Attitudes of dentists and physicians toward the use of dietary fluoride supplements.
One of the major goals of the reported research was to determine how consistent health practitioners' knowledge, attitudes and practices are with the consensus of the public health and research communities regarding caries prevention. Both professions are aware of current caries preventive methods, but have very mixed reactions toward their relative effectiveness in the United States, today. Dentists and physicians see a great deal of value in community water fluoridation and see some effectiveness from fluoridating school water supplies. They regard the prescription of dietary fluoride supplements as an effective caries prevention measure, but to a much lesser extent, and base their use of these prescriptions on the age of the child and the level of fluoride in the community's water system. Topical fluoride applications and fluoride dentifrices, as well, are thought to be very effective preventive measures by only a small proportion of dentists and physicians, as are fluoride mouth rinses. Dentists and physicians rate systemic fluorides as effective more often than they do other selected methods, as would the research community; but they are not as solidly behind these, as evidence would suggest they should be. Both community water fluoridation and dietary fluoride supplements are known to be very effective caries prevention measures, yet only 66 percent of the physicians think community water fluoridation is very effective and only 37 percent think dietary fluoride supplements are very effective.(ABSTRACT TRUNCATED AT 250 WORDS)


The role of the state hospital: a new mandate for a new era.
We are fast approaching a centennial of New York State's institutional system, the anniversary of the State Care Act of 1980. This can be evaluated against another important anniversary; the quarter century mark of the current convulsion/revolution of the mental hygiene care system of the entire United States, commonly referred to as deinstitutionalization. The state institutions, which for the past century were built up and maintained as the major locus of care for the chronically mentally ill, no longer occupy that central place in many localities. Yet these hospitals must continue to struggle with overwhelming burdens. Their inpatient populations, although now much smaller, still include many seriously mentally ill patients as well as the essentially non-dischargeable elderly. In addition, they must provide for young adults with a new profile of difficult behavior and challenging demands. This article is an attempt to redefine the role of the state institution in what has become the new era of community care, and to suggest fruitful new directions for the future which incorporate a contemporary shift in focus: from the concept of illness to that of disability, and from a reliance on a facility or specific program to the development of a comprehensive and integrated system of treatment and support services.


Thiocarbamates from Moringa oleifera Seeds Bioactive against Virulent and Multidrug-Resistant Vibrio Species.
Prospect of antibacterial agents may provide an alternative therapy for diseases caused by multidrug-resistant bacteria. This study aimed to evaluate the in vitro bioactivity of Moringa oleifera seed extracts against 100 vibrios isolated from the marine shrimp Litopenaeus vannamei. Ethanol extracts at low (MOS-E) and hot (MOS-ES) temperature are shown to be bioactive against 92% and 90% of the strains, respectively. The most efficient Minimum Inhibitory Concentration (MIC) levels of MOS-E and MOS-ES against a high percentage of strains were 32 µg mL-1. Bioguided screening of bioactive compounds showed that the ethyl acetate fraction from both extracts was the only one that showed antibacterial activity. Vibriocidal substances, niazirine and niazimicine, were isolated from the aforementioned fraction through chromatographic fractionation.


[The effect of the laser irradiation of the blood on its lipid and phospholipid components in diabetes mellitus].
Study results of the laser irradiation impact on the blood lipid and phospholipid components and membrane erythrocyte in patients with diabetes mellitus and pyo-necrotic injuries of lower extremities when treated by laser intravenously or epicutaneously. The results prove, that the laser irradiation of low intensity favourably affects the blood components in a complex treatment of diabetes mellitus. Intravenous irradiation positive dynamics are more easily observed.


Angiogenesis and Full-Thickness Wound Healing Efficiency of a Copper-Doped Borate Bioactive Glass/Poly(lactic- co-glycolic acid) Dressing Loaded with Vitamin E in Vivo and in Vitro.
There is an urgent demand for wound healing biomaterials because of the increasing frequency of traffic accidents, industrial contingencies, and natural disasters. Borate bioactive glass has potential applications in bone tissue engineering and wound healing; however, its uncontrolled release runs a high risk of rapid degradation and transient biotoxicity. In this study, a novel organic-inorganic dressing of copper-doped borate bioactive glass/poly(lactic- co-glycolic acid) loaded with vitamin E (0-3.0 wt % vitamin E) was fabricated to evaluate its efficiency for angiogenesis in cells and full-thickness skin wounds healing in rodents. In vitro results showed the dressing was an ideal interface for the organic-inorganic mixture and a controlled release system for Cu2+ and vitamin E. Cell culture suggested the ionic dissolution product of the copper-doped and vitamin E-loaded dressing showed the best migration, tubule formation, and vascular endothelial growth factor (VEGF) secretion in human umbilical vein endothelial cells (HUVECs) and higher expression levels of angiogenesis-related genes in fibroblasts in vitro. Furthermore, this dressing also suggested a significant improvement in the epithelialization of wound closure and an obvious enhancement in vessel sprouting and collagen remodeling in vivo. These results indicate that the copper-doped borate bioactive glass/poly(lactic- co-glycolic acid) dressing loaded with vitamin E is effective in stimulating angiogenesis and healing full-thickness skin defects and is a promising wound dressing in the reconstruction of full-thickness skin injury.


Prolonged Natural Deferment of Hatching in Killifish.
The drying up of flooded lowlands stranded eggs of Fundulus confluentus, which were unhatched and viable after as much as 3 months' exposure. The eggs were found in the moist plant debris on the soil surface. When ovigerous sods were immersed in tap water, normal fish hatched within 15 to 30 minutes.


Assessment of municipal waste compost as a daily cover material for odour control at landfill sites.
The ability of municipal waste compost as a daily cover material to reduce the odorous emissions associated with landfill surfaces was investigated. Trials were carried out using landfill gas, a certified sulphurous gas mix and ambient air as a control. Odorous gas was passed through portable test column filled with compost at different densities (590 kg/m3 and 740 kg/m3). Gas samples were taken from the inlet, outlet and at varying column depths and examined using a combination of sensory analysis (olfactometry) and a novel analytical method (Transportable Selected Ion Flow Tube--TSIFT). Results for the trials using landfill gas showed a 69% odour reduction (OU/m3) through the column for compost with a bulk density of 590 kg/m3, and a reduction of 97% using compost with a bulk density of 740 kg/m3. TSIFT analysis showed an overall decrease in the concentration of terpenes, and sulphurous compounds in the outlet gas from the column for both bulk densities. No significant trend could be identified for the concentrations at different depths within the column. Results show the ability of compost to reduce landfill odours under differing conditions. The inconclusive data provided by TSIFT analysis may be due to the analysis of compounds that are not contributing to odour, and thus highlights the potential for synergetic effects and the importance of sensory measurement when examining odorous emissions.


Prevalence of Group B Streptococcus in Pregnant Women in Iran: A Systematic Review and Meta-analysis.
Group B Streptococcus (GBS or S. agalactiae) is a major cause of severe disease in neonates. In perinatal infections or early-onset disease, GBS is transmitted vertically to the newborn from the birth canal during labor and delivery. Limited information is available on the prevalence of GBS recto-vaginal colonization among pregnant women in Iran. We performed a systematic search by using different electronic databases including Medline (via Pubmed), Embase, Web of Science and Iranian Database. Meta-analysis was performed by Comprehensive Meta-Analysis (Biostat V2.2) software. Of 250 articles published from January 2000 to September 2016, 25 studies that reported incidence of GBS colonization in pregnant women were included in this review. The meta-analyses showed that the prevalence of GBS colonization among Iranian pregnant women was 9.8% (95% confidence interval, 7.9-12). The results of this study indicate that GBS screening measures and chemoprophylaxis guidelines concerning GBS infections must be established for pregnant women in Iran, and these guidelines must provide guidance for obstetricians, midwives and neonatologists on the prevention of GBS infections.


Combination of immunocytochemistry and radioligand receptor assay to identify beta-adrenergic receptor subtypes on astroglia in vitro.
There is an increasing need to assess the distribution of receptors for neuroactive substances on specific neural cell types. This study describes the establishment of methodology that combines the quantification of beta-adrenergic receptor subtypes by radioligand binding assays with immunocytochemical analysis of the contribution of astroglia (identified by the presence of glial fibrillary acidic protein) and fibroblasts (identified by the presence of fibronectin) to cultures prepared from neonatal rat cerebral cortex. The effects of subtle changes in culture methodology on the cellular composition of cerebral cortical cultures and the distribution of beta-adrenergic receptor subtypes were examined. The data indicate that (1) a decrease in the density of the initial plating suspension, (2) an increase in the age of the animals, or (3) supplementation of the cortical cell suspension with meningeal fibroblasts all result in an increase in fibronectin staining and a decrease in glial fibrillary acidic protein antibody staining. This change in the cellular composition of the cortical cultures correlated with an increase in the number of beta 2-adrenergic receptors and a corresponding decrease in the number of beta 1-adrenergic receptors. These observations point out the care which must be exercised when preparing primary astroglial cultures of sufficient purity for large-scale biochemical and pharmacological studies.


