, microdrops (mean drop volume 5.6 microl) and commercially available standard drops (mean drop volume 35.4 microl) of cyclopentolate, phenylephrine and tropicamide's clinical efficacy and systemic side effects were compared. Sixty-one infants requiring diagnostic pupil dilatation were studied for pupillary diameter, systemic blood pressure, heart rate and skin flushing changes related to the instillation of mydriatic drops. Both microdrops and standard drops of the drugs produced significant increase in pupillary diameter compared with the baseline (p<0.01). In cyclopentolate and phenylephrine groups, there was no significant pupillary diameter changes between microdrops and standard drops (p>0.05). Mean blood pressure increased significantly in infants given standard drops. There was no significant change in the group that was given microdrops. In our opinion, reduced volume of mydriatics can prevent possible side effects.


Associations between basal cortisol levels and memory retrieval in healthy young individuals.
Cortisol is known to affect memory processes. On the one hand, stress-induced or pharmacologically induced elevations of cortisol levels enhance memory consolidation. On the other hand, such experimentally induced elevations of cortisol levels have been shown to impair memory retrieval. However, the effects of individual differences in basal cortisol levels on memory processes remain largely unknown. Here we tested whether individual differences in cortisol levels predict picture learning and recall in a large sample. A total of 1225 healthy young women and men viewed two different sets of emotional and neutral pictures on two consecutive days. Both sets were recalled after a short delay (10 min). On Day 2, the pictures seen on Day 1 were additionally recalled, resulting in a long-delay (20 hr) recall condition. Cortisol levels were measured three times on Days 1 and 2 via saliva samples before encoding, between encoding and recall as well as after recall testing. We show that stronger decreases in cortisol levels during retrieval testing were associated with better recall performance of pictures, regardless of emotional valence of the pictures or length of the retention interval (i.e., 10 min vs. 20 hr). In contrast, average cortisol levels during retrieval were not related to picture recall. Remarkably during encoding, individual differences in average cortisol levels as well as changes in cortisol did not predict memory recall. Our results support previous findings indicating that higher cortisol levels during retrieval testing hinders recall of episodic memories and extend this view onto interindividual changes in basal cortisol levels.


Understanding pressure ulcer research and education needs: a comparison of the association for the advancement of wound care pressure ulcer guideline evidence levels and content validity scores.
 Although difficult to quantify due to methodological variations, the worldwide burden of pressure ulcers (PUs) is substantial. Recognizing the importance of providing evidence-based care to help reduce this burden, the North American Wound Care Council societies collaborated to identify PU research and education opportunities using the PU "Guideline of Guidelines" developed and tested by Association for the Advancement of Wound Care Guideline Department (AAWC GD). Volunteer AAWC GD members compiled recommendations from PU guidelines available in 2008, searched the lit- erature for additional research as needed, and developed evidence levels for all recommendations using an established level-of-evidence rating scheme. At the same time, AAWC members and Ostomy Wound Management readers were invited via email to participate in a content validation study of the 368 recommendations, rating items on a scale of 1 (not relevant) to 4 (very relevant and succinct). Items with a content validity index (CVI) >0.75 were considered valid. Recommendations with support from two or more randomized controlled PU trials or two or more cohort studies for diagnostic or predictive validity (A-level evidence) and a CVI >75 were grouped as ready for implementation. Recommendations with content validity but without A-level evidence were determined to be opportunities for research; recommendations that lacked content validity but that had A-level evidence were viewed as opportunities for education. Thirty-two (32) multidisciplinary healthcare professionals participated in the content validation study. Most (93.2%) recommendations were rated as valid. Of the 97 (26%) recommendations with A-level evidence, 90 (24.5% of total) met both strong content validity and strong evidence criteria and were rated as ready for implementation as standard of care. Most recommendations (253, 68.8%) were rated as valid but had B- or C-level evidence, representing opportunities for research. Only seven (1.9%) recommendations had a low CVI but A-level evidence, suggesting a need for education. The results show that most of the guideline recommendations are valid, that the number of PU intervention recommendations with A-level evidence is increasing, but that, in general, the need for research to replace opinion with evidence remains high across the entire spectrum of PU prevention and treatment. Understanding what is known (recommendation: ready to implement), what is not known (research needed), and what clinicians need to know (education needed) is an important step toward reducing the burden of pressure ulcers. difficile are warranted.


Cloning and expression of Clostridium acetobutylicum endoglucanase, cellobiase and amino acid biosynthesis genes in Escherichia coli.
Clostridium acetobutylicum P262 endoglucanase and cellobiase genes, cloned on a 4.9 kb DNA fragment in the recombinant plasmid pHZ100, were expressed from their own promoter in Escherichia coli. Active carboxymethylcellulase and cellobiase enzymes were produced, but there was no degradation of Avicel. The endoglucanase activities observed in cell extracts of E. coli HB101(pHZ100) differed in their pH and temperature optima from those previously reported for C. acetobutylicum P270. Complementation of E. coli arg and his mutations by cloned C. acetobutylicum DNA was also observed.


[The inherent malformations in the structure of infant mortality in Ivanovskaya oblast].
The dynamics and role of inherent malformations in the structure of infant mortality in Ivanovskaya oblast from 2007 to 2008 is analyzed. The data on the rate of inherent handicaps in population is received. The decrease of mortality among children younger than 1 year is revealed. The higher percentage of inherent malformations in the structure of infant mortality due to inherent valvular heart disease, nervous system, kidney diseases and multiple inherent malformations in male newborns are identified.


Synthesis, antimalarial activity, and intracellular targets of MEFAS, a new hybrid compound derived from mefloquine and artesunate.
A new synthetic antimalarial drug, a salt derived from two antimalarial molecules, mefloquine (MQ) and artesunate (AS), here named MEFAS, has been tested for its pharmacological activity. Combinations of AS plus MQ hydrochloride are currently being used in areas with drug-resistant Plasmodium falciparum parasites; although AS clears parasitemia in shorter time periods than any other antimalarial drug, it does not cure infected patients; in addition, MQ causes side effects and is rather expensive, important problems considering that malaria affects mostly populations in poor countries. Here, we show that MEFAS is more effective than the combination of AS and MQ, tested in parallel at different mass proportions, against P. falciparum (chloroquine-resistant clone W2 and chloroquine-sensitive clone 3D7) in vitro and in mice infected with Plasmodium berghei, promoting cure of this infection. MEFAS tested against HepG2 hepatoma cells exhibited lower toxicity than the antimalarials AS and MQ alone or combined. Possible targets of MEFAS have been studied by confocal microscopy using fluorescent probes (Fluo-4 AM and BCECF-AM) in P. falciparum synchronous culture of W2-infected red blood cells. Dynamic images show that MEFAS exhibited intracellular action increasing cytoplasmic Ca(2+) at 1.0 ng/ml. This effect was also observed in the presence of tapsigargin, an inhibitor of SERCA, suggesting an intracellular target distinct from the endoplasmic reticulum. Trophozoites loaded with BCECF-AM, when treated with MEFAS, were still able to mobilize protons from the digestive vacuole (DV), altering the pH gradient. However, in the presence of bafilomycin A1, an inhibitor of the H(+) pump from acidic compartments of eukaryotic cells, MEFAS had no action on the DV. In conclusion, the endoplasmic reticulum and DV are intracellular targets for MEFAS in Plasmodium sp., suggesting two modes of action of this new salt. Our data support MEFAS as a candidate for treating human malaria.