Carvacrol Induced Program Cell Death and Cell Cycle Arrest in Androgen-Independent Human Prostate Cancer Cells via Inhibition of Notch Signaling.
Several studies have revealed that abnormal activation of Notch signaling is closely related with the development and progression of prostate cancer. Although there are numerous therapeutic strategies, a more effective modality with least side effects is urgently required for the treatment of prostate cancer. Carvacrol is a monoterpenoid phenol and majorly present in the essential oils of Lamiaceae family plants. Many previous reports have shown various biological activities of carvacrol like antioxidant, antiinflammatory and anticancer properties. Recently, we have shown potent anticancer property of carvacrol against prostate cancer cell line DU145. In the current study, we report the chemopreventive and therapeutic potential of carvacrol against another prostate cancer cell line PC-3 with its detailed mechanism of action. To determine the effect of the carvacrol on prostate cancer cells, the cell viability was estimated by MTT assay and cell death was estimated by LDH release assay. The apoptotic assay was performed by DAPI staining and FITC-Annexin V assay. Reactive Oxygen Species (ROS) was estimated by DCFDA method. Cell cycle analysis was performed by flow cytometry. Gene expression analysis was performed by quantitative real time PCR. Our results suggested that the carvacrol treatment significantly reduced the cell viability of PC-3 cells in a dose- and time-dependent manner. The antiproliferative action of carvacrol was correlated with apoptosis which was confirmed by nuclear condensation, FITC-Annexin V assay, modulation in expression of Bax, Bcl-2 and caspase activation. The mechanistic insight into carvacrol-induced apoptosis leads to finding of elevated level of Reactive Oxygen Species (ROS) and mitochondrial membrane potential disruption. Cell cycle analysis revealed that carvacrol prevented cell cycle in G0/G1 that was associated with decline in expression of cyclin D1 and Cyclin-Dependent Kinase 4 (CDK4) and augmented expression of CDK inhibitor p21. Having been said the role of hyperactivation of Notch signaling in prostate cancer, we also deciphered that carvacrol could inhibit Notch signaling in PC-3 cells via downregulation of Notch-1, and Jagged-1. Thus, our previous and current findings have established the strong potential of carvacrol as a chemopreventive agent against androgen-independent human prostate cancer cells.


Inhibition of growth by imidazol(on)e propionic acid: evidence in vivo for coordination of histidine catabolism with the catabolism of other amino acids.
Imidazole propionic acid (ipa), a gratuitous inducer of the histidine-utilization (hut) system in Salmonella typhimurium, inhibits the organism's growth on succinate minimal medium. Induction of the hut system is necessary, but not sufficient, to cause inhibition. A study of the ability of single amino acids to relieve ipa-restricted growth suggests that insufficient glutamate is the cause of slow growth. The inhibition of growth by imidazolone propionic acid (iopa), an intermediate in the catabolism of histidine to glutamate, is similar to that by ipa. Studies using 2, 3, 5-triphenyl tetrazolium chloride plates to examine amino acid catabolism suggest that accumulation of ipa or iopa leads to inactivation of aspartate amino-transferase (AAT). This interpretation is supported by studies of an Escherichia coli mutant lacking AAT. The mutant grows poorly on succinate minimal medium, and the poor growth is relieved by the same amino acids that relieve ipa- and iopa-restricted growth. These and other findings are discussed in terms of coordination of the histidine-utilization system with enzymatic activities involved in the catabolism of other amino acids.


Microbial antagonists of Escherichia coli O157:H7 on fresh-cut lettuce and spinach.
Fresh-cut lettuce and spinach can become contaminated with pathogens at numerous points from the field to the retail market. Natural microflora present on fresh produce may help reduce the pathogen load. The objective of this study was to isolate natural microflora from fresh-cut iceberg lettuce and baby spinach and to determine whether these bacteria were antagonistic toward Escherichia coli O157:H7. Samples were collected under conditions that mimicked actual practices between production and retail sale. Evidence of naturally occurring microorganisms on fresh lettuce (295 isolates) and spinach (200 isolates) and of possible antagonistic activity toward E. coli O157:H7 was documented. Inhibitory activity by several isolates was due to either acid production or antimicrobial peptides. Bacteria with inhibitory activity were isolated from every step in the processing and handling of the fresh-cut iceberg lettuce and baby spinach.


CcpA regulates biofilm formation and competence in Streptococcus gordonii.
Streptococcus gordonii is an important member of the oral biofilm community. As an oral commensal streptococcus, S. gordonii is considered beneficial in promoting biofilm homeostasis. CcpA is known as the central regulator of carbon catabolite repression in Gram-positive bacteria and is also involved in the control of virulence gene expression. To further establish the role of CcpA as central regulator in S. gordonii, the effect of CcpA on biofilm formation and natural competence of S. gordonii was investigated. These phenotypic traits have been suggested to be important to oral streptococci in coping with environmental stress. Here we demonstrate that a CcpA mutant was severely impaired in its biofilm-forming ability, showed a defect in extracellular polysaccharide production and reduced competence. The data suggest that CcpA is involved in the regulation of biofilm formation and competence development in S. gordonii.


Biochemical Markers of Colorectal Cancer - Present and Future.
According to a report by the National Cancer Institute, colorectal cancer (CRC) is one of the most common types of cancer worldwide. CRC is often recognized too late for successful therapy. Tumor markers have been sought for a number of years to detect the transformation of malignant cells at the earliest possible stage. They are usually proteins associated with a malignancy and might be clinically useful in patients with cancer. Several classical markers have been used to recognize colorectal cancer, including carcinoembryonic antigen (CEA), carbohydrate antigen (CA 19.9), tissue polypeptide specific antigen (TPS) and tumor-associated glycoprotein-72 (TAG-72). None of these tests, however, have excellent diagnostic accuracy. Recent studies have been conducted on the use of hematopoietic growth factors (HGFs) and various enzymes in the diagnosis and prognosis of colorectal cancer. These include macrophage-colony stimulating factor (M-CSF) and granulocyte-macrophage-colony stimulating factor (GM-CSF), interleukin-3, interleukin-6 and enzymes (alcohol dehydrogenase and lysosomal exoglycosidases). Significantly, most cancer deaths are not caused by the primary tumor itself but by its spread. Analysis of circulating cancer cells (CTCs), ie, factors responsible for metastasis, may be a source of information useful in the treatment of patients with colorectal cancer. Currently available markers have significant limitations.


Neonatal Morbidities among Moderately Preterm Infants with and without Exposure to Antenatal Corticosteroids.
We aimed to compare the rates of "surfactant treated respiratory disease" and other neonatal morbidities among moderately preterm (MPT) infants exposed to no, partial, or a complete course of antenatal corticosteroids (ANS). This observational cohort study evaluated MPT infants (290/7-336/7 weeks' gestational age), born between January 2012 and November 2013 and enrolled in the "MPT Registry" of the National Institute of Child Health and Human Development Neonatal Research Network. Data were available for 5,886 infants, including 676 with no exposure, 1225 with partial, and 3,985 with a complete course of ANS. Among no, partial, and complete ANS groups, respectively, there were significant differences in rates of delivery room resuscitation (4.1, 1.4, and 1.2%), surfactant-treated respiratory disease (26.5, 26.3, and 20%), and severe intracranial hemorrhage (3, 2, and 0.8%). Complete ANS course was associated with lower surfactant-treated respiratory disease, compared with partial ANS (odds ratio [OR] 0.62; 95% confidence interval [CI] 0.52-0.74), and no ANS groups (OR 0.52; 95% CI 0.41-0.66) on adjusted analysis. In MPT infants, ANS exposure is associated with lower delivery room resuscitation, surfactant-treated respiratory disease, and severe intracranial hemorrhage; with the lowest frequency of morbidities associated with a complete course.


Polymorphisms in the canine IL7R 3'UTR are associated with thymic output in Labrador retriever dogs and influence post-transcriptional regulation by microRNA 185.
Interleukin-7 (IL-7) and its receptor (IL-7R) are essential for T cell development in the thymus, and changes in the IL-7/IL-7R pathway have been implicated in age-associated thymic involution which results in a reduction of naïve T cell output. The aim of this study was to investigate the relationship between IL7 and IL7R genetic variation and thymic output in dogs. No single nucleotide polymorphisms (SNPs) were identified in the canine IL7 gene, but a number were present in the canine IL7R gene. Polymorphisms in the IL7R exon 8 and 3'UTR were found to be associated with signal joint T cell receptor excision circle (sj-TREC) values (a biomarker of thymic output) in young and geriatric Labrador retrievers. Additionally, one of the SNPs in the IL7R 3'UTR (SNP 14 c.1371 + 446 A > C) was found to cause a change in the seed-binding site for microRNA 185 which, a luciferase reporter assay demonstrated, caused changes in post-transcriptional regulation, and therefore might be capable of influencing IL-7R expression. The research findings suggest a genetic link between IL7R genotype and thymic output in dogs, which might impact on immune function as these animals age and provide further evidence of the involvement of IL-7/IL-7R pathway in age-associated thymic involution.


Inactivation and modification of superoxide dismutase by glyoxal: prevention by antibodies.
Glyoxal is an endogenous compound, the levels of which are increased in various pathologies associated with hyperglycaemia and other related disorders. It has been reported to inactivate critical cellular enzymes by promoting their cross-linking and perpetuates advanced glycation end-product (AGE) formation. In this study, we used superoxide dismutase (SOD) as a model to investigate the ability of specific anti-enzyme antibodies and monomer Fab fragments to protect against glyoxal-induced deactivation and aggregate formation. We found that glyoxal deactivated SOD, in a concentration and time-dependent fashion. The enzymatic activity was monitored spectrophotometrically and it was found that enzyme lost approximately 95% of its original activity, when exposed to 10 mM glyoxal for 120 h. SDS-polyacrylamide gel electrophoresis demonstrated the formation of high molecular weight aggregates in SOD samples exposed to glyoxal. Surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS) showed increase in relative molecular mass (M(r)), upon exposure to glyoxal. Specific anti-enzyme antibodies and monomer Fab fragments markedly inhibited SOD deactivation caused by glyoxal and decreased the extent of cross-linking or formation of aggregates. This protection by the antibodies or Fab fragments was specific since, other non-specific antibodies were not able to protect SOD. Previously, antibodies have been used to prevent aggregation of beta-amyloid peptides in Alzheimer and prion-protein disease. Our findings provide a new perspective, for use of antibodies to prevent the biomolecules against glycation-induced deactivation and alteration.


When Social Interaction Backfires: Frequent Social Interaction During the COVID-19 Pandemic Is Associated With Decreased Well-Being and Higher Panic Buying.
The present research investigated a backfiring effect of social interaction on well-being and general confidence in Western populations during the COVID-19 pandemic. Across two studies, we observed that stronger self-other connectedness and frequent social communication with others during the first few weeks into the quarantine period were associated with worsened well-being and decreased general confidence. In Study 1 (n = 331), we showed that people who reported higher social connectedness and more frequent social interaction experienced declined well-being. In Study 2 (n = 327), we replicated the backfiring effect and showed that those who engaged in frequent social interaction, especially in COVID-19 related conversations, reported decreased general confidence, which mediated the accelerating effect of social interaction on panic buying. Overall, our findings indicated that frequent social interaction under a highly novel and uncertain crisis can relate to negative consequences on mental health and behavior.


[The main directions of public health reforms in the Republic of Uzbekistan].
The article covers the directive documents regulating the development of public health. The main directions of reforms of public health system of the Republic of Uzbekistan are covered too. The statistical data reflecting the structural changes in public health is presented. The purpose and tasks of reformation of the key public health issues in the Republic of Uzbekistan are explained.


The Schizosaccharomyces pombe homolog of Saccharomyces cerevisiae HAP2 reveals selective and stringent conservation of the small essential core protein domain.
The fission yeast Schizosaccharomyces pombe is immensely diverged from budding yeast (Saccharomyces cerevisiae) on an evolutionary time scale. We have used a fission yeast library to clone a homolog of S. cerevisiae HAP2, which along with HAP3 and HAP4 forms a transcriptional activation complex that binds to the CCAAT box. The S. pombe homolog php2 (S. pombe HAP2) was obtained by functional complementation in an S. cerevisiae hap2 mutant and retains the ability to associate with HAP3 and HAP4. We have previously demonstrated that the HAP2 subunit of the CCAAT-binding transcriptional activation complex from S. cerevisiae contains a 65-amino-acid "essential core" structure that is divisible into subunit association and DNA recognition domains. Here we show that Php2 contains a 60-amino-acid block that is 82% identical to this core. The remainder of the 334-amino-acid protein is completely without homology to HAP2. The function of php2 in S. pombe was investigated by disrupting the gene. Strikingly, like HAP2 in S. cerevisiae, the S. pombe gene is specifically involved in mitochondrial function. This contrasts to the situation in mammals, in which the homologous CCAAT-binding complex is a global transcriptional activator.


Bayesian estimation of herd-level prevalence and risk factors associated with BoHV-1 infection in cattle herds in the State of Paraíba, Brazil.
A cross-sectional study was carried out to estimate the animal- and herd-level prevalence of bovine herpesvirus 1 (BoHV-1) infection in cattle in the State of Paraíba, and to identify risk factors associated with herd-level infection. The state was divided into three sampling strata, and for each stratum, the prevalence of herds infected with BoHV-1 was estimated through a two-stage sampling survey carried out from September 2012 to January 2013. In total, 2443 animals were sampled from 478 herds. A virus-neutralization test was used for BoHV-1 antibody detection. A Bayesian latent-class model was used to describe the data, taking into account imperfect diagnostic test characteristics and the non-independence of test results from animals within the same herd, and using a dynamic within-model risk factor selection method based on indicator variable selection. The adjusted herd-level prevalence was estimated to be 84% (95% CI: 80-88%) for the State of Paraíba, and the animal-level prevalence was estimated to be 73% (95% CI: 66-84%). Only five of the available risk factors were used by the model, with the three most influential being disposal of aborted foetuses (3.78, 95% CI: 1.11-13.85), sharing resources with other farms (3.0, 95% CI: 1.1-8,6), and a herd size of > 23 animals (2.5, 95% CI: 1.1-6.0). Our findings suggest that the animal- and herd-level seroprevalence of BoHV-1 infection in the State of Paraíba is high. While some risk factors such as herd size and sharing resources were identified as risk factors for BoHV-1 infection, these risk factors are initially likely to be of only minor relevance in a control programme due to the extremely high prevalence of infected farms. However, the results are relevant to the risk of reintroduction of disease on farms that have previously eradicated the disease.


The development of audio-visual materials to prepare patients for medical procedures: an oncology application.
This paper describes a systematic process for the development of educational audio-visual materials that are designed to prepare patients for potentially threatening procedures. Literature relating to the preparation of patients for potentially threatening medical procedures, psychological theory, theory of diffusion of innovations and patient information was examined. Four key principles were identified as being important: (1) stakeholder consultation, (2) provision of information to prepare patients for the medical procedure, (3) evidence-based content, and (4) promotion of patient confidence. These principles are described along with an example of the development of an audio-visual resource to prepare patients for chemotherapy treatment. Using this example, practical strategies for the application of each of the principles are described. The principles and strategies described may provide a practical, evidence-based guide to the development of other types of patient audio-visual materials.


Comparative analysis of NFAT (nuclear factor of activated T cells) complex in human T and B lymphocytes.
Nuclear factor of activated T cells (NFAT) is a transcriptional activator that binds to sequences in the interleukin-2 (IL-2) promoter and is thought to be largely responsible for the T cell-specific inducibility of IL-2 expression. Electrophoretic mobility shift assays (EMSA) showed that specific NFAT binding activity could also be induced in human B cells. The B cell NFAT complex, however, was not functional, since it failed to activate transcription from an NFAT-driven chloramphenicol acetyltransferase (CAT) construct. Competition with an AP-1 motif or with anti-Jun and anti-Fos antibodies abolished binding to the NFAT motif in both T and B cells, indicating that Jun and Fos are critical for NFAT complex formation in both cell types. Purified recombinant Jun and Fos proteins failed to bind directly to the NFAT motif. However, when combined with unstimulated B or T cell extracts, full-length, but not truncated, Jun/Fos heterodimers were able to form an NFAT complex, indicating the presence of a constitutively expressed nuclear factor(s) in B and T cells necessary for the formation of the NFAT complex in both cell types. An NFAT oligonucleotide carrying mutations in the 5' purine-rich part of the NFAT sequence failed to form a complex and to compete with the wild type motif for NFAT complex formation in both T and B cells. We therefore propose a model whereby a core NFAT complex consisting of Jun, Fos, and a constitutive nuclear factor is formed in both T and B cells, but an additional factor and/or post-translational modification of a factor, missing in B cells, might be required for transactivation by NFAT.


Dyspnea and pulmonary function in the L-tryptophan-associated eosinophilia-myalgia syndrome.
We reviewed the pulmonary history, dyspnea ratings, and pulmonary function test results in 16 patients with L-tryptophan-induced eosinophilia myalgia syndrome to determine the correlation between reported pulmonary complaints and pulmonary function abnormalities. All patients reported pulmonary symptoms. Dyspnea, seen in 14 of 16 (87 percent) patients, was the most common symptom. The severity of dyspnea was graded by the baseline dyspnea index and the oxygen cost diagram. Pulmonary function testing including maximal static inspiratory and expiratory pressures were measured. The DCO was diminished in 12 of 16 (75 percent) patients. The MSIP was decreased in seven out of ten (70 percent) and the MSEP was decreased in nine out of ten (90 percent) of those patients tested. There was a statistically significant correlation between the severity of dyspnea as graded by the BDI and OCD, and the decrease in DCO. These results and a review of the literature of the pulmonary manifestations of EMS lead us to conclude that patients with EMS have a high prevalence of dyspnea, and it appears to be caused by both lung parenchymal involvement, as well as respiratory muscle weakness.


Medial frontal theta dissociates unsuccessful from successful avoidance and is modulated by lack of perseverance.
Medial frontal activity in the EEG is enhanced following negative feedback and varies in relation to dimensions of impulsivity. In 22 undergraduate students (Mage = 18.92 years, range 18-22 years), we employed a probabilistic negative reinforcement learning paradigm in which choices to avoid were followed by cues indicating successful or unsuccessful avoidance of an impending aversive noise. Our results showed that medial frontal theta power was enhanced following a cue that signaled avoidance was unsuccessful. In addition, self-reported lack of perseverance, a dimension of impulsivity characterized by an inability to maintain focus and determination during a challenging task, was negatively correlated with medial frontal theta elicited to an unsuccessful avoidance cue. We also observed robust differences in alpha attenuation and beta modulation following unsuccessful avoidance cue presentation. To our knowledge, this is the first study in humans to show a functional relation between medial frontal theta modulation and avoidance success. We discuss our findings in the context of frontal theta and self-regulation, negative reinforcement, and anxiety.


Caenorhabditis elegans: a model to monitor bacterial air quality.
Low environmental air quality is a significant cause of mortality and morbidity and this question is now emerging as a main concern of governmental authorities. Airborne pollution results from the combination of chemicals, fine particles, and micro-organisms quantitatively or qualitatively dangerous for health or for the environment. Increasing regulations and limitations for outdoor air quality have been decreed in regards to chemicals and particles contrary to micro-organisms. Indeed, pertinent and reliable tests to evaluate this biohazard are scarce. In this work, our purpose was to evaluate the Caenorhaditis elegans killing test, a model considered as an equivalent to the mouse acute toxicity test in pharmaceutical industry, in order to monitor air bacterial quality. The present study investigates the bacterial population in dust clouds generated during crop ship loading in harbor installations (Rouen harbor, Normandy, France). With a biocollector, airborne bacteria were impacted onto the surface of agar medium. After incubation, a replicate of the colonies on a fresh agar medium was done using a velvet. All the replicated colonies were pooled creating the "Total Air Sample". Meanwhile, all the colonies on the original plate were isolated. Among which, five representative bacterial strains were chosen. The virulence of these representatives was compared to that of the "Total Air Sample" using the Caenorhaditis elegans killing test. The survival kinetic of nematodes fed with the "Total Air Sample" is consistent with the kinetics obtained using the five different representatives strains. Bacterial air quality can now be monitored in a one shot test using the Caenorhaditis elegans killing test.


Retrograde Intramedullary Nailing for Recurrent Fracture in Congenital Pseudarthrosis of the Tibia.
We present the case of a 23-year-old male with congenital pseudarthrosis of the tibia, who had undergone treatment with Ilizarov ring fixation and had experienced 4 episodes of repeat fracture. He had associated type 1 neurofibromatosis, and his radiographs confirmed a type 6 Boyd's congenital pseudarthrosis of the left tibia, with concomitant arthritic ankle and subtalar joints. He was treated successfully with retrograde intramedullary nailing of the tibia and autologous bone grafting. At his final follow-up visit at 3 years postoperatively, he displayed complete union with no repeat fractures.


The mediating effect of global self-worth on physical activity in African-American adolescent females.
Having an excess of body fat has been identified as a predictor for participatory frequency in physical activity, a behavior that influences the development and persistence of obesity. However, the psychological factors that contribute to this pathway have not been as easily identified. This is particularly significant for population subgroups that are not only uniquely impacted by obesity-related morbidities but who are underrepresented in research as well. This study sample consisted of African-American adolescent females (N = 310), from 14 to 18 years of age, who were recruited from the urban South. Data obtained from self-reported and demographic questionnaires, as well as from anthropometric measurements, were analyzed to explore the mediating effect of global self-worth between BMI and physical activity. Mediation analysis revealed that 2% of the influence that BMI exerts on how frequently African-American adolescent females engaged in physical activity can be attributed to global self-worth.


Etiology of corneal sensitivity changes accompanying contact lens wear.
Corneal touch threshold was monitored while corneal edema was experimentally induced by exposing the cornea to either an oxygen-free environment or hypotonic saline. No change in sensitivity occurred during these conditions. Contact lens wearers who were fully adapted to their lenses and did not develop corneal edema during wear showed an increase of 96% in corneal touch threshold. Refitting these subjects with an experimental contact lens which caused a 6% increase in corneal thickness did not further alter the corneal sensitivity. The decrease in corneal sensitivity accompanying contact lens wear is independent of corneal edema and is likely a result of sensory adaptation to a mechanical stimulant.


[Clinical and immunological studies of the therapeutical effect of cytokines combined with 5-fluorouracil in metastatic kidney cancer].
The authors present the results of a six-year clinicoimmunological study of a therapeutic effect of cytkins combined with 5-fluoruracyl in metastatic renal-cell carcinoma. Two therapeutic regiments have been used: rhIFN-a + 5-FU and rhIL-2 + RHifn-A + 5-FU. In cytokin-sensitive patients, both therapy protocols vrs conventional therapeutic alternatives (cytostatics, hormones, irradiation) have been shown to increase the frequency of achievement of remission by objective scoring and life span of the patients. There was an improvement in patients on having received the complex with IL-2 but a higher therapeutic effect appeared to be accompanied by substantial side effects. Recommendatory measures well-targeted to those patients with metastatic renal-cell carcinoma who are to be placed on cytokinotherapy are presented together with immunological indices to monitor the treatments administered and prognosis.


Structural Characterization and Anticoagulant Activities of a Keratan Sulfate-like Polysaccharide from the Sea Cucumber Holothuria fuscopunctata.
A sulfated polysaccharide (AG) was extracted and isolated from the sea cucumber H. fuscopunctata, consisting of GlcNAc, GalNAc, Gal, Fuc and lacking any uronic acid residues. Importantly, several chemical depolymerization methods were used to elucidate the structure of the AG through a bottom-up strategy. A highly sulfated galactose (oAG-1) and two disaccharides labeled with 2,5-anhydro-D-mannose (oAG-2, oAG-3) were obtained from the deaminative depolymerized product along with the structures of the disaccharide derivatives (oAG-4~oAG-6) identified from the free radical depolymerized product, suggesting that the repeating building blocks in a natural AG should comprise the disaccharide β-D-GalS-1,4-D-GlcNAc6S. The possible disaccharide side chains (bAG-1) were obtained with mild acid hydrolysis. Thus, a natural AG may consist of a keratan sulfate-like (KS-like) glycosaminoglycan with diverse modifications, including the sulfation types of the Gal residue and the possible disaccharide branches α-D-GalNAc4S6S-1,2-α/β-L-Fuc3S linked to the KS-like chain. Additionally, the anticoagulant activities of the AG and its depolymerized products (dAG1-9) were evaluated in vitro using normal human plasma. The AG could prolong activated partial thromboplastin time (APTT) in a dose-dependent manner, and the activity potency was positively related to the chain length. The AG and dAG1-dAG3 could prolong thrombin time (TT), while they had little effect on prothrombin time (PT). The results indicate that the AG could inhibit the intrinsic and common coagulation pathways.


Effects of Intermittent Fasting on Specific Exercise Performance Outcomes: A Systematic Review Including Meta-Analysis.
Intermittent fasting (IF) has been studied in athletes during Ramadan and in those willing to decrease adiposity while maintaining or increasing lean body mass. The purpose of this systematic review was to summarize the effects of IF on performance outcomes. We searched peer-reviewed articles in the following databases: PubMed, Web of Science and Sport Discus (up to December 2019). Studies were selected if they included samples of adults (≥18 years), had an experimental or observational design, investigated IF (Ramadan and time-restricted feeding (TRF)), and included performance outcomes. Meta-analytical procedures were conducted when feasible. Twenty-eight articles met the eligibility criteria. Findings indicated that maximum oxygen uptake is significantly enhanced with TRF protocols (SMD = 1.32, p = 0.001), but reduced with Ramadan intermittent fasting (Ramadan IF; SMD = -2.20, p < 0.001). Additional effects of IF may be observed in body composition (body mass and fat mass). Non-significant effects were observed for muscle strength and anaerobic capacity. While Ramadan IF may lead to impairments in aerobic capacity, TRF may be effective for improving it. As there are few studies per performance outcome, more research is needed to move the field forward.


The immune modulator FTY720 targets sphingosine 1-phosphate receptors.
Immunosuppressant drugs such as cyclosporin have allowed widespread organ transplantation, but their utility remains limited by toxicities, and they are ineffective in chronic management of autoimmune diseases such as multiple sclerosis. In contrast, the immune modulating drug FTY720 is efficacious in a variety of transplant and autoimmune models without inducing a generalized immunosuppressed state and is effective in human kidney transplantation. FTY720 elicits a lymphopenia resulting from a reversible redistribution of lymphocytes from circulation to secondary lymphoid tissues by unknown mechanisms. Using FTY720 and several analogs, we show now that FTY720 is phosphorylated by sphingosine kinase; the phosphorylated compound is a potent agonist at four sphingosine 1-phosphate receptors and represents the therapeutic principle in a rodent model of multiple sclerosis. Our results suggest that FTY720, after phosphorylation, acts through sphingosine 1-phosphate signaling pathways to modulate chemotactic responses and lymphocyte trafficking.


Pseudo-branched polyester copolymer: an efficient drug delivery system to treat cancer.
In this study, a new hyperbranched polyester copolymer was designed using a proprietary monomer and diethylene glycol or triethylene glycol as monomers. The synthesis was carried out using standard melt polymerization technique and catalyzed by p-tolulenesulfonic acid. The progress of the reaction was monitored with respect to time and negative pressure, with samples being subjected to standard characterization protocols. The resulting polymers were purified using the solvent precipitation method and characterized using various chromatographic and spectroscopic methods including GPC, MALDI-TOF, and NMR. We have observed polymers with a molecular weight of 29 643 Da and 33 996 Da, which is ideal to be used as a drug delivery system. Thus, these polymers were chosen for further modification into folate-functionalized polymeric nanoparticles for the targeted treatment of cancer, in this case we have chosen prostate cancer cells as a model. We hypothesized that due to the 3D structure of the A2B monomer, we expect a pseudo-branched polymer that is globular in shape which will be ideal for drug carrying and delivery. We used a solvent diffusion method for the one-pot formulation of water-dispersable polymeric nanoparticles as well as theraputic drug (doxorubicin) encapsulation. The efficacy of this delivery system was gauged by treating LNCaP cells with the drug-loaded nanoparticles and assessing the results of the treatment. The results were analyzed by cytotoxicity (MTT) assays, drug release studies, and fluorescence microscopy. The experimental results collectively show a nanoparticle that was biocompatible, target-specific, and successfully initiated apoptosis in an in vitro prostate cancer model.


Management and outcome of severely elevated blood pressure in primary care: a prospective observational study.
In primary care the management of patients with acute severely elevated blood pressure (BP) is challenging. The aim of the study was to evaluate the initial management and outcome of patients presenting to their general practitioner (GP) with severe high blood pressure. Twenty five general practitioners prospectively identified 164 patients presenting with severely elevated blood pressure (systolic BP >180 mm Hg and/or diastolic BP >110 mm Hg). At baseline, patients were categorised as having a hypertensive emergency, urgency or asymptomatic BP elevation. The therapeutic approach of the GPs was assessed and patient outcome at 12 month follow-up was analysed. Median age of 164 patents was 71 (range 22 to 97) years, 60 (37%) were male and 107 (65%) had pre-existing hypertension. Mean baseline systolic BP was 198 ± 16 (range 145 to 255) mm Hg, mean baseline diastolic BP was 101 ± 15 (range 60 to 130). In total, 99 (60%) of patients had asymptomatic BP elevation, 50 (31%) had hypertensive urgency, and 15 (9%) had a hypertensive emergency. Only around two thirds (61%) of patients were given immediate blood pressure lowering medication (most frequently calcium antagonists). Ten patients (6%) were immediately admitted to hospital. Systolic and diastolic BP declined significantly (p <0.01) between one and six hours after study inclusion (drop of systolic and diastolic BP, 24 ± 9 and 10 ± 1, respectively) and were significantly lower (p <0.01) at three month follow-up compared to the initial measurement (drop of systolic and diastolic BP, 37 ± 6 and 14 ± 4, respectively). On average systolic BP was still above target values after three months (148 ± 21). During 12 months of follow-up patients with hypertensive emergency, hypertensive urgency, and asymptomatic BP elevation experienced a cardiovascular event in 27% vs. 6% vs. 16%, of cases respectively (p = 0.17). The majority of 164 patients who presented with acutely and severely elevated blood pressure (BP >180 +/or >110 mm Hg) to their GPs was asymptomatic, had pre-existing hypertension and was managed in GP's office unless a hypertensive emergency was present. At three month follow-up mean systolic BP was still above target values.


Isolation and characterization of lipoproteins produced by human hepatoma-derived cell lines other than HepG2.
A total of six established human hepatoma-derived cell lines, including Hep3B, NPLC/PRF/5 (NPLC), Tong/HCC, Hep 10, huH1, and huH2, were screened for their ability to accumulate significant quantities of lipoproteins in serum-free medium. Only two cell lines, Hep3B and NPLC, secreted quantitatively significant amounts of lipoproteins. In a 24-h period the accumulated mass of apolipoproteins (apo) A-I, A-II, B, and E and albumin for Hep3B cells was 1.96, 1.01, 1.96, 1.90, and 53.2 micrograms/mg cell protein per 24 h, respectively. NPLC cells secreted no detectable albumin but the 24-h accumulated mass for apolipoproteins A-I, A-II, B, and E was 0.45, 0.05, 0.32, and 0.68 micrograms/mg cell protein per 24 h, respectively. Twenty four-hour serum-free medium of Hep3B cells contained lipoproteins corresponding to the three major density classes of plasma; percent protein distribution among the lipoprotein classes was 4%, 41%, and 56% for very low density lipoprotein ("VLDL"), low density lipoprotein ("LDL"), and high density lipoprotein ("HDL"), respectively. NPLC was unusual since most of the lipoprotein mass was in the d 1.063-1.235 g/ml range. Hep3B "LDL", compared with plasma LDL, contained elevated triglyceride, phospholipid, and free cholesterol. Nondenaturing gradient gel electrophoresis revealed that Hep3B "LDL" possessed a major component at 25.5 nm and a minor one at 18.3 nm. Immunoblots showed that the former contained only apoB while the latter possessed only apoE. Like plasma VLDL, Hep3B "VLDL" particles (30.5 nm diameter) isolated from serum-free medium contained apoB, apoC, and apoE. "HDL" harvested from Hep3B and NPLC medium were enriched in phospholipid and free cholesterol and poor cholesteryl ester which is similar to the composition of HepG2 "HDL." "HDL" from Hep3B and NPLC culture medium on gradient gel electrophoresis had peaks at 7.5, 10, and 11.9 nm which were comparable to major components found in HepG2 cell medium. Hep3B cells, in addition, possessed a particle that banded at 8.2 nm which appeared to be an apoA-II without apoA-I particle by Western blot analysis. The cell line also produced a subpopulation of larger-sized "HDL" not found in HepG2 medium. NPLC "HDL" had a distinct peak at 8.3 nm which by Western blot was an apoE-only particle. Electron microscopy revealed that "HDL" harvested from Hep3B and NPLC medium consisted of discoidal and small, spherical particles like those of HepG2. The "HDL" apolipoprotein content of each cell line was distinct from that of HepG2. ApoA-II at 35% of apolipoprotein distinguishes Hep3B "HDL" from HepG2, which contains only 10%.(ABSTRACT TRUNCATED AT 400 WORDS)


Inhibition of neointimal hyperplasia in vascular grafts by sustained perivascular delivery of paclitaxel.
Neointimal hyperplasia occurs commonly at the anastomoses of arteriovenous grafts for chronic hemodialysis, causing stenosis and occlusion. Antiproliferative drugs may be effective in inhibiting hyperplasia, but local drug delivery would be required to minimize systemic side effects. We examined the feasibility of local drug delivery to inhibit neointimal hyperplasia at dialysis grafts in a canine model. Bilateral polytetrafluoroethylene loop grafts (10-cm length and 6-mm internal diameter) were placed between the femoral artery and ipsilateral femoral vein of five mongrel dogs. At the time of surgery or 1 to 5 weeks later, 2 mL of a thermosensitive biodegradable copolymer (ReGel) mixed with 0.26 mg or 0.65 mg paclitaxel were applied to the external surface of one graft around the anastomoses to provide a depot for sustained release of the drug. ReGel alone without paclitaxel was applied to the contralateral graft as a control. The grafts and the connecting vessels were explanted at eight or nine weeks, and the cross-sections were examined histologically. The degree of hyperplasia at the anastomoses was graded by five blinded independent reviewers, with scores ranging from 0 to 5. The median (25th-75th percentile) hyperplasia score of both arterial and venous anastomoses was 1.80 (0.90-3.05) in the grafts treated with ReGel alone, and 0.95 (0.70-1.50) in the grafts treated with ReGel/paclitaxel (N= 8; P < 0.05 by Wilcoxon signed rank test). There were no noticeable localized or systemic complications attributed to the treatments in these animals. Paclitaxel levels in the plasma obtained from forelimb veins were undetectable (<10 ng/mL). These results suggest that the local delivery of antiproliferative agents using a thermosensitive, injectable biodegradable copolymer (ReGel) for sustained delivery is a promising strategy to inhibit neointimal hyperplasia of arteriovenous hemodialysis grafts.


Food insecurity among senior citizens in high out-migration areas: evidence from Western Nepal.
Food insecurity is a critical public health challenge, particularly in low- and middle-income countries such as Nepal. The demographic transition has resulted in a growing population of senior citizens. However, the determinants of food insecurity among Nepali senior citizens remain unknown. This study aims to fill this gap by assessing food insecurity among the older populations in the far-western region, one of the poorest regions of the country. Further, we also aim to assess the potential association between adult children's migration and the food insecurity status of the left behind older parents. A community-based cross-sectional study was conducted among 260 randomly selected senior citizens in the Kanchanpur district in far-western Nepal. The short form of the household food security scale, originally developed by the United States Department of Agriculture, was used to measure household food security. Associations were examined by logistic regression. The prevalence of food insecurity in senior citizens' households was 41.1%. Senior citizen households with their adult children's migration (AOR = 0.47, 95% CI: 0.24-0.95) had lower odds of being food insecure whereas households with lower family income (<$100 compared to ≥ $100) had two times higher odds of being food insecure (AOR = 2.26, 95% CI: 1.08-4.76). Also, households owning a cultivable land/farm (AOR = 0.14, 95% CI: 0.05-0.40), primary source of income as service/pension (AOR = 0.26, 95% CI: 0.08-0.89) or business (AOR = 0.15, 95% CI: 0.03-0.59) and participants who received geriatric allowances (AOR = 0.05, 95% CI = 0.01-0.16) had lower odds of being food insecure. The prevalence of food insecurity among households with a senior citizen in Kanchanpur district was high and associated with the migration status of adult children, and household socioeconomic status. This calls for a greater policy response focused specifically on households with older adults and the integration of gerontological evidence into the existing food security and nutrition strategies.


Bioconversion of Digestate, Pig Manure and Vegetal Residue-Based Waste Operated by Black Soldier Fly Larvae, Hermetia illucens L. (Diptera: Stratiomyidae).
Insects can play an important role to upgrade waste streams into high-grade proteins and fats as food and feed ingredients or non-food products. The aim of this research was to assess the feasibility to use waste streams with a low value for direct application as animal feed as substrates to grow BSF larvae in terms of larval growth rate, waste reduction index, and efficiency of conversion of ingested feed. The growth of black soldier fly (BSF), Hermetia illucens larvae and conversion of biowaste was assessed in triplicate in biowaste substrates: chicken feed (CF; reference diet), pig manure solid (PMS), Betafert® solid (BTFS), swill (SW), olive pulp (OP), pig manure liquid mixed with chicken feed (PMLCF), and silage grass (SG). Per kilogram fresh substrate 2500 starter (8-days-old, second instar) larvae were incubated in 21 plastic containers (75 × 47 × 15 cm). The BSF larvae were fed according to a batch feeding system. Highest growth rate was found in larvae reared on SW (13.4 mg/d). Larval growth rate was even higher than in larvae reared on the reference substrate CF (7.2 mg/d). Growth rate in larvae reared on PMLCF (7.3 mg/d) did not differ from CF, whereas growth rate of larvae reared on PMS (3.2 mg/d) was lower than on CF. Growth rate of larvae reared on BTFS, OP and SG was very low (0.6, 0.2 and 0.7 mg/d, respectively). Waste Reduction Index (WRI) was highest on SW (11.3), followed by PMLCF (9.3), and both were higher than WRI on CF (8.5). Waste Reduction Index further decreased in descending order from PMS, SG, BTFS to OP (7.6, 4.0, 2.9 and 1.7, respectively). The Efficiency of Conversion of Ingested substrate (ECI) was highest on SW (0.31), followed in descending order by PMLCF, CF and PMS (0.25, 0.21 and 0.18, respectively). The substrates OP, BTFS and SG (0.16, 0.15 and 0.14, respectively) resulted in a lower ECI than other substrates. Highest CO2 and lowest NH3 concentrations were found above substrates with the highest larval growth performances. This study showed that BSF larvae can be reared on different biowaste substrates; the growth rate of the larvae was extremely high on SW. The effects of chemical composition and physical properties of the substrates on larval growth and gas emissions should be further considered.


[Expert consensus on the implementation of enhanced recovery after surgery in spinal fusion surgery for advanced age patients].
Chinese society is progressively aging, and more and more patients suffer from spinal diseases in advanced age patients (>75 years). Surgery is still the most effective solution for patients who have failed conservative treatment or who present with progressively worsening symptoms. Excluding surgical and anesthetic technical failures, the key factors affecting the incidence of postoperative complications are the stress response to surgery and the increased demands on organ function after surgery. Late old patients generally have a poor ability to withstand surgical shock, the implementation of enhanced recovery after surgery (ERAS) to reduce surgical stress response is more important for late old patients undergoing spinal surgery. Specific measures to familiarize more spinal surgeons with older spinal ERAS. On the basis of evidence-based medicine, experts from the Geriatric Group of Orthopaedic Branch of Beijing Medical Association, Geriatric Anesthesiology Group of Anesthesiology Branch of Chinese Medical Association reached the following expert consensus through multiple discussions and votes based on the existing clinical experience and published relevant data, for the reference of academic colleagues.


Square-wave pulse with ultra-wide tuning range in a passively mode-locked fiber laser.
We report the generation of ultrawide tunable square-wave pulse in an erbium-doped mode-locked fiber laser. The pulse width can be tuned in an ultrawide range of more than 1700 ns by simply increasing the pump power. The pulse-width tuning is 5.1 ns/mW. To the best of our knowledge, this is the widest pulse-width tuning range of any square-wave pulse in an all-fiber passively mode-locked fiber laser. Experimental results show that the fiber nonlinearity plays an important role in the tuning range of the output pulse width. The high nonlinearity helps to increase the tuning range of the pulse width.


Direction distributions of neutrons and reference values of the personal dose equivalent in workplace fields.
Within the EC project EVIDOS, double-differential (energy and direction) fluence spectra were determined by means of novel direction spectrometers. By folding the spectra with fluence-to-dose equivalent conversion coefficients, contributions to H*(10) for 14 directions, and values of the personal dose equivalent Hp(10) and the effective dose E for 6 directions of a person's orientation in the field were determined. The results of the measurements and calculations obtained within the EVIDOS project in workplace fields in nuclear installations in Europe, i.e., at Krümmel (boiling water reactor and transport cask), at Mol (Venus research reactor and fuel facility Belgonucléaire) and at Ringhals (pressurised reactor and transport cask) are presented.


Effect of disuse on sarcoplasmic reticulum in fast and slow skeletal muscle.
The effect of 6 wk of hindlimb immobilization on rat skeletal muscle sarcoplasmic reticulum (SR) was determined in the slow-twitch, type I soleus (SOL), the fast-twitch, type IIA deep region of the vastus lateralis (DVL), and the fast-twitch, type IIB superficial region of the vastus lateralis (SVL). Immobilization produced a significant decline in the Ca2+ uptake rate (Vmax) of SR vesicles from the slow SOL (0.930 +/- 0.116 to 0.365 +/- 0.071 mumol Ca2+ . mg-1 . min-1), while the SR Vmax increased in the fast SVL (2.763 +/- 0.133 to 5.209 +/- 0.687) and was unaltered in the DVL. Vesicles from the fast SVL and DVL also exhibited a higher total Ca2+ uptake capacity following immobilization. An evaluation of the time course of the immobilization-mediated effect revealed an increased Ca2+ uptake capacity in all three samples after 1 wk. In the SOL total Ca2+ uptake returned to control level after 2 wk, while in the fast-twitch muscles the higher capacities were maintained. The Ca2+-stimulated SR ATPase activity was not altered in any of the muscles studies, although the total SR ATPase activity increased twofold in the slow SOL.


Regional amyloid deposition in amnestic mild cognitive impairment and Alzheimer's disease evaluated by [18F]AV-45 positron emission tomography in Chinese population.
To compare the neocortical amyloid loads among cognitively normal (CN), amnestic mild cognitive impairment (aMCI), and Alzheimer's disease (AD) subjects with [(18)F]AV-45 positron emission tomography (PET). [(18)F]AV-45 PET was performed in 11 CN, 13 aMCI, and 12 AD subjects to compare the cerebral cortex-to-whole cerebellum standard uptake value ratios (SUVRs) of global and individual volumes of interest (VOIs) cerebral cortex. The correlation between global cortical [(18)F]AV-45 SUVRs and Mini-Mental State Examination (MMSE) scores was analyzed. The global cortical [(18)F]AV-45 SUVRs were significantly different among the CN (1.08±0.08), aMCI (1.27±0.06), and AD groups (1.34±0.13) (p = 0.0003) with amyloidosis positivity rates of 9%, 62%, and 92% in the three groups respectively. Compared to CN subjects, AD subjects had higher SUVRs in the global cortical, precuneus, frontal, parietal, occipital, temporal, and posterior cingulate areas; while aMCI subjects had higher values in the global cortical, precuneus, frontal, occipital and posterior cingulate areas. There were negative correlations of MMSE scores with SUVRs in the global cortical, precuneus, frontal, parietal, occipital, temporal, posterior cingulate and anterior cingulate areas on a combined subject pool of the three groups after age and education attainment adjustment. Amyloid deposition occurs relatively early in precuneus, frontal and posterior cingulate in aMCI subjects. Higher [(18)F]AV-45 accumulation is present in parietal, occipital and temporal gyri in AD subjects compared to the aMCI group. Significant correlation between MMSE scores and [(18)F]AV-45 SUVRs can be observed among CN, aMCI and AD subjects.


Poor Imitative Performance of Unlearned Gestures in Children with Probable Developmental Coordination Disorder.
It has been hypothesized that deficits in imitation, linked to abnormal functioning of the mirror neuron system (MNS), may contribute to the motor impairments associated with developmental coordination disorder (DCD). The authors aimed to examine imitation of complex novel postures and sequences of gestures in children with and without probable DCD (pDCD), using the postural praxis and sequencing praxis subtests of the Sensory Integration and Praxis Tests (Ayres, 1989 ). Participants were 29 boys with pDCD between 6.08 and 13.33 years old, and 29 group age-matched typically developing boys between 6.08 and 13.83 years old. Responses of children with pDCD on both imitation tasks were less accurate than controls, with group differences more apparent with increasing task complexity. Furthermore, as a group, children with pDCD were slower and had a higher number of non-mirror-imitated responses. There was considerable variability within the pDCD group, with some children displaying imitation scores within the normative range. Given the importance of imitation and visual learning for motor development, the difficulties in imitation displayed by some children with pDCD have the potential to impact on movement acquisition. Interventions to target imitation may be beneficial for these children. The results show that children with pDCD had difficulty imitating complex novel postures, children with pDCD had difficulty imitating gesture sequences, children with pDCD had slower responses than controls, group differences in imitation performance increased with task complexity, and not all children with pDCD displayed imitation deficits.


Tumor stage in patients operated for rectal cancer: a comparison of the pre-operative MR and the resection specimen, with specific attention to the effect of neo-adjuvant radiotherapy.
Evaluate the preoperative TN stage with MR and the postoperative stage with histology. Patients diagnosed with rectal cancer (2002-2015) and a pre-operative MR were included. A chart review was done. Pathology reports were evaluated for the post-operative tumor stage. Down staging was defined as a lower disease stage in the resection specimen compared with the pre-operative MR. Upgrading ("progression") was defined as a higher disease stage in the resection specimen. The study was approved by ethical committee of the Zaans Medisch Centrum. From 176 out of 231 operated patients a pre-operative MR was available for evaluation. 142 patients (80.7%) underwent neo-adjuvant treatment; the remainder 19.3% underwent immediate surgery. Neo-adjuvant therapy resulted in significant down staging. However, almost 14% of patients had a higher TN stage as determined by the pre-operative MR. In patients who underwent immediate surgery the percentage with "progression" was 30%. The number of patients with stage 1 and 2 were higher in the group not treated with neo-adjuvant therapy. There was no significant difference in tumor stage as determined by histological examination of the resection specimen. The diagnostic accuracy of the MR is not perfect. Underestimation as well as overestimation of the tumor occurred both in the patients treated with radiotherapy as well as those who underwent immediate operation. As such, MR results should be interpreted with caution when devising a treatment strategy.


Intraocular penetration of sequentially instilled topical moxifloxacin, gatifloxacin, and levofloxacin.
The objective of the study was to compare the intraocular penetration levels of the newer fluoroquinolones, moxifloxacin, gatifloxacin, and levofloxacin in the rabbit's cornea, aqueous humor, and conjunctiva after topical instillation. 0.5% moxifloxacin, 0.3% gatifloxacin, and 0.5% levofloxacin were instilled in random sequence in both eyes of nine New Zealand White rabbits at two-minute intervals. Instillation was repeated every 15 minutes for a total of three drops of each fluoroquinolone per eye. Three additional animals had only moxifloxacin instilled bilaterally using the same schedule. Sixty minutes after the final instillation, the rabbits were sacrificed for determination of corneal, aqueous humor, and conjunctival fluoroquinolone concentrations using high-performance liquid chromatography. Moxifloxacin achieved significantly higher concentrations than levofloxacin and gatifloxacin in the cornea (P = 0.0102 and P = 0.0006, respectively), aqueous humor (P = 0.0015 and P < 0.0001, respectively), and conjunctiva (P = 0.0191 and P = 0.0236, respectively). 0.5% moxifloxacin eyedrops provided superior intraocular penetration in rabbits' eyes compared with the two other fluoroquinolones, 0.5% levofloxacin and 0.3% gatifloxacin.


Multiscale Metabolic Modeling of C4 Plants: Connecting Nonlinear Genome-Scale Models to Leaf-Scale Metabolism in Developing Maize Leaves.
C4 plants, such as maize, concentrate carbon dioxide in a specialized compartment surrounding the veins of their leaves to improve the efficiency of carbon dioxide assimilation. Nonlinear relationships between carbon dioxide and oxygen levels and reaction rates are key to their physiology but cannot be handled with standard techniques of constraint-based metabolic modeling. We demonstrate that incorporating these relationships as constraints on reaction rates and solving the resulting nonlinear optimization problem yields realistic predictions of the response of C4 systems to environmental and biochemical perturbations. Using a new genome-scale reconstruction of maize metabolism, we build an 18000-reaction, nonlinearly constrained model describing mesophyll and bundle sheath cells in 15 segments of the developing maize leaf, interacting via metabolite exchange, and use RNA-seq and enzyme activity measurements to predict spatial variation in metabolic state by a novel method that optimizes correlation between fluxes and expression data. Though such correlations are known to be weak in general, we suggest that developmental gradients may be particularly suited to the inference of metabolic fluxes from expression data, and we demonstrate that our method predicts fluxes that achieve high correlation with the data, successfully capture the experimentally observed base-to-tip transition between carbon-importing tissue and carbon-exporting tissue, and include a nonzero growth rate, in contrast to prior results from similar methods in other systems.


Hormonal regulation of malic enzyme and glucose-6-phosphate dehydrogenase in brown adipose tissue.
The activities of malic enzyme (ME) and glucose-6-phosphate dehydrogenase (G-6-PDH), two NADPH-generating lipogenic enzymes, were measured in brown adipose tissue (BAT) of rats undergoing various neurohormonal manipulations. Methimazole-induced hypothyroidism doubled the activity of these two enzymes but, surprisingly, triiodothyronine (T3) given to hypothyroid rats caused a time- and dose-dependent stimulation of up to three- to fourfold. Unilateral BAT denervation modestly reduced the activity of these enzymes (approximately 30%) and failed to prevent the stimulation induced by hypothyroidism, whereas growth hormone (GH) successfully blocked this effect of hypothyroidism. Insulin stimulated both enzymes regardless of the thyroid status but failed to abolish the inhibitory effect of GH. In intact rats, cold exposure caused a time-dependent increase in the activity of both ME and G-6-PDH, which reached 5.2- and 3-fold, respectively, after 96 h. This cold-induced stimulation was not observed in hypothyroid rats, but it was restored by physiological doses of thyroxine (800 ng.100 g body wt-1.24 h-1). Replacement with T3 (300 ng.100 g body wt-1.24 h-1), in contrast, did not have this effect. In hypothyroid rats with hemidenervation of BAT, norepinephrine (NE) modestly increased ME and G-6-PDH activities in the denervated side, with little or no effect in the intact side. Receptor-saturating doses of T3 (50 micrograms.100 g body wt-1.day-1 over 48 h) stimulated two- and threefold both enzymes in both sides, reducing or obliterating the effect of denervation. The data suggest a complex neurohormonal regulation of the activity of ME and G-6-PDH in BAT.(ABSTRACT TRUNCATED AT 250 WORDS)


Radiochemical assay for gamma-aminolevulinate synthase.
We describe here a standard protocol for the radiochemical assay of gamma-aminolevulinate synthase from 17-day chick embryo liver mitochondria and starved male rat liver mitochondria. The assay is sensitive to at least 15 pmol of the gamma-aminolevulinate produced and can be adapted to suit most tissue types. A number of possible modifications to the procedure are discussed.


A mutant cell line partially responsive to both IFN-alpha and IFN-gamma.
A recessive mutant cell line, B7, which is partially responsive to both interferon (IFN)-alpha and IFN-gamma is described. B7 was FACS sorted from a cellular pool, which was obtained from the parental cell line 2C4, after several rounds of mutagenesis. The partial responsiveness to IFN was observed both in terms of expression of cell surface markers (CD2, class I and II HLAs) and mRNA expression of IFN-stimulated genes (9-27; 6-16; 2'-5' OAS; GBP and HLA-DR alpha). A genetic cross with the U4 mutant (JAK1-, a member of the Janus family of nonreceptor tyrosine kinase) did not restore full IFN responsiveness to B7, and JAK1 cDNA transfection into B7 restored the wild phenotype of the cell line, defining B7 as a member of the U4 complementation group. Nevertheless, JAK1 mRNA was not detected in this mutant. Transcriptional regulator complexes such as IRF1/2 (IFN-regulatory factor) and ISGF3-gamma (IFN-stimulated gene factor) were constitutively formed in the B7 mutant and co-migrated with the IFN-induced complexes expressed in the parental cell line 2C4. Thus, this cell line seems to be useful for understanding cis-acting elements governing JAK1 mRNA expression.


Development and application of a three-dimensional finite element vapor intrusion model.
Details of a three-dimensional finite element model of soil vapor intrusion, including the overall modeling process and the stepwise approach, are provided. The model is a quantitative modeling tool that can help guide vapor intrusion characterization efforts. It solves the soil gas continuity equation coupled with the chemical transport equation, allowing for both advective and diffusive transport. Three-dimensional pressure, velocity, and chemical concentration fields are produced from the model. Results from simulations involving common site features, such as impervious surfaces, porous foundation sub-base material, and adjacent structures are summarized herein. The results suggest that site-specific features are important to consider when characterizing vapor intrusion risks. More importantly, the results suggest that soil gas or subslab gas samples taken without proper regard for particular site features may not be suitable for evaluating vapor intrusion risks; rather, careful attention needs to be given to the many factors that affect chemical transport into and around buildings.


Interpretation of the effect of CYP2C9, VKORC1 and CYP4F2 variants on warfarin dosing adjustment in Turkey.
It was aimed to underline the importance and explain the meaning of genetic testing in warfarin dosing and investigate and evaluate the contributions of the CYP2C9, VKORC1, and CYP4F2 variants in a Turkish population. Two hundred patients were genotyped for CYP2C9 (rs1799853, rs1057910 and rs56165452), VKORC1 (rs9934438, rs8050894, rs9923231, rs7294 and rs2359612) and CYP4F2 (rs2108622), yet, only 127 patients were found suitable for further evaluation in terms of their personal response to warfarin due to long term usage and available INR and dose usage information. The DNA sequences were determined by the ABI PRISM 3100 Genetic Analyzer to 3130xl System (Applied Biosystems, Foster City, California). Warfarin dose application suggestions by warfaringdosing.org, FDA and MayoClinic were followed. Dose requirements in the Turkish population were found higher than the suggested doses by warfarindosing.org. The multivariate logistic regression analysis reveals the utilization of VCORC1 genetic evaluation is valuable in warfarin dosing (low and moderate vs. high) in this study (p < 0.001). The present study provides findings for clinicians to adapt the genetic data to the daily practice. We observed that the VKORC1 variant showed a more potent impact in warfarin dosing in this study.


Identifications of conserved 7-mers in 3'-UTRs and microRNAs in Drosophila.
MicroRNAs (miRNAs) are a class of endogenous regulatory small RNAs which play an important role in posttranscriptional regulations by targeting mRNAs for cleavage or translational repression. The base-pairing between the 5'-end of miRNA and the target mRNA 3'-UTRs is essential for the miRNA:mRNA recognition. Recent studies show that many seed matches in 3'-UTRs, which are fully complementary to miRNA 5'-ends, are highly conserved. Based on these features, a two-stage strategy can be implemented to achieve the de novo identification of miRNAs by requiring the complete base-pairing between the 5'-end of miRNA candidates and the potential seed matches in 3'-UTRs. We presented a new method, which combined multiple pairwise conservation information, to identify the frequently-occurred and conserved 7-mers in 3'-UTRs. A pairwise conservation score (PCS) was introduced to describe the conservation of all 7-mers in 3'-UTRs between any two Drosophila species. Using PCSs computed from 6 pairs of flies, we developed a support vector machine (SVM) classifier ensemble, named Cons-SVM and identified 689 conserved 7-mers including 63 seed matches covering 32 out of 38 known miRNA families in the reference dataset. In the second stage, we searched for 90 nt conserved stem-loop regions containing the complementary sequences to the identified 7-mers and used the previously published miRNA prediction software to analyze these stem-loops. We predicted 47 miRNA candidates in the genome-wide screen. Cons-SVM takes advantage of the independent evolutionary information from the 6 pairs of flies and shows high sensitivity in identifying seed matches in 3'-UTRs. Combining the multiple pairwise conservation information by the machine learning approach, we finally identified 47 miRNA candidates in D. melanogaster.


[Prognostic factors of the immediate results of surgical treatment of organic hyperinsulinism].
The clinic obtains the experience of treatment of 245 patients with organic hyperinsulinism. The main goal of the treatment of that category of patients is an improvement of immediate results of surgical treatment which leads to the decrease in mortality level. Authors set the diagnostic and intra- and postoperative treatment algorithm, as well as the major prognostic factors of postoperative morbidity rates. The use of the algorithm allowed the 1,5 decrease in postoperative morbidity and twice decreased the lethality rate.


In vitro potential antioxidant activity of (1-->3),(1-->6)-beta-D-glucan and protein fractions from Saccharomyces cerevisiae cell walls.
(1-->3),(1-->6)-Beta-D-Glucan, a cell wall polysaccharide in many microorganisms, fungi and algae, is a well-known biological response modifier. Recently, it was found that (1-->3)-beta-D-glucan from Saccharomyces cerevisiae also exhibits antioxidative capabilities. In this study the antioxidative activity of the cell wall fractions of brewer's yeast was investigated. Particular emphasis was put on the question to which extent glucan is responsible for the antioxidative activity of the cell walls and how the other cell wall components might contribute. For the experiments yeast cell walls from brewery fermentations were used. Glucan was isolated by a three-step extraction procedure including a combination of hot water and enzymatic treatment. The level of (1-->3),(1-->6)-beta-D-glucan in the cell walls was analyzed enzymatically. The antioxidant activity was determined by electron paramagnetic resonance spectrometry and Trolox equivalent antioxidant capacity assay. The results show that the antioxidative activity of yeast cell wall proteins exceeds that of beta-glucan greatly. Especially aromatic side chains and free thiols from denatured proteins seem to work as antioxidants.


The prevalence and association of chronic kidney disease and diabetes in liver cirrhosis using different estimated glomerular filtration rate equation.
Chronic kidney disease (CKD) in cirrhosis is one of the dreaded complications associated with a steep rise in mortality and morbidity, including diabetes. There are limited data on the prevalence of CKD and the association with diabetes in outpatients with cirrhosis. This is a cross-sectional study of 7,440 adult liver cirrhosis patients enrolled from August 2001 to April 2010 in a medical center. Case control matching by age and sex with 1,967 pairs, and conditional logistic regression for odds of diabetes was analyzed using adjusted model. CKD was present in 46.0%, 45.7% and 45.6% of the study population using the MDRD-6, CKD-EPI and MDRD-4 estimated glomerular filtration rate (eGFR) equations, respectively. Using a conditional logistic regression model after adjusting for other risk factors, odds for diabetes increased significantly compared with non-CKD in CKD stage 3 to 5 (stage 3~5) based on MDRD-6-adjusted model, ORs were: stage 3~5, 2.34 (95% CI, 1.78-3.01); MDRD-4-adjusted model, ORs were: stage 3~5, 8.51 (95% CI, 5.63-11.4); CKD-EPI-adjusted model, ORs were: stage 3~5, 8.61 (95% CI, 5.13-13.9). In cirrhosis patients, prevalence of diabetes was higher in patients with advanced stage of CKD. For patients with cirrhosis, patients with CKD stages 3~5 defined by MDRD-4, MDRD-6, and CKD-EPI eGFR equations had increased risk for diabetes. More severe cirrhosis, indicated by the Child-Turcott-Pugh classification was also accompanied by an increased risk for diabetes.


Severe cranial deformity following cerebrospinal fluid diversion in an adolescent with osteogenesis imperfecta.
Osteogenesis imperfecta (OI) is an inherited connective tissue disorder that causes bone fragility and deformity. Neurological manifestations, including macrocephaly and hydrocephalus, have been reported. Increased vascular fragility or bleeding diathesis also predisposes OI patients to intracranial hemorrhage. The development of chronic subdural fluid collections or hydrocephalus may require CSF diversion. The authors report a previously unrecognized complication of CSF diversion in a patient with OI, that is, a delayed severe cranial deformity, presumably due to over-shunting. In addition to the cosmetic concern, the deformity caused severe headaches and tenderness. The patient underwent craniectomy and titanium mesh cranioplasty, which resulted in the complete resolution of symptoms. This report raises the possibility that over-shunting in patients with OI could predispose to the formation of cranial deformity requiring surgical intervention.


[Surgical treatment of spinal tuberculosis: an orthopedic service experience].
Tuberculosis is responsible for more than 40% of spine infections. While tuberculostatic chemotherapy remains the gold-standard treatment, surgical intervention is necessary only in specific cases. This paper reports the results of 33 patients with spine tuberculosis operated in our department in the last 15 years. Evaluate retrospectively patients with spine tuberculosis operated in the last 15 years - from 1996 to 2011; evaluate the surgical options, infection resolution results, deformity correction, functional results and outcome in cases of neurological injury. Analysis of clinical and radiological assessments of patients diagnosed with spine tuberculosis and operated between 1996 and 2011. In this period 33 patients were operated with average age of 46.7 years; 17 patients had thoracic infection, 11 patients lumbar infection and 5 thoraco-lumbar infection. Paravertebral abscess was identified in 26 cases with intracanal extension in 16 patients. Nine patients had neurological injury. The anterior surgical approach was used in seven cases, the posterior approach in 11 and anterior-posterior approach was preferred in 15 occasions. Antituberculous chemotherapy was maintained on average for 14 months, with mean follow up of 24 months. The infection was eradicated in all patients. Bone fusion was found in average at 10.6 months follow-up. The anterior approach did not produce correction of the initial deformity, while the posterior approach allowed average correction of 12.7° and the anterior-posterior approach a mean correction of 8.7°. Five patients with neurological injury experienced improvement of 2 or 3 levels in ASIA score. We also report complications in two cases where superficial wound infection was diagnosed. Treatment with antituberculosis drugs is the first-line therapy in the treatment of tuberculous spondylodiscitis, while surgical treatment has specific indications. The surgical option, when indicated, allows deformity correction and bone fusion. The anterior-posterior or only posterior surgical approach is preferred in this context. The complication rate was not significant despite the introduction of osteosynthesis hardware.


Evaluating the quality of care for postpartum hemorrhage with a new quantitative tool: a population-based study.
To develop a new tool to assess the global quality of care for post-partum hemorrhage (PPH)-the leading preventable cause of maternal mortality worldwide-and to identify characteristics of maternity units associated with inadequate PPH management. This is a secondary analysis of the EPIMOMS population-based study conducted in 2012-2013 in 119 french maternity units (182,309 women who gave birth). We included women with severe PPH. We first developed a score to quantify the quality of care for PPH. Then, we identified characteristics of the maternity units associated with "inadequate care" defined by a score below the 25th percentile, with multi-level logistic regression adjusted for individual characteristics. The score combined 8 key components of care and took into account delivery mode and PPH cause. For PPH after vaginal delivery, the risk of inadequate care was increased in low versus high-volume maternity units (< 1000 deliveries/year: aOR-2.20 [1.12-4.32], [1000-2000 [deliveries/year: aOR-1.90 [1.02-3.56] compared to ≥ 3500 deliveries/year), in private versus public units (aOR-1.72 [1.00-2.97]), and in low versus high-level of care units (aOR-2.04 [1.24-3.35]). For PPH after cesarean, the only characteristic associated with an increased risk of inadequate care was the absence of 24/24-onsite anesthesiologist (aOR-4.34 [1.41-13.31]). These results indicate where opportunities for improvement are the greatest.


Matter, energy and information network of a graphene-peptide-based fluorescent sensing system for molecular logic computing, detection and imaging of cancer stem cell marker CD133 in cells and tumor tissues.
Tumorigenesis, metastasis, and the recurrence of cancer, which may result from the abnormal presence or activation of cancer stem cells (CSCs), are involved in disorders of exchanged matter (biomarkers), energy and information in living organisms. Rapid and sensitive detection and imaging of CSC biomarkers (such as CD133) are helpful for early diagnosis and therapeutic evaluation of tumors. Recently, a preliminary exploration of a few affinity molecules (like peptide-based probes) has just begun for chemical measurements and imaging of CSC biomarker CD133. However, a comprehensive analysis of the matter, energy and information in an artificial molecular system has not been demonstrated and applied to biosensing and disease diagnosis. In this study, a graphene-peptide-based fluorescent sensing system was constructed by utilizing a graphene oxide platform and a CD133-specific recognition peptide and comprehensively analysed with respect to matter (molecular events), energy (fluorescence) and information flow. The molecular event interaction networks in this system were further used to perform molecular logic computing, for the sensitive detection of CSC marker CD133 (with a linear range from 0 to 630 nM and a detection limit of 7.91 nM), and for an application involving targeting the imaging of cells and tumor tissues that highly express CD133 (with a detection limit of 1.1 × 103 cells per mL for CT26 CSCs). The present report will provide more opportunities for the development and design of molecular-level intelligent complex systems and will probably promote the development of artificial intelligent sensing and treatment systems, a molecular-level "Internet of Things", and artificial life.


Physical foundation of the fluid particle dynamics method for colloid dynamics simulation.
Colloid dynamics is significantly influenced by many-body hydrodynamic interactions mediated by a suspending fluid. However, theoretical and numerical treatments of such interactions are extremely difficult. To overcome this situation, we developed a fluid particle dynamics (FPD) method [H. Tanaka and T. Araki, Phys. Rev. Lett., 2000, 35, 3523], which is based on two key approximations: (i) a colloidal particle is treated as a highly viscous particle and (ii) the viscosity profile is described by a smooth interfacial profile function. Approximation (i) makes our method free from the solid-fluid boundary condition, significantly simplifying the treatment of many-body hydrodynamic interactions while satisfying the incompressible condition without the Stokes approximation. Approximation (ii) allows us to incorporate an extra degree of freedom in a fluid, e.g., orientational order and concentration, as an additional field variable. Here, we consider two fundamental problems associated with these approximations. One is the introduction of thermal noise and the other is the incorporation of coupling of the colloid surface with an order parameter introduced into a fluid component, which is crucial when considering colloidal particles suspended in a complex fluid. Here, we show that our FPD method makes it possible to simulate colloid dynamics properly while including full hydrodynamic interactions, inertia effects, incompressibility, thermal noise, and additional degrees of freedom of a fluid, which may be relevant for wide applications in colloidal and soft matter science.


Start codon disruption with CRISPR/Cas9 prevents murine Fuchs' endothelial corneal dystrophy.
A missense mutation of collagen type VIII alpha 2 chain (COL8A2) gene leads to early-onset Fuchs' endothelial corneal dystrophy (FECD), which progressively impairs vision through the loss of corneal endothelial cells. We demonstrate that CRISPR/Cas9-based postnatal gene editing achieves structural and functional rescue in a mouse model of FECD. A single intraocular injection of an adenovirus encoding both the Cas9 gene and guide RNA (Ad-Cas9-Col8a2gRNA) efficiently knocked down mutant COL8A2 expression in corneal endothelial cells, prevented endothelial cell loss, and rescued corneal endothelium pumping function in adult Col8a2 mutant mice. There were no adverse sequelae on histology or electroretinography. Col8a2 start codon disruption represents a non-surgical strategy to prevent vision loss in early-onset FECD. As this demonstrates the ability of Ad-Cas9-gRNA to restore the phenotype in adult post-mitotic cells, this method may be widely applicable to adult-onset diseases, even in tissues affected with disorders of non-reproducing cells.


Protective effect of alpha-lipoic acid against chloroquine-induced hepatotoxicity in rats.
Oral administration of a-lipoic acid, a metavitamin, was investigated for its possible hepatoprotective effect in Wistar rats against chloroquine-induced toxicity. Rats were treated orally with alpha-lipoic acid (10, 30 and 100 mg x kg(-1) day(-1)) for 7 days before a single oral administration of chloroquine (970 mg x kg(-1) day(-1)) and alpha-lipoic acid treatment was continued for three more days. The increased level of serum enzymes (aspartate transaminase, alanine transaminase and alkaline phosphatase), bilirubin, lipids and plasma thiobarbituric acid-reactive substances (TBARS) and hydroperoxides observed in rats treated with chloroquine were very much reduced in rats treated with alpha-lipoic acid plus chloroquine. A significant decrease in plasma antioxidants such as reduced glutathione (GSH), vitamin C and vitamin E were observed in chloroquine-treated rats when compared with control rats. Administration of alpha-lipoic acid significantly improved the levels of plasma antioxidants GSH, vitamin C and vitamin E in chloroquine-treated rats. In the case of 100 mg x kg(-1) day(-1) the effect was highly significant compared with the other doses (10 and 30 mg x kg(-1) day(-1)). The results of the study revealed that alpha-lipoic acid could offer protection against chloroquine-induced hepatotoxicity. alpha-Lipoic acid had a better protective effect when compared with silymarin, a reference drug.


When the marginal artery is not marginal.
In the course of dissection one does not normally pay much attention to the anastomosing loops forming the marginal artery. The observation of a significant precolic anastomosing loop on the descending colon of a spare subject came as quite a surprise. The same was noted on a second subject, an obese male with sagging abdomen and, to a lesser degree, on a third. Such an occurrence would have surgical significance, if only because the evaluation of the blood supply to the segment of bowel that was to be resected would be much more difficult. In addition, the blood supply to the distal bowel could be impaired following resection, depending upon the collateral circulation.


Teriflunomide Treatment of Multiple Sclerosis Selectively Modulates CD8 Memory T Cells.
Inhibition of de novo pyrimidine synthesis in proliferating T and B lymphocytes by teriflunomide, a pharmacological inhibitor of dihydroorotate dehydrogenase (DHODH), has been shown to be an effective therapy to treat patients with MS in placebo-controlled phase 3 trials. Nevertheless, the underlying mechanism contributing to the efficacy of DHODH inhibition has been only partially elucidated. Here, we aimed to determine the impact of teriflunomide on the immune compartment in a longitudinal high-dimensional follow-up of patients with relapse-remitting MS (RRMS) treated with teriflunomide. High-dimensional spectral flow cytometry was used to analyze the phenotype and the function of innate and adaptive immune system of patients with RRMS before and 12 months after teriflunomide treatment. In addition, we assessed the impact of teriflunomide on the migration of memory CD8 T cells in patients with RRMS, and we defined patient immune metabolic profiles. We found that 12 months of treatment with teriflunomide in patients with RRMS does not affect the B cell or CD4 T cell compartments, including regulatory TREG follicular helper TFH cell and helper TH cell subsets. In contrast, we observed a specific impact of teriflunomide on the CD8 T cell compartment, which was characterized by decreased homeostatic proliferation and reduced production of TNFα and IFNγ. Furthermore, we showed that DHODH inhibition also had a negative impact on the migratory velocity of memory CD8 T cells in patients with RRMS. Finally, we showed that the susceptibility of memory CD8 T cells to DHODH inhibition was not related to impaired metabolism. Overall, these findings demonstrate that the clinical efficacy of teriflunomide results partially in the specific susceptibility of memory CD8 T cells to DHODH inhibition in patients with RRMS and strengthens active roles for these T cells in the pathophysiological process of MS.


Predicting folic acid intake among college students.
Annually in the United States, approximately 3,000 babies are born with neural tube defects (NTDs). Folic acid supplementation can reduce NTDs by 50% to 70%. Despite recommendations for folic acid intake, only 30% of women ages 18 to 24 report folic acid supplementation and 6% have knowledge of when to take folic acid. There is little information regarding lifestyle factors that correlate with consuming folic acid. The purpose was to describe folic acid consumption among college students; and explore the relationship between folic acid intake and the variables of: age, gender, year in college, alcohol and tobacco use, and vitamin supplement intake. This was a descriptive study with secondary analysis of data from 1,921 college-aged student participants in North Carolina who took part in a pretest/posttest-designed intervention to increase folic acid consumption and knowledge. Surveys included demographic, lifestyle, folic acid knowledge, and consumption questions adapted from the Centers for Disease Control and Prevention questionnaire. Quantitative analyses included descriptive statistics and logistic regression. Of the 1,921 college students, 83.3% reported taking a vitamin supplement, but only 47.6% stated that the vitamin contained folic acid. A relationship was found between age, year in school, gender, and vitamin intake. Lifestyle variables were not significant predictors of folic acid consumption. Identification of variables associated with folic acid intake, marketing, and education can be focused to increase supplementation levels, and ultimately reduce the number of NTDs.


Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration.
The corticospinal tract (CST) is the most important motor system in humans, yet robust regeneration of this projection after spinal cord injury (SCI) has not been accomplished. In murine models of SCI, we report robust corticospinal axon regeneration, functional synapse formation and improved skilled forelimb function after grafting multipotent neural progenitor cells into sites of SCI. Corticospinal regeneration requires grafts to be driven toward caudalized (spinal cord), rather than rostralized, fates. Fully mature caudalized neural grafts also support corticospinal regeneration. Moreover, corticospinal axons can emerge from neural grafts and regenerate beyond the lesion, a process that is potentially related to the attenuation of the glial scar. Rat corticospinal axons also regenerate into human donor grafts of caudal spinal cord identity. Collectively, these findings indicate that spinal cord 'replacement' with homologous neural stem cells enables robust regeneration of the corticospinal projection within and beyond spinal cord lesion sites, achieving a major unmet goal of SCI research and offering new possibilities for clinical translation.


Hyaluronan as a propellant for epithelial movement: the development of semicircular canals in the inner ear of Xenopus.
The membranous labyrinth of the inner ear, with its three semicircular canals, originates from a simple spheroidal otic vesicle. The process is easily observed in Xenopus. The vesicle develops three dorsal outpocketings; from the two opposite faces of each outpocketing pillars of tissue are protruded into the lumen; and these paired 'axial protrusions' eventually meet and fuse, to form a column of tissue spanning the lumen of the outpocketing like the hub of a wheel, with a tube of epithelium forming the semicircular canal around the periphery. Each axial protrusion consists of epithelium encasing a core of largely cell-free extracellular matrix that stains strongly with alcian blue. In sections, at least 60% of the stainable material is removed by treatment with Streptomyces hyaluronidase. When Streptomyces hyaluronidase is microinjected into the core of a protrusion in vivo, the protrusion collapses and the corresponding semicircular canal fails to form. Hyaluronan (hyaluronic acid) in the core of the protrusion therefore seems to be essential in driving the extension of the protrusion. Autoradiography with tritiated glucosamine indicates that the hyaluronan-rich matrix is synthesised by the epithelium covering the tip of the protrusion; the basal lamina here appears to be discontinuous. These findings indicate that the epithelium of the axial protrusion propels itself into the lumen of the otocyst by localised synthesis of hyaluronan. Hyaluronan may be used in a similar way in the development of other organs, such as the heart and the secondary palate.


YAP: The nexus between metabolism and cardiac remodeling.
Cardiomyocyte hypertrophy is an integral part of cardiac remodeling that occurs under physiological or pathological stresses. It can lead to heart failure in a pathological form or oppose functional deterioration in a compensatory one. The mechanisms underlying an adaptive outcome of hypertrophy are ill defined. In this issue of the JCI, Kashihara et al. explored the role of the Yes-associated protein 1 (YAP) transcription factor in the heart, using cell culturing and mouse models. YAP activity was found to be associated with changes in genes of the glycolytic and auxiliary pathways under stress. Notably, YAP upregulated glucose transporter 1 (GLUT1), and inhibition of GLUT1 blocked YAP-induced hypertrophy but worsened heart function. These findings suggest that YAP is a regulator of metabolic reprogramming in the heart during compensatory hypertrophy. This insight may help in the development of future therapies for heart failure.


Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies.
Curcuminoids, which include natural acyclic diarylheptanoids and the synthetic analogs of curcumin, have considerable potential for fighting against all the characteristics of invasive cancers. The epithelial-to-mesenchymal transition (EMT) is a fundamental process for embryonic morphogenesis, however, the last decade has confirmed it orchestrates many features of cancer invasiveness, such as tumor cell stemness, metabolic rewiring, and drug resistance. A wealth of studies has revealed EMT in cancer is in fact driven by an increasing number of parameters, and thus understanding its complexity has now become a cornerstone for defining future therapeutic strategies dealing with cancer progression and metastasis. A specificity of curcuminoids is their ability to target multiple molecular targets, modulate several signaling pathways, modify tumor microenvironments and enhance the host's immune response. Although the effects of curcumin on these various parameters have been the subject of many reviews, the role of curcuminoids against EMT in the context of cancer have never been reviewed so far. This review first provides an updated overview of all EMT drivers, including signaling pathways, transcription factors, non-coding RNAs (ncRNAs) and tumor microenvironment components, with a special focus on the most recent findings. Secondly, for each of these drivers the effects of curcumin/curcuminoids on specific molecular targets are analyzed. Finally, we address some common findings observed between data reported in the literature and the results of investigations we conducted on experimental malignant mesothelioma, a model of invasive cancer representing a useful tool for studies on EMT and cancer.


Effect of cooking on the total antioxidant capacity and phenolic profile of some whole-meal African cereals.
At present, sorghum, fonio and millet are not placed as important commodities in the North American and European food basket, but their importance as ingredients in multigrain and gluten-free cereal products is highlighted. Therefore in this study the phenolic profile (evaluated by liquid chromatography/tandem mass spectrometry), total phenolic content (assessed by Folin-Ciocalteu assay) and total antioxidant capacity were measured in three African whole grains, i.e. sorghum (Sorghum bicolor ssp. bicolor), fonio (Digitaria exilis) and pearl millet (Pennisetum glaucum L.), before and after a cooking procedure. After the cooking process, soluble phenolic acids increased significantly in sorghum, whereas bound ones and anthocyanins decreased significantly. In millet the cooking process significantly enhanced soluble phenolic acids without affecting those bound, whereas in fonio a slight but significant decrease in almost all soluble phenolic acids was observed along with a significant increase in bound ones. Finally, the cooking process negatively affected both total phenolic content and total antioxidant capacity. This is one of the few reports dealing with the antioxidant compounds of these three African whole grains in which the effect of cooking was also evaluated. The data suggested that, to improve their antioxidant properties, specific cultivars should be selected and the cooking procedures carefully considered.


The Association Between Childhood Trauma and Attachment Functioning in Patients With Personality Disorders.
Attachment (mal)functioning and a history of childhood trauma (CT) are both considered psychological determinants of personality disorders (PDs). Their interaction, however, remains largely uninvestigated. In this study, the authors assessed adult and childhood attachment style in a sample of patients with diverse PDs (N = 75) and determined the relation with both occurrence and severity of CT. The authors found that the sample was characterized by severe attachment malfunctioning and high levels of CT. Using cross-tabulations and analysis of variance, the authors showed that patients with a fearful or dismissive attachment style experienced more severe CT than patients with a preoccupied attachment style. Patients reporting an affectionless control bonding style to either parent suffered frequent and severe CT. Although temporal causality cannot be determined, these findings stress the necessity to screen for CT in PDs and suggest that attachment-centered psychotherapy for these patients may benefit from preceding or concurrent trauma treatment.


Italian Euromelanoma Day Screening Campaign (2005-2007) and the planning of melanoma screening strategies.
Although no study has definitively shown that unfocused screening of skin cancer is effective, many campaigns have been organized with the aim of increasing awareness on melanoma risk factors. The objective of this study was to analyse the results of the Skin Cancer Screening Day in Italy during the period 2005-2007, to determine the priorities for melanoma control plans in a Mediterranean country. A total of 5002 patients were screened by dermatologists in 31 cities. Individuals who considered themselves to have many naevi and those with a family history of melanoma showed a higher number of common and atypical naevi. Ten melanomas, 20 basal cell carcinomas and two squamous cell carcinomas were histopathologically confirmed. Our observations provide the following suggestions for melanoma prevention strategies: (a) an unfocused campaign is suitable to inform the public about the importance of self-examination of the skin, but is not useful to identify a larger number of melanomas; and (b) melanoma screening campaigns should focus on a selected population, which meets rigorous risk criteria to maintain higher cost-effectiveness. The financial support to effective melanoma screening programmes could be increased, especially in southern populations where lower levels of self-surveillance and socioeconomic conditions represent risk factors for late identification of melanoma.


Implementation and impact on length of stay of a post-discharge remote patient monitoring program for acutely hospitalized COVID-19 pneumonia patients.
In order to manage COVID-19 patient population and bed capacity issues, remote patient monitoring (RPM) is a strategy used to transition patients from inpatients to home. We describe our RPM implementation process for post-acute care COVID-19 pneumonia patients. We also evaluate the impact of RPM on patient outcomes, including hospital length of stay (LOS), post-discharge Emergency Department (ED) visits, and hospital readmission. We utilized a cloud-based RPM platform (Vivify Health) and a nurse-monitoring service (Global Medical Response) to enroll COVID-19 patients who required oxygen supplementation after hospital discharge. We evaluated patient participation, biometric alerts, and provider communication. We also assessed the program's impact by comparing RPM patient outcomes with a retrospective cohort of Control patients who similarly required oxygen supplementation after discharge but were not referred to the RPM program. Statistical analyses were performed to evaluate the 2 groups' demographic characteristics, hospital LOS, and readmission rates. The RPM program enrolled 75 patients with respondents of a post-participation survey reporting high satisfaction with the program. Compared to the Control group (n = 150), which had similar demographics and baseline characteristics, the RPM group was associated with shorter hospital LOS (median 4.8 vs 6.1 days; P=.03) without adversely impacting return to the ED or readmission. We implemented a RPM program for post-acute discharged COVID-19 patients requiring oxygen supplementation. Our RPM program resulted in a shorter hospital LOS without adversely impacting quality outcomes for readmission rates and improved healthcare utilization by reducing the average LOS.


Evidence for a dynamic cycle between Mn and Co in the water column of a stratified lake.
The geochemical behavior of Co in aquatic systems has often been related to the presence of Fe and Mn particles. A few studies have shown that Co is exclusively associated with particulate Mn, but the dynamics of Co and Mn cycling have never been determined in real time under natural conditions. In this study, we used a combination of analytical techniques to study the temporal and spatial evolution of Mn microparticles (MnOx) over 2 weeks in the water column of a shallow stratified lake (Paul Lake, MI). We report a temporal accumulation of dissolved Mn at the oxic-anoxic transition, and we show that this accumulation is due to the reductive dissolution of Mn particles. The reductant has not been identified, but abiotic reduction by sigmaH2S and ferrous iron is excluded because they are produced below the zone of MnOx reduction. Hybridization of RNA isolated from Paul Lake with oligonucleotide probes targeting the delta proteobacteria, which include metal-reducing species, suggests that their activity is greatest at and just below the oxic-anoxic transition, so that Mn reduction may be influenced by bacterial activity. Mn-oxidizing bacteria were isolated from this zone as well. We also demonstrate that the dynamic evolution of MnOx has a direct influence on the distribution of Co in the water column of this lake: dissolved Co is released during the reductive dissolution of MnOx and accumulates at the redox interface.