Inhibition of human cytomegalovirus replication by interferon alpha can involve multiple anti-viral factors.
The shortcomings of current direct-acting anti-viral therapy against human cytomegalovirus (HCMV) has led to interest in host-directed therapy. Here we re-examine the use of interferon proteins to inhibit HCMV replication utilizing both high and low passage strains of HCMV. Pre-treatment of cells with interferon alpha (IFNα) was required for robust and prolonged inhibition of both low and high passage HCMV strains, with no obvious toxicity, and was associated with an increased anti-viral state in HCMV-infected cells. Pre-treatment of cells with IFNα led to poor expression of HCMV immediate-early proteins from both high and low passage strains, which was associated with the presence of the anti-viral factor SUMO-PML. Inhibition of HCMV replication in the presence of IFNα involving ZAP proteins was HCMV strain-dependent, wherein a high passage HCMV strain was obviously restricted by ZAP and a low passage strain was not. This suggested that strain-specific combinations of anti-viral factors were involved in inhibition of HCMV replication in the presence of IFNα. Overall, this work further supports the development of strategies involving IFNα that may be useful to inhibit HCMV replication and highlights the complexity of the anti-viral response to HCMV in the presence of IFNα.


Multiple blocks to human immunodeficiency virus type 1 replication in rodent cells.
The recent identification of human gene products that are required for early steps in the human immunodeficiency virus type 1 (HIV-1) life cycle has raised the possibility that rodents might be engineered to support HIV-1 infection. Therefore, we have examined the ability of modified mouse, rat, and hamster cell lines to support productive HIV-1 replication. Rodent cells, engineered to support Tat function by stable expression of a permissive cyclin T1 protein, proved to be able to support reverse transcription, integration, and early gene expression at levels comparable to those observed in human cell lines. Surprisingly, however, levels of CD4- and coreceptor-dependent virus entry were reduced to a variable but significant extent in both mouse and rat fibroblast cell lines. Additional posttranscriptional defects were observed, including a reduced level of unspliced HIV-1 genomic RNA and reduced structural gene expression. Furthermore, the HIV-1 Gag precursor is generally inefficiently processed and is poorly secreted from mouse and rat cells in a largely noninfectious form. These posttranscriptional defects, together, resulted in a dramatically reduced yield of infectious virus (up to 10,000-fold) over a single cycle of HIV-1 replication, as compared to human cells. Interestingly, these defects were less pronounced in one hamster cell line, CHO, which not only was able to produce infectious HIV-1 particles at a level close to that observed in human cells, but also could support transient, low-level HIV-1 replication. Importantly, the blocks to infectious virus production in mouse and rat cells are recessive, since they can be substantially suppressed by fusion with uninfected human cells. These studies imply the existence of one or more human gene products, either lacking or nonfunctional in most rodent cells that are critical for infectious HIV-1 virion morphogenesis.


The physics of the colloidal glass transition.
As one increases the concentration of a colloidal suspension, the system exhibits a dramatic increase in viscosity. Beyond a certain concentration, the system is said to be a colloidal glass; structurally, the system resembles a liquid, yet motions within the suspension are slow enough that it can be considered essentially frozen. For several decades, colloids have served as a valuable model system for understanding the glass transition in molecular systems. The spatial and temporal scales involved allow these systems to be studied by a wide variety of experimental techniques. The focus of this review is the current state of understanding of the colloidal glass transition, with an emphasis on experimental observations. A brief introduction is given to important experimental techniques used to study the glass transition in colloids. We describe features of colloidal systems near and in glassy states, including increases in viscosity and relaxation times, dynamical heterogeneity and ageing, among others. We also compare and contrast the glass transition in colloids to that in molecular liquids. Other glassy systems are briefly discussed, as well as recently developed synthesis techniques that will keep these systems rich with interesting physics for years to come.


Do tiger keelback snakes (Rhabdophis tigrinus) recognize how toxic they are?
Animals that depend on defensive chemicals acquired from food may face a decision when attempting to deter predatory attacks: Should they exhibit antipredator behavior that relies on the toxicity of the sequestered chemicals or should they adopt other behaviors that can avoid predation without using the chemical defense, such as flight? Thus, it is reasonable to assume that animals that sequester prey toxins have evolved the ability to flexibly change their antipredator responses according to the amount of toxin-resource they have consumed. We tested this hypothesis using an Asian snake, Rhabdophis tigrinus, that sequesters toxins from toads consumed as food and stores them in specialized organs back of the head, called nuchal glands. We reared hatchling snakes from toad-free and toad-rich islands on controlled diets and examined their subsequent antipredator responses after 3 and 6 month feeding. Juveniles from a toad-free island that had been fed a diet including toads for 3 months showed antipredator displays associated with the nuchal glands more frequently than those that had been fed a diet without toads. They showed a similar, but less clear, tendency after 6 months feeding. Juveniles from the toad-rich island did not show a clear tendency of dietary effect. We discuss possible reasons for the different dietary effects between the 2 populations and between the ages. Our results, along with previous related phenomena in other animals, suggest that the ability of self-toxicity-recognition may be widespread in animals that sequester defensive toxins from facultative food. (PsycINFO Database Record


Development of an oxirane/acrylate interpenetrating polymer network (IPN) resin system.
Develop a hydrophobic, degradation-resistant dental restorative based on an Oxirane-Acrylate IPN System (OASys) with low shrinkage-stress to substantially extend clinical lifetime. Unfilled OASys blends were prepared using dipenta-erythritol-hexaacrylate (DPHA) and p-cycloaliphatic-diepoxide (EP5000). Varying proportions of camphorquinone/iodonium photoinitiator, with a co-reactant oligomeric-diol, served as the experimental curing system. The effects of oxirane-acrylate ratio on the degree-of-cure (Durometer-D hardness), hydrophobicity (contact angle), mechanical properties (3-point bending), near-infrared FTIR degree-of-conversion (DoC), polymerization shrinkage, and shrinkage stress were determined. 70:30 BisGMA:TEGDMA resin served as control. Oxirane tended to decrease hardness and increase hydrophobicity. 0:100, 25:75, 50:50 EP5000:DPHA are harder after 24h than control. 75:25 and 100:0 EP5000:DPHA increased in hardness over 24h, but were softer than control. All groups increased in contact angle over 24h. After 24h, 50:50, 75:25 and 0:100 EP5000:DPHA were more hydrophobic (∼75-84°) than the control (∼65°). Acrylate DoC was ∼60% across all experimental groups. Initial oxirane conversion varied from ∼42% in 100:0 EP5000:DPHA to ∼82% 75:25 EP5000:DPHA. However, oxirane DoC increased for 100:0 EP5000:DPHA to ∼73° over 24h, demonstrating dark cure. Moduli and ultimate transverse strengths of OASys groups were higher than for 0:100 EP5000:DPHA, with 50:50 EP5000:DPHA having higher modulus than other experimental groups. However, the control had higher modulus and UTS than all experimental groups. Volumetric shrinkage averaged 7% for experimental groups, but stress decreased dramatically with increasing oxirane content. Hydrophobic, low shrinkage-stress OASys resins are promising for development of composites that improve longevity and reduce the cost of dental care.


Evaluation of the genotoxicity of zerumbone in cultured human peripheral blood lymphocytes.
The chromosomal aberrations (CA) assay and micronucleus (MN) test were employed to investigate the effect in vitro of zerumbone (ZER) on human chromosomes. ZER is a sesquiterpene compound isolated from the rhizomes of wild ginger, Zingiber zerumbet Smith. The rhizomes of the plant are employed as a traditional medicine for some ailments and as condiments. ZER has been shown to have anti-cancer and apoptosis-inducing properties against various human tumour cells. It has also been shown to be active in vivo against a number of induced malignancies. Studies on ZER genotoxicity in cultured human peripheral blood lymphocytes (PBL) have not been reported so far. Therefore, the present study was undertaken to investigate the ability of ZER to induce chromosomal aberrations and micronuclei formation in human lymphocytes in vitro. Human blood samples were obtained from four healthy, non-smoking males aged 25-35years. Cultures were exposed to the drug for 48h at four final concentrations: 10, 20, 40 and 80 microM. Mitomycin C (MMC) was used as a positive control. The results of chromosomal aberrations assay showed that ZER was not clastogenic, when compared to untreated control, meanwhile MN test results showed a dose-dependent increase in MN formation. The overall clastogenic effect of ZER on human PBL was statistically not significant. In conclusion, ZER is a cytotoxic but not a clastogenic substance in human PBL.


The selective neurokinin 3 antagonist AZD2624 does not improve symptoms or cognition in schizophrenia: a proof-of-principle study.
Problems with the efficacy of second-generation antipsychotics on negative symptoms and cognition have highlighted the need for further development of drugs targeting central nervous system neurotransmitter systems other than dopamine. One target in development is neurokinin 3 (NK(3)) tachykinin receptors, which are coreleased and interact with dopamine. This study investigates the efficacy, tolerability, and cognitive effects of AZD2624, a selective, orally active NK(3) receptor antagonist, in symptomatic patients with schizophrenia. Patients were randomly assigned to 1 of 3 treatment groups: AZD2624 40 mg, placebo, or olanzapine 15 mg. Treatment lasted for 28 days, and the Positive and Negative Syndrome Scale, the Clinical Global Impression Severity Scale and Improvement Scales, and cognition as assessed by CogState were used as primary outcome measures. There were no significant differences in patients treated with AZD2624 versus placebo on change in Positive and Negative Syndrome Scale total score and Clinical Global Impression Severity Scale; in addition, no change in CogState measures was found. Results of the trial do not support a role for the NK(3) antagonist AZD2624 as a therapeutic treatment for acute schizophrenia when used as monotherapy.


Child characteristics and parental educational expectations: evidence for transmission with transaction.
Parents' expectations for their children's ultimate educational attainment have been hypothesized to play an instrumental role in socializing academically relevant child behaviors, beliefs, and abilities. In addition to social transmission of educationally relevant values from parents to children, parental expectations and child characteristics may transact bidirectionally. We explore this hypothesis using both longitudinal and genetically informative twin data from the Early Childhood Longitudinal Study-Birth and Kindergarten cohorts. Our behavior genetic results indicate that parental expectations partly reflect child genetic variation, even as early as 4 years of age. Two classes of child characteristics were hypothesized to contribute to these child-to-parent effects: behavioral tendencies (approaches toward learning and problem behaviors) and achievement (math and reading). Using behavior genetic models, we find within-twin-pair associations between these child characteristics and parental expectations. Using longitudinal cross-lagged models, we find that initial variation in child characteristics predicts future educational expectations above and beyond previous educational expectations. These results are consistent with transactional frameworks in which parent-to-child and child-to-parent effects co-occur.


Load-sensitive coupling of proton translocation and torque generation in the bacterial flagellar motor.
The Salmonella flagellar motor consists of a rotor and about a dozen stator elements. Each stator element, consisting of MotA and MotB, acts as a proton channel to couple proton flow with torque generation. A highly conserved Asp33 residue of MotB is directly involved in the energy coupling mechanism, but it remains unknown how it carries out this function. Here, we show that the MotB(D33E) mutation dramatically alters motor performance in response to changes in external load. Rotation speeds of the MotA/B(D33E) and MotA(V35F)/B(D33E) motors were markedly slower than the wild-type motor and fluctuated considerably at low load but not at high load, whereas the rotation rate of the wild-type motor was stable at any load. At low load, pausing events were frequently observed in both mutant motors. The proton conductivities of these mutant stator channels in their 'unplugged' forms were only half of the conductivity of the wild-type channel. These results suggest that the D33E mutation induces a load-dependent inactivation of the MotA/B complex. We propose that the stator element is a load-sensitive proton channel that efficiently couples proton translocation with torque generation and that Asp33 of MotB is critical for this co-ordinated proton translocation.


Exogenous cAMP and cGMP modulate branching in fusarium graminearum.
A study was made of the effects of adenosine 3',5'-cyclic monophosphate (cAMP), guanosine 3',5'-cyclic monophosphate (cGMP) and choline on the morphology and growth of a wild-type strain (A 3/5) and a highly branched, 'colonial' mutant strain (C106) of Fusarium graminearum. Addition of up to 50 mM-cAMP or cGMP to the medium had no effect on the specific growth rate of strain A 3/5. For strain A 3/5, but not for strain C106, exogenous cAMP caused significant decreases in both mean hyphal extension rate (E) and hyphal growth unit length (G), i.e. cAMP caused mycelia of strain A 3/5 to branch profusely. By contrast, for both strains, cGMP caused significant increases in both E and G, i.e. exogenous cGMP caused mycelia to branch more sparsely. The effects of exogenous cGMP and choline in increasing E and G were synergistic, but the effects of cGMP and choline counteracted the effect of cAMP. The mutant phenotype of strain C106 was not correlated with altered levels of endogenous cAMP or cGMP.


Determination of mutagenicity and genotoxicity of indium tin oxide nanoparticles using the Ames test and micronucleus assay.
In this study, the mutagenicity and genotoxicity of indium tin oxide (ITO) nanomaterial were assessed using two standard genotoxicity assays, the Salmonella reverse mutation assay (Ames test) and the in vitro micronucleus (MN) assay. Seven different concentrations (12.5, 25, 50, 75, 100, 125, and 150 µg/plate) of this nanomaterial were tested using the Ames test on the TA98 and TA100 strains in the presence and absence of the S9 mixture. At all the concentrations tested, this substance did not significantly increase the number of revertant colonies compared with the control with or without S9 mixture. The genotoxic effects of ITO were investigated in human peripheral lymphocytes treated with 125, 250, 500, and 750 µg/ml concentrations of this substance for 24- and 48-h treatment periods using an MN test. Nuclear division index (NDI) was also calculated in order to determine the cytotoxicity of ITO. It was determined that ITO increased MN frequency in the 750 µg/ml concentration in 24- and 48-h treatments. In addition, ITO dose dependently decreased the NDI significantly for two treatment periods.


Comparative genomics and metagenomics of the metallomes.
Biological trace metals are needed by all living organisms in very small quantities. They play important roles in a variety of key cellular processes, resulting in a varying degree of dependence on metals for different organisms. While most effort has been placed on identifying metal metabolic pathways and characterizing metalloproteins and their functions, computational and systematical analyses of the metallomes (or metalloproteomes) have been limited. In the past several years, comparative genomics of the metallomes has arisen, which provides significant insights into the metabolism and function of metals as well as their evolution. This review focuses on recent progress in comparative genomic analysis of trace metals (such as copper, molybdenum, nickel, cobalt, selenium, iron and zinc) in both prokaryotes and eukaryotes. These studies reveal distinct and dynamic evolutionary patterns of the utilization of different metals and metalloproteins. We also discuss advances in comparative metagenomic analysis of metals in microbial communities in diverse environments such as the global marine ecosystem, which offer new clues to the relationship between metal utilization and different types of environmental factors. Overall, comparative genomic and metagenomic analyses of the metallomes provide a foundation for systematic understanding of metal utilization, function and related evolutionary trends in the three domains of life.


Agave negatively regulates YAP and TAZ transcriptionally and post-translationally in osteosarcoma cell lines.
Osteosarcoma (OS) is the most aggressive type of primary solid tumor that develops in bone. Whilst conventional chemotherapy can improve survival rates, the outcome for patients with metastatic or recurrent OS remains poor, so novel treatment agents and strategies are required. Research into new anticancer therapies has paved the way for the utilisation of natural compounds as they are typically less expensive and less toxic compared to conventional chemotherapeutics. Previously published works indicate that Agave exhibits anticancer properties, however potential molecular mechanisms remain poorly understood. In the present study, we investigate the anticancer effects of Agave leaf extract in OS cells suggesting that Agave inhibits cell viability, colony formation, and cell migration, and can induce apoptosis in OS cell lines. Moreover, Agave sensitizes OS cells to cisplatin (CDDP) and radiation, to overcome chemo- and radio-resistance. We demonstrate that Agave extract induces a marked decrease of Yes Associated Protein (YAP) and Tafazzin (TAZ) mRNA and protein expression upon treatment. We propose an initial mechanism of action in which Agave induces YAP/TAZ protein degradation, followed by a secondary event whereby Agave inhibits YAP/TAZ transcription, effectively deregulating the Nuclear Factor kappa B (NF-κB) p65:p50 heterodimers responsible for transcriptional induction of YAP and TAZ.


[Adolescent transgressors and the weakening of their social network when they return to the community].
The goal of this case study was to understand the success (or failure) of the ICPAE initiative (from Portuguese: Intern with possibility of External Activity) of the Foundation for Social-Educative Services of Rio Grande do Sul in the light of the characteristics of the social network of these young transgressors and of their perception of the functioning of their family. Five adolescents were investigated in the beginning and in the end of the ICPAE experience. We used a social network map, and for evaluating the functioning of the family we used the GARF scale (Global Assessment of Relational Functioning Scale). It was observed that the social network of these youths tended to be poorer than in the first map and also that they were centered on the family. The second ICPAE assessment revealed significantly worse results in comparison to the first, except in the case of one adolescent who had the most complete social network in both moments.


[His Majesty's distillers: distillation and chemical medicine in the court of Phillip II].
The present work studies the appearance and development of Paracelsian Practices in the Spanish Court through a linked series of events that took place between 1564 and 1602. These were: the creation of Philippine distillation laboratories, the ordenance of the protophysician Francisco de Valles regarding distilled waters; the concession of a patent to Diego de Santiago for the invention of a steam distillery; the publication of the last treatise by Francisco de Valles, dedicated to weights, measures, and distilled waters; the appearance of a distiller on the founding staff of the Royal Apothecary, in charge of preparing all the distilled waters and chemical medicines; and the creation of a new post within the Court health organigram, that of Distiller Major.


[Myasthenia gravis as an anesthesia risk].
Myasthenics must be considered as surgical risk patients. It is imperative to know the exact pathophysiology of the disease pattern with its three types of crisis including their treatment in order to perform safe anaesthesia and to reduce the rate of perioperative complications. In the preoperative phase we must consider a few specific angles besides the routine manipulations: Treatment with cholinesterase inhibitors as practised in myasthenics is continued unchanged or with only slightly reduced dosage up to the day of the operation. If necessary, oral administration may be changed to intramuscular or intravenous application. Premedication is carried out as far as possible without any drugs contraindicated in myasthenics. The patient may get regional or full anaesthesia, the latter always via intubation. We prefer inhalation anaesthetics because they are easily monitored. Neuroleptanalgesia, however, is also possible. One must accept the somewhat higher risk of postoperative respiratory insufficiency since in most cases subsequent artificial respiration must be performed anyway. Relaxation is effected, if at all necessary, via a non-depolarising muscle relaxant in low dosage (one-half to one-tenth of normal dosage). Measurement and monitoring of neuromuscular transmission via the nerve stimulator is mandatory. Succinylcholine is used only in case of vital indication (half of the normal dose). After surgery the patient is transferred to the intensive care ward in intubated position, extubation being performed only after spontaneous breathing has been safely assured. In postoperative analgetic treatment the opiate antagonist pentazocine (Fortral) showed the best results as far as our experience goes. With careful monitoring, however, it is also possible to employ other highly effective analgesics.(ABSTRACT TRUNCATED AT 250 WORDS)


Role of cytomegalovirus in cardiac allograft vasculopathy.
Cardiac allograft vasculopathy is the most common cause of death and retransplantation following heart transplantation, and about 10% of patients per year have evidence of accelerated vascular disease; 50% at 5 years. Cytomegalovirus (CMV) infection has been associated with accelerated cardiac vasculopathy and decreased 5-year survival. Prophylactic therapy using ganciclovir has reduced the incidence of CMV disease, but not in the group at highest risk, namely the seronegative recipient of an allograft from a seropositive donor (D+/R-). Combination prophylaxis consisting of CMV hyperimmune globulin (CMV-IGIV) plus ganciclovir is associated with decreased intimal thickening, reduced coronary artery disease and obliterative bronchiolitis, and improved survival.


Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study.
Evaluate the activity of everolimus (RAD001) in combination with octreotide long-acting repeatable (LAR) in patients with advanced low- to intermediate-grade neuroendocrine tumors. Treatment consisted of RAD001 5 mg/d (30 patients) or 10 mg/d (30 patients) and octreotide LAR 30 mg every 28 days. Thirty carcinoid and 30 islet cell patients were enrolled. Intent-to-treat response rate was 20%. Per protocol, there were 13 with partial responses (22%), 42 with stable disease (SD; 70%), and five patients with progressive disease (8%). Overall median progression-free survival (PFS) was 60 weeks. Median PFS for patients with known SD at entry was longer than for those who had progressive disease (74 v 50 weeks; P < .01). Median overall survival has not been reached. One-, 2-, and 3-year survival rates were 83%, 81%, and 78%, respectively. Among 37 patients with elevated chromogranin A, 26 (70%) achieved normalization or more than 50% reduction. Most common toxicity was mild aphthous ulceration. Grade 3/4 toxicities occurring in >or= 10% of patients included hypophosphatemia (11%), fatigue (11%), and diarrhea (11%). Treatment was associated with a dose-dependent rise in lactate dehydrogenase (LDH). Those with lower than 109 U/L rise in LDH at week 4 had shorter PFS (38 v 69 weeks; P = .01). Treatment was also associated with a decrease in proliferation marker Ki-67 among patients who underwent optional paired pre- and post-treatment biopsy (P = .04). RAD001 at 5 or 10 mg/d was well tolerated in combination with octreotide LAR, with promising antitumor activity. Confirmatory studies are ongoing.


ERISA failures and the erosion of workers' rights: the urgent need to protect private & public workers' pension and benefits.
On March 11, 2011, Governor Scott Walker of Wisconsin signed into law a bill that eliminated most collective bargaining rights for the state's public-sector workers. Many other cash-strapped states followed Wisconsin's lead and introduced or enacted similar restraints on the rights of their workers. Thousands of public workers, whose only means of protecting their rights rested in their ability to collectively bargain, suddenly found their retirement benefits in jeopardy. This truth highlighted the lack of protections for public worker benefits similar to those of the private sector. However, the Employee Retirement Income Security Act, enacted for that purpose, has failed to secure these benefits. This article seeks to provide a broad overview of the crisis facing the pension and benefits system in the United States and offers some possible solutions. More importantly, the goal is to spur discourse on the urgent need to protect the benefits of all workers, public and private.


Dexras1 Induces Dysdifferentiation of Oligodendrocytes and Myelin Injury by Inhibiting the cAMP-CREB Pathway after Subarachnoid Hemorrhage.
White matter damage (WMD), one of the research hotspots of subarachnoid hemorrhage (SAH), mainly manifests itself as myelin injury and oligodendrocyte differentiation disorder after SAH, although the specific mechanism remains unclear. Dexamethasone-induced Ras-related protein 1(Dexras1) has been reported to be involved in nervous system damage in autoimmune encephalitis and multiple sclerosis. However, whether Dexras1 participates in dysdifferentiation of oligodendrocytes and myelin injury after SAH has yet to be examined, which is the reason for creating the research content of this article. Here, intracerebroventricular lentiviral administration was used to modulate Dexras1 levels in order to determine its functional influence on neurological injury after SAH. Immunofluorescence, transmission electron microscopy, and Western blotting methods, were used to investigate the effects of Dexras1 on demyelination, glial cell activation, and differentiation of oligodendrocyte progenitor cells (OPCs) after SAH. Primary rat brain neurons were treated with oxyhemoglobin to verify the association between Dexras1 and cAMP-CREB. The results showed that Dexras1 levels were significantly increased upon in vivo SAH model, accompanied by OPC differentiation disturbances and myelin injury. Dexras1 overexpression significantly worsened OPC dysdifferentiation and myelin injury after SAH. In contrast, Dexras1 knockdown ameliorated myelin injury, OPC dysdifferentiation, and glial cell activation. Further research of the underlying mechanism discovered that the cAMP-CREB pathway was inhibited after Dexras1 overexpression in the in vitro model of SAH. This study is the first to confirm that Dexras1 induced oligodendrocyte dysdifferentiation and myelin injury after SAH by inhibiting the cAMP-CREB pathway. This present research may reveal novel therapeutic targets for the amelioration of brain injury and neurological dysfunction after SAH.


Therapeutic vaccination using minimal HPV16 epitopes in a novel MHC-humanized murine HPV tumor model.
Therapeutic vaccination as a treatment option for HPV-induced cancers is actively pursued because the two HPV proteins E6 and E7 represent ideal targets for immunotherapy, as they are non-self and expressed in all tumor stages. MHC-humanized mice are valuable tools for the study of therapeutic cancer vaccines - given the availability of a suitable tumor model. Here, we present for the first time an HPV16 tumor model suitable for fully MHC-humanized A2.DR1 mice, PAP-A2 cells, which in contrast to existing HPV16 tumor models allows the exclusive study of HLA-A2- and DR1-mediated immune responses, without any interfering murine MHC-presented epitopes. We used several HPV16 epitopes that were shown to be presented on human cervical cancer cells by mass spectrometry for therapeutic anti-tumor vaccination in the new tumor model. All epitopes were immunogenic when rendered amphiphilic by incorporation into a molecule containing stearic acids. Prophylactic and therapeutic vaccination experiments with the epitope E7/11-19 demonstrated that effective immune responses could be induced with these vaccination approaches in A2.DR1 mice. Interestingly, the combination of E7/11-19 with other immunogenic HPV16 E6/E7 epitopes caused a reduction of vaccine efficacy, although all tested combinations resulted in a survival benefit. In summary, we present the first HPV16 tumor model for exclusive studies of HLA-A2-mediated anti-HPV tumor immune responses and show anti-tumor efficacy of minimal epitope vaccines.


SCYL1 arginine methylation by PRMT1 is essential for neurite outgrowth via Golgi morphogenesis.
Arginine methylation is a common posttranslational modification that modulates protein function. SCY1-like pseudokinase 1 (SCYL1) is crucial for neuronal functions and interacts with γ2-COP to form coat protein complex I (COPI) vesicles that regulate Golgi morphology. However, the molecular mechanism by which SCYL1 is regulated remains unclear. Here, we report that the γ2-COP-binding site of SCYL1 is arginine-methylated by protein arginine methyltransferase 1 (PRMT1) and that SCYL1 arginine methylation is important for the interaction of SCYL1 with γ2-COP. PRMT1 was colocalized with SCYL1 in the Golgi fraction. Inhibition of PRMT1 suppressed axon outgrowth and dendrite complexity via abnormal Golgi morphology. Knockdown of SCYL1 by small interfering RNA (siRNA) inhibited axon outgrowth, and the inhibitory effect was rescued by siRNA-resistant SCYL1, but not SCYL1 mutant, in which the arginine methylation site was replaced. Thus, PRMT1 regulates Golgi morphogenesis via SCYL1 arginine methylation. We propose that SCYL1 arginine methylation by PRMT1 contributes to axon and dendrite morphogenesis in neurons.


Molecular Pap smear: HPV genotype and DNA methylation of ADCY8, CDH8, and ZNF582 as an integrated biomarker for high-grade cervical cytology.
The Pap smear has remained the foundation for cervical cancer screening for over 70 years. With advancements in molecular diagnostics, primary high-risk human papillomavirus (hrHPV) screening has recently become an accepted stand-alone or co-test with conventional cytology. However, both diagnostic tests have distinct limitations. The aim of this study was to determine the association between HPV genotypes and cellular epigenetic modifications in three grades of cervical cytology for screening biomarker discovery. This prospective, cross-sectional study used residual liquid-based cytology samples for HPV genotyping and epigenetic analysis. Extracted DNA was subjected to parallel polymerase chain reactions using three primer sets (MY09/11, FAP59/64, E6-E7 F/B) for HPV DNA amplification. HPV+ samples were genotyped by DNA sequencing. Promoter methylation of four candidate tumor suppressor genes (adenylate cyclase 8 (ADCY8), cadherin 8, type 2 (CDH8), MGMT, and zinc finger protein 582 (ZNF582)) out of 48 genes screened was quantified by bisulfite-pyrosequencing of genomic DNA. Independent validation of methylation profiles was performed by analyzing data from cervical cancer cell lines and clinical samples from The Cancer Genome Atlas (TCGA). Two hundred seventy-seven quality cytology samples were analyzed. HPV was detected in 31/100 (31 %) negative for intraepithelial lesion or malignancy (NILM), 95/100 (95 %) low-grade squamous intraepithelial lesion (LSIL), and 71/77 (92 %) high-grade squamous intraepithelial lesion (HSIL) samples. The proportion of IARC-defined carcinogenic HPV types in sequenced samples correlated with worsening grade: NILM 7/29 (24 %), LSIL 53/92 (58 %), and HSIL 65/70 (93 %). Promoter methylation of ADCY8, CDH8, and ZNF582 was measured in 170 samples: NILM (N = 33), LSIL (N = 70), and HSIL (N = 67) also correlated with worsening grade. Similar hypermethylation patterns were found in cancer cell lines and TCGA samples. The combination of four biomarkers, i.e., HPV genotype and three-gene promoter methylation, predicted HSIL (AUC 0.89) better than HPV alone (AUC 0.74) by logistic regression and probabilistic modeling. HPV genotype and DNA methylation of ADCY8, CDH8, and ZNF582 are correlated with cytological grade. Collectively, these biomarkers may serve as a molecular classifier of Pap smears.


European Survey on Adult People With Type 1 Diabetes and Their Caregivers: Insights Into Perceptions of Technology.
Type 1 diabetes (T1D) is a complex condition requiring constant monitoring and self-management. The landscape of diabetes management is evolving with the development of new technologies. This survey aimed to gain insight into the perceptions and experiences of people with T1D (PWD) and their caregivers on the use of technology in diabetes care, and identify future needs for T1D management. PWD and caregivers (≥18 years) living in five European countries (France, Germany, Italy, Spain, and the United Kingdom) completed an online survey. Data were collected during July and August 2021. Responders included 458 PWD and 54 caregivers. More than 60% of PWD perceived devices/digital tools for diabetes management as useful and 63% reported that access to monitoring device data made their life easier. Nearly half of participants hoped for new devices and/or digital tools. While approximately one-third of all PWD had used teleconsultation, perceptions and usage varied significantly between countries and by age (both P < .0001), with the lowest use in Germany (20%) and the highest in Spain (48%). The proportions of PWD contributing to diabetes care costs varied by device and were highest for smart insulin pen users at 83% compared with 44% for insulin pen users and 37% for insulin pump users. One-quarter (24%) of PWD and 15% of caregivers felt they lacked knowledge about devices/digital tools for T1D. Most PWD and caregivers had positive perceptions and experiences of new technologies/digital solutions for diabetes management, although improved support and structured education for devices/digital tools are still required.


Finding the optimal design of a passive microfluidic mixer.
The ability to thoroughly mix two fluids is a fundamental need in microfluidics. While a variety of different microfluidic mixers have been designed by researchers, it remains unknown which (if any) of these mixers are optimal (that is, which designs provide the most thorough mixing with the smallest possible fluidic resistance across the mixer). In this work, we automatically designed and rationally optimized a microfluidic mixer. We accomplished this by first generating a library of thousands of different randomly designed mixers, then using the non-dominated sorting genetic algorithm II (NSGA-II) to optimize the random chips in order to achieve Pareto efficiency. Pareto efficiency is a state of allocation of resources (e.g. driving force) from which it is impossible to reallocate so as to make any one individual criterion better off (e.g. pressure drop) without making at least one individual criterion (e.g. mixing performance) worse off. After 200 generations of evolution, Pareto efficiency was achieved and the Pareto-optimal front was found. We examined designs at the Pareto-optimal front and found several design criteria that enhance the mixing performance of a mixer while minimizing its fluidic resistance; these observations provide new criteria on how to design optimal microfluidic mixers. Additionally, we compared the designs from NSGA-II with some popular microfluidic mixer designs from the literature and found that designs from NSGA-II have lower fluidic resistance with similar mixing performance. As a proof of concept, we fabricated three mixer designs from 200 generations of evolution and one conventional popular mixer design and tested the performance of these four mixers. Using this approach, an optimal design of a passive microfluidic mixer is found and the criteria of designing a passive microfluidic mixer are established.


COVID-19's impact on Australian wine markets and regions.
This paper provides an empirical case study of impacts of COVID-19 on Australia's wine sector. Wine exports were subject to disruptions and, like domestic wine sales, were adversely affected not only by temporary declines in consumers' expected incomes but also by the social distancing measures and self-isolation that led to closure of restaurants, bars, cafes and clubs plus declines in international travel and tourism. Partly offsetting this has been a boost to off-premise and direct e-commerce sales. We first estimate those impacts and their expected partial recovery in 2021 using a new model of global beverage markets. Then, we add results on regional effects, including through domestic wine tourism, using a new economy-wide model with sub-national regions. The paper concludes by drawing lessons on how this sector's resilience to future global shocks could be strengthened.


In vitro sensitivities of Plasmodium falciparum isolates from the China-Myanmar border to piperaquine and association with polymorphisms in candidate genes.
The recent reports of resistance in Plasmodium falciparum to artemisinin derivatives and their partner drugs demand intensive studies toward understanding the molecular mechanisms of resistance. In this study, we examined the in vitro susceptibility of 63 P. falciparum field isolates collected from the China-Myanmar border area to chloroquine (CQ) and piperaquine (PPQ). Parasite isolates remained highly resistant to CQ, with the geometric mean 50% inhibitory concentration (IC50) of 252.7 nM and a range of 51.9 to 1,052.0 nM. In comparison, these parasites had a geometric mean IC50 of 28.4 nM for PPQ, with a fairly wide range of 5.3 to 132.0 nM, suggesting that certain parasite isolates displayed relatively high levels of resistance to PPQ. Interestingly, within the 4 years of study, the parasites exhibited a continuous decline in susceptibilities to both CQ and PPQ, and there was a significant correlation between responses to CQ and PPQ (Pearson correlation coefficient = 0.79, P < 0.0001). Consistent with the CQ-resistant phenotype, all parasites carried the pfcrt K76T mutation, and most parasites had the CVIET type that is prevalent in Southeast Asia. In contrast, pfmdr1 mutations were relatively rare, and no gene amplification was detected. Only the pfmdr1 N1042D mutation was associated with resistance to CQ. For the pfmrp1 gene, four substitutions reached relatively high prevalence of >22%, and the I876V mutation was associated with reduced sensitivity to CQ. However, we could not establish a link between PPQ responses and the polymorphisms in the three genes associated with quinoline drug resistance.


Heterogeneity on long-term disability trajectories in patients with secondary progressive MS: a latent class analysis from Big MS Data network.
Over the decades, several natural history studies on patients with primary (PPMS) or secondary progressive multiple sclerosis (SPMS) were reported from international registries. In PPMS, a consistent heterogeneity on long-term disability trajectories was demonstrated. The aim of this study was to identify subgroups of patients with SPMS with similar longitudinal trajectories of disability over time. All patients with MS collected within Big MS registries who received an SPMS diagnosis from physicians (cohort 1) or satisfied the Lorscheider criteria (cohort 2) were considered. Longitudinal Expanded Disability Status Scale (EDSS) scores were modelled by a latent class growth analysis (LCGA), using a non-linear function of time from the first EDSS visit in the range 3-4. A total of 3613 patients with SPMS were included in the cohort 1. LCGA detected three different subgroups of patients with a mild (n=1297; 35.9%), a moderate (n=1936; 53.6%) and a severe (n=380; 10.5%) disability trajectory. Median time to EDSS 6 was 12.1, 5.0 and 1.7 years, for the three groups, respectively; the probability to reach EDSS 6 at 8 years was 14.4%, 78.4% and 98.3%, respectively. Similar results were found among 7613 patients satisfying the Lorscheider criteria. Contrary to previous interpretations, patients with SPMS progress at greatly different rates. Our identification of distinct trajectories can guide better patient selection in future phase 3 SPMS clinical trials. Additionally, distinct trajectories could reflect heterogeneous pathological mechanisms of progression.


Visual scenes are categorized by function.
How do we know that a kitchen is a kitchen by looking? Traditional models posit that scene categorization is achieved through recognizing necessary and sufficient features and objects, yet there is little consensus about what these may be. However, scene categories should reflect how we use visual information. Therefore, we test the hypothesis that scene categories reflect functions, or the possibilities for actions within a scene. Our approach is to compare human categorization patterns with predictions made by both functions and alternative models. We collected a large-scale scene category distance matrix (5 million trials) by asking observers to simply decide whether 2 images were from the same or different categories. Using the actions from the American Time Use Survey, we mapped actions onto each scene (1.4 million trials). We found a strong relationship between ranked category distance and functional distance (r = .50, or 66% of the maximum possible correlation). The function model outperformed alternative models of object-based distance (r = .33), visual features from a convolutional neural network (r = .39), lexical distance (r = .27), and models of visual features. Using hierarchical linear regression, we found that functions captured 85.5% of overall explained variance, with nearly half of the explained variance captured only by functions, implying that the predictive power of alternative models was because of their shared variance with the function-based model. These results challenge the dominant school of thought that visual features and objects are sufficient for scene categorization, suggesting instead that a scene's category may be determined by the scene's function.


Neural correlates of prospective and retrospective memory.
This study examines the event-related brain potential (ERP) correlates of retrieval processes in prospective and retrospective memory (i.e., recognition and cued-recall). In contrast to previous research that has compared performance on tasks measuring prospective and retrospective memory, the stimulus materials and encoding and response demands of the prospective and retrospective components of the tasks were reasonably well matched for the two forms of memory. This resulted in the primary difference between the assessments of prospective and retrospective memory being the requirement for self-initiated retrieval in prospective memory. Analyses of mean amplitude measures revealed modulations of the ERPs typically associated with prospective memory (i.e., N300 and prospective positivity) and retrospective memory (i.e., FN400, parietal positivity and frontal slow waves). Partial least squares analyses revealed one latent variable related to the retrieval of a previously studied item that contrasted retrospective hits and prospective hits from ongoing activity trials and prospective lures; and one latent variable uniquely associated with prospective hits. These findings indicate that similar neural processes support retrieval in prospective and retrospective memory and that the realization of intentions is additionally dependent on processes that are uniquely related to prospective memory.


Novel LRPPRC compound heterozygous mutation in a child with early-onset Leigh syndrome French-Canadian type: case report of an Italian patient.
Mitochondrial diseases, also known as oxidative phosphorylation (OXPHOS) disorders, with a prevalence rate of 1:5000, are the most frequent inherited metabolic diseases. Leigh Syndrome French Canadian type (LSFC), is caused by mutations in the nuclear gene (2p16) leucine-rich pentatricopeptide repeat-containing (LRPPRC). It is an autosomal recessive neurogenetic OXPHOS disorder, phenotypically distinct from other types of Leigh syndrome, with a carrier frequency up to 1:23 and an incidence of 1:2063 in the Saguenay-Lac-St Jean region of Quebec. Recently, LSFC has also been reported outside the French-Canadian population. We report a male Italian (Sicilian) child, born preterm at 28 + 6/7 weeks gestation, carrying a novel LRPPRC compound heterozygous mutation, with facial dysmorphisms, neonatal hypotonia, non-epileptic paroxysmal motor phenomena, and absent sucking-swallowing-breathing coordination requiring, at 4.5 months, a percutaneous endoscopic gastrostomy tube placement. At 5 months brain Magnetic Resonance Imaging showed diffuse cortical atrophy, hypoplasia of corpus callosum, cerebellar vermis hypoplasia, and unfolded hippocampi. Both auditory and visual evoked potentials were pathological. In the following months Video EEG confirmed the persistence of sporadic non epileptic motor phenomena. No episode of metabolic decompensation, acidosis or ketosis, frequently observed in LSFC has been reported. Actually, aged 14 months corrected age for prematurity, the child shows a severe global developmental delay. Metabolic investigations and array Comparative Genomic Hybridization (aCGH) results were normal. Whole-exome sequencing (WES) found a compound heterozygous mutation in the LRPPRC gene, c.1921-7A > G and c.2056A > G (p.Ile686Val), splicing-site and missense variants, inherited from the mother and the father, respectively. We first characterized the clinical and molecular features of a novel LRPPRC variant in a male Sicilian child with early onset encephalopathy and psychomotor impairment. Our patient showed a phenotype characterized by a severe neurodevelopmental delay and absence of metabolic decompensation attributable to a probable residual enzymatic activity. LRPPRC is a rare cause of metabolic encephalopathy outside of Québec. Our patient adds to and broaden the spectrum of LSFC phenotypes. WES analysis is a pivotal genetic test and should be performed in infants and children with hypotonia and developmental delay in whom metabolic investigations and aCGH are normal.


Blood staining of the cornea: a histopathologic analysis of 16 cases.
Sixteen eyes with corneal blood staining were examined by light microscopy. Two corneal buttons were also studied by electron microscopy and immunohistochemistry. By light microscopy, most eyes disclosed hyphema, angle-closure glaucoma, and endothelial attenuation with marked corneal edema. Extra- and intracellular hemoglobin particles as well as intracellular hemosiderin were found mostly in the central cornea. Frequently we observed a gradient of hemoglobin degradation from the posterior to the anterior corneal stroma with extracellular hemoglobin particles being more concentrated posteriorly while hemosiderin-laden keratocytes predominated anteriorly. By electron microscopy, moderately electron-dense, amorphous material consistent with hemoglobin was found extracellularly as well as incorporated into stromal keratocytes, while highly electron-dense, membrane-bound granules, consistent with hemosiderin, were found intracellularly. There was marked necrosis of keratocytes, mainly those that were overloaded with hemoglobin. We conclude that hemoglobin diffuses into the corneal stroma across an intact Descemet's membrane. Continuous overload with hemoglobin leads to necrosis of keratocytes and irreversible corneal blood staining.


Availability of serologic and virologic testing for herpes simplex virus in the largest sexually transmitted disease clinics in the United States.
The prevalence of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in the United States is estimated to be 57.7% for HSV 1 and 17.0% for HSV 2. The Centers for Disease Control and Prevention recommends that both virologic and serologic tests be available at clinics that examined clients at risk for sexually transmitted diseases. A telephone survey was conducted. Providers at the 230 largest sexually transmitted disease clinics in the United States were surveyed regarding the availability of HSV virologic and serologic testing at their clinics. Of the 230 clinics, 37% (87) had neither serological nor virologic testing available, 36% (87) had only virologic, 23% (50) had both serologic and virologic, and 4% (8) had only serologic testing. States in the western and northern regions were significantly more likely to offer any type of HSV testing than the southern and Midwestern states (P < 0.05). The ability and techniques used to diagnose HSV varied widely by site and ranged from diagnosing by clinical examinations only to offer serological testing for all patients. Almost three-quarters of the clinics did not comply with Centers for Disease Control and Prevention recommendations. Further efforts are needed to implement national guidelines for HSV testing.


Two-dimensional polyacylamide gel electrophoresis of envelope proteins of Escherichia coli.
A method of separating envelope proteins by two-dimensional polyacrylamide gel electrophoresis is described. Escherichia coli envelopes (inner and outer membranes) were prepared by French pressing and washed by repeated centrifugation. Membrane proteins were solubilized with guanidine thiocyanate and were dialyzed against urea prior to two-dimensional electrophoretic analysis. The slab gel apparatus and conditions were similar to the technique developed by Metz and Bogorad (1974) for the separation of ribosomal proteins. This separation occurs in 8 M urea for the first dimension and in 0.2% sodium dodecyl sulfate for the second dimension. The technique separates about 70 different membrane proteins in a highly reproducible fashion according to both intrinsic charge and molecular weight. Some examples of alterations in the membrane protein pattern are demonstrated. These alterations are caused by a mutation affecting a sugar transport system and by growth in the presence of D-fucose, inducer of the transport system. A further example of membrane protein changes introduced by growth at the nonpermissive temperature of a temperature-sensitive cell division mutant is shown. Finally, it is demonstrated that the major outer membrane component of Escherichia coli K-12 contains more than four proteins of similar molecular weight.


Selective activation of neuromuscular compartments within the human trapezius muscle.
Task-dependent differences in relative activity between "functional" subdivisions within human muscles are well documented. Contrary, independent voluntary control of anatomical subdivisions, termed neuromuscular compartments is not observed in human muscles. Therefore, the main aim of this study was to investigate whether subdivisions within the human trapezius can be independently activated by voluntary command using biofeedback guidance. Bipolar electromyographical electrodes were situated on four subdivisions of the trapezius muscle. The threshold for "active" and "rest" for each subdivision was set to >12% and <1.5% of the maximal electromyographical amplitude recorded during a maximal voluntary contraction. After 1h with biofeedback from each of the four trapezius subdivisions, 11 of 15 subjects learned selective activation of at least one of the four anatomical subdivisions of the trapezius muscle. All subjects managed to voluntarily activate the lower subdivisions independently from the upper subdivisions. Half of the subjects succeeded to voluntarily activate both upper subdivisions independently from the two lower subdivisions. These findings show that anatomical subdivisions of the human trapezius muscle can be independently activated by voluntary command, indicating neuromuscular compartmentalization of the trapezius muscle. The independent activation of the upper and lower subdivisions of the trapezius is in accordance with the selective innervation by the fine cranial and main branch of the accessory nerve to the upper and lower subdivisions. These findings provide new insight into motor control characteristics, learning possibilities, and function of the clinically relevant human trapezius muscle.


Expression of the 40 kDa catecholamine regulated protein in the normal and injured rat retina.
Catecholamine regulated protein 40 (CRP40) has been shown to be expressed in the central nervous system (CNS) of several mammalian species where it may function in a similar manner to members of the heat shock protein (HSP) family. Immunohistochemical and immunoblotting techniques were utilized to investigate whether CRP40 is expressed in normal rat retinas. In addition, changes in CRP40 expression were studied following optic nerve transection. The immunohistochemical results showed that CRP40 is expressed in the normal rat retina. The protein was found to be highly expressed in the ganglion cell layer (GCL), the inner nuclear layer (INL) and the outer plexiform layer (OPL). In addition, a low level of CRP40 was found in the inner plexiform layer (IPL), and in the inner segment layer (ISL). No expression was found in the outer nuclear layer (ONL) of normal rat retina. The immunoblotting results show that CRP40 expression decreased in a time-dependent fashion after the optic nerve transection. This decrease indicates that the expression of CRP40 is dependent on the neuron's normal physiological state and that it plays an important function in physiological and pathological conditions in the retina.


Iron-catalyzed direct alkenylation of 2-substituted azaarenes with N-sulfonyl aldimines via C-H bond activation.
A novel iron-catalyzed alkenylation of 2-substituted azaarenes through sp(3) C-H bond activation has been developed. A favorable E2-elimination is proposed as a key step to cleavage of C-H and C-N bonds for the construction of a C═C bond in high stereoselectivity. This transformation represents an efficient way to synthesize 2-alkenylated azaarenes from simple starting materials.


Green tea protects against memory deficits related to maternal deprivation.
Maternal deprivation (MD) in early life affects the development of the brain, causing cognitive losses in adulthood. Oxidative imbalance may be one of the factors that trigger these deficits. Therapies with antioxidant components, like green tea from Camellia sinensis (GT) has been used to treat or prevent memory deficits in a variety of conditions related to oxidative stress. Here we demonstrate that memory deficits caused by MD can be prevented by GT antioxidant activity in hippocampus. Pregnant female rats were used. Her puppies were submitted to MD and intake of GT. Recognition and aversive memory were evaluated, as well as hippocampal oxidative status. Data showed that MD prejudice short and long-term recognition and aversive memory and that GT protected memory. Hippocampal reactive oxygen species levels were increased in MD rats; this increase was avoided by GT supplementation. GSH was decreased on hippocampus MD rats. GT did not avoid GSH decrease, but promote the increase of total antioxidant capacity in MD rats' hippocampus. In conclusion, GT protects against memory deficits related to MD, and one of the implicated mechanism seems to be the antioxidant effects of GT.


Do panic symptom profiles influence response to a hypoxic challenge in patients with panic disorder? A preliminary report.
This study examined how panic symptom profiles affect response to a hypoxic laboratory challenge in patients with panic disorder. Seven patients whose naturally occurring panic attacks were characterized by prominent respiratory symptoms (Resp subgroup) were compared and contrasted with seven patients who did not report respiratory symptoms during panic attacks (NonResp subgroup). All were administered a novel 12% O2 challenge and assessed with measures of tidal volume, respiratory rate, end-tidal CO2, anxiety, and panic symptoms. Although the Resp and NonResp subgroups showed equivalent increases in anxiety and panic symptoms, the Resp subgroup showed greater fluctuation in tidal volume during and after the challenge as well as overall lower levels of end-tidal CO2. Our results suggest the importance of panic symptom profiles in determining respiratory responses to a hypoxic challenge in patients with panic disorder. These findings are discussed in light of current theories of panic disorder, with particular attention to respiratory disturbances in this disorder.


Antimicrobial peptides in burns and wounds.
Burn-induced immunosuppression not only increases susceptibility to infection, but also predisposes burn patients to related adverse sequelae, including systemic inflammatory response syndrome and sepsis. Although burn-related immunosuppression is not fully understood, it is characterized by decreased T- and B-lymphocyte function and by impaired functions of circulating leukocytes and complement. Alterations in defensins, a family of cationic, naturally occurring antimicrobial peptides, may underlie these immune deficiency patterns. Defensins are considered important components of the innate immune system, as they inhibit bacterial, fungal, and viral colonization. They also chemoattract immature dendritic cells and T lymphocytes, recruit neutrophils, macrophages, and monocytes, modulate complement and adjuvant activity, and promote inflammation and wound healing. Infectious states are associated with upregulation of circulating defensins, which suggests an underlying antimicrobial role. In addition, data from our laboratory demonstrated diminished levels of certain defensins in burned tissue. The inference is that decreased defensin levels in burn injury may facilitate infection and subsequent sepsis. It may also alter functions of T- and B-lymphocytes, neutrophils, macrophages, and complement, thereby contributing to the pathophysiology of burn-related systemic inflammatory responses. This article is a comprehensive review on the role of antimicrobial peptides in burns and wounds.


Extraction of Clostridium perfringens spores from bottom sediment samples.
Two extraction-separation procedures were developed and evaluated for use in conjunction with the mCP membrane filter method for the enumeration of Clostridium perfringens spores in bottom sediments. In the more facile of the two procedures, a distilled-water suspension of the sediment sample is pulse sonicated for 10 s and allowed to settle. Portions of the supernatant are then removed for membrane filtration. This procedure is recommended for general use. The more complicated procedure is recommended for situations in which the presence of high levels of toxic materials is suspected or in which relatively low spore densities are present in fine silts. In this procedure, sonication is followed by a distilled water wash. The centrifuged sediment is resuspended in distilled water and mixed with the components of a two-phase separation system (50% polyethylene glycol in distilled water and 25% sucrose in 3 M phosphate buffer [pH 7.1]). After equilibration of the system and low-speed centrifugation, the top phase and interphase are removed, mixed, and membrane filtered. The recoveries of C. perfringens spores by the two procedures, when used in conjunction with the mCP method, were comparable to each other and significantly greater than those by the British most-probable-number method. It was estimated that more than 85% of the spores were recovered by the procedures. The precision of the sonicate-and-settle-mCP procedure was markedly better than that obtained theoretically by the most-probable-number method and approached that theoretically attributable to counting an average of 85 colonies on each of two plates.


Associations of retrospective and concurrent lipid levels with subclinical atherosclerosis prediction after 20 years of follow-up: the Coronary Artery Risk Development in Young Adults (CARDIA) study.
Using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, we sought to determine how well lipids measured at baseline and at 20 years predict the presence of subclinical atherosclerosis. Complete risk factor, coronary artery calcification (CAC), and carotid intima media thickness (CIMT) data were available for 2435 participants. Lipids were categorized into quartiles, CAC at Y20 was dichotomized as present/absent, and CIMT was dichotomized as ≥84 or <84th overall percentile. Multivariable logistic regression was used to model the association between lipids and CAC/CIMT. C statistics were used to assess the discriminative value of each lipid measure in predicting the presence of CAC or CIMT at Y20. Lipid levels measured in young adulthood as well as middle age were both associated with subclinical disease in middle age. The discriminatory value of lipids was virtually identical at baseline, when participants were 18-30 years of age, and 20 years later. Neither baseline nor Y20 lipid data were strong predictors of Y20 subclinical disease despite statistically significant associations. These results are consistent with a growing body of evidence that early-life exposure to nonoptimal lipids matters and lifestyle modifications administered earlier in the lifespan could slow the progress of the atherosclerotic plaques.


Impact of baseline nasal polyp size and previous surgery on efficacy of fluticasone delivered with a novel device: a subgroup analysis.
Little information exists on the impact of baseline polyp size and previous nasal surgery on the efficacy of intranasal steroids. This study was designed to investigate whether baseline polyp size and previous nasal surgery influence the efficacy of an intranasal steroid delivered with a novel device. A post hoc analysis of recently published results with intranasal administration using a novel bidirectional delivery device containing fluticasone propionate (Opt-FP) was performed in 109 patients with mild-to-moderate bilateral polyposis. Patients were allocated to subgroups based on summed polyp score at baseline (2, 3, or 4) and on their history of previous sinus surgery. A highly significant and progressive reduction in summed polyp size was observed for Opt-FP versus placebo in all three polyp size subgroups (p < 0.001). A greater relative reduction in polyp size (p < 0.05) and an increase in peak nasal inspiratory flow (p < 0.001) were observed for Opt-FP at 12 weeks in the 28 patients with a baseline summed score of 3 and 4 compared with the 27 with a summed score of 2. Nevertheless, in patients with small polyps at baseline, the polyps were completely resolved on both sides in 7 of 27 patients. Previous sinus surgery had no impact on efficacy. The highly significant progressive treatment effect of Opt-FP was observed regardless of baseline polyps score. Coupled with the complete removal of polyps in many patients with small polyps, this suggests that improved deposition to target sites achieved with the bidirectional delivery device may translate into true clinical benefits and reduced need for surgery.


Gastroparesis: from concepts to management.
While the symptoms of gastroparesis are common, an accurate diagnosis is based on a combination of those symptoms with a documented delay in gastric emptying. Typical symptoms include nausea, vomiting, early satiety, postprandial fullness, bloating, and abdominal discomfort. Patients with gastroparesis face many diagnostic and therapeutic challenges. The most common origins of gastroparesis are idiopathic causes and diabetes mellitus. The increased use of certain medications in medicine today, including opiates and drugs with anticholinergic properties, can alter gastrointestinal functions and mimic symptoms of gastroparesis. Accordingly, alternative explanations for symptoms and altered gastrointestinal function need to be considered. Numerous clinical sequelae, including weight loss and severe protein-calorie malnutrition, may be seen in advanced stages of gastroparesis. This article provides an overview of gut sensorimotor function to help the reader better understand the clinical presentation of patients with dyspepsia and those who may have accompanying delayed gastric emptying that meets criteria for gastroparesis. Techniques available for diagnosing motor dysfunction and the principles of gastroparesis management are reviewed. Nutrition recommendations and a review of pharmacologic agents, nonpharmacologic techniques, and novel treatment modalities are provided.


Risk of complication and revision total hip arthroplasty among Medicare patients with different bearing surfaces.
To address the long-term problems of bearing surface wear and osteolysis associated with conventional metal-polyethylene (M-PE) total hip arthroplasty (THA), metal-metal (M-M), and ceramic-ceramic (C-C) bearings have been introduced. These bearing surfaces are associated with unique risks and benefits and higher costs. However the relative risks of these three bearings in an older population is unknown. We compared the short-term risk of complication and revision THA among Medicare patients having a primary THA with metal-polyethylene (M-PE), metal-metal (M-M), and ceramic-ceramic (C-C) bearings. We used the 2005 to 2007 100% Medicare inpatient claim files to perform a matched cohort analysis in three separate cohorts of THA patients (M-PE, M-M, and C-C) who were matched by age, gender, and US census region. Multivariate Cox proportional-hazards models were constructed to compare complication and revision THA risk among cohorts, adjusting for medical comorbidities, race, socioeconomic status, and hospital factors. After adjusting for patient and hospital factors, M-M bearings were associated with a higher risk of periprosthetic joint infection (hazard ratio, 3.03; confidence interval, 1.02-9.09) when compared with C-C bearings (0.59% versus 0.32%, respectively). There were no other differences among bearing cohorts in the adjusted risk of revision THA or any other complication. The risk of short-term complication (including dislocation) and revision THA were similar among appropriately matched Medicare THA patients regardless of bearing surface. Hard-on-hard THA bearings are of questionable value in Medicare patients, given the higher cost associated with their use and uncertain long-term benefits in older patients. Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.


ArfGAP1 inhibits mTORC1 lysosomal localization and activation.
The mammalian target of rapamycin complex 1 (mTORC1) integrates nutrients, growth factors, stress, and energy status to regulate cell growth and metabolism. Amino acids promote mTORC1 lysosomal localization and subsequent activation. However, the subcellular location or interacting proteins of mTORC1 under amino acid-deficient conditions is not completely understood. Here, we identify ADP-ribosylation factor GTPase-activating protein 1 (ArfGAP1) as a crucial regulator of mTORC1. ArfGAP1 interacts with mTORC1 in the absence of amino acids and inhibits mTORC1 lysosomal localization and activation. Mechanistically, the membrane curvature-sensing amphipathic lipid packing sensor (ALPS) motifs that bind to vesicle membranes are crucial for ArfGAP1 to interact with and regulate mTORC1 activity. Importantly, ArfGAP1 represses cell growth through mTORC1 and is an independent prognostic factor for the overall survival of pancreatic cancer patients. Our study identifies ArfGAP1 as a critical regulator of mTORC1 that functions by preventing the lysosomal transport and activation of mTORC1, with potential for cancer therapeutics.


Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade.
CTL-associated antigen 4 (CTLA-4) can inhibit T-cell activation and helps maintain peripheral self-tolerance. Previously, we showed immune-related adverse events (IRAE) and objective, durable clinical responses in patients with metastatic melanoma treated with CTLA-4 blockade. We have now treated 139 patients in two trials and have sufficient follow-up to examine factors associated with clinical response. A total of 139 patients with metastatic melanoma were treated: 54 patients received ipilimumab in conjunction with peptide vaccinations and 85 patients were treated with intra-patient dose escalation of ipilimumab and randomized to receive peptides in accordance with HLA-A*0201 status. Three patients achieved complete responses (CR; ongoing at 29+, 52+, and 53+ months); an additional 20 patients achieved partial responses (PR) for an overall objective response rate of 17%. The majority of patients (62%, 86 of 139) developed some form of IRAE, which was associated with a greater probability of objective antitumor response (P = 0.0004); all patients with CR had more severe IRAEs. Prior therapy with IFNalpha-2b was a negative prognostic factor, whereas prior high-dose interleukin-2 did not significantly affect the probability of response. There were no significant differences in the rate of clinical response or development of IRAEs between the two trials. The duration of tumor response was not affected by the use of high-dose steroids for abrogation of treatment-related toxicities (P = 0.23). There were no treatment-related deaths. In patients with metastatic melanoma, ipilimumab can induce durable objective clinical responses, which are related to the induction of IRAEs.


Endoscopic-assisted interhemispheric parieto-occipital transtentorial approach for microsurgical resection of a pineal region tumor: operative video and technical nuances.
The angle of the straight sinus and tentorium cerebelli can often influence the choice of surgical approach to the pineal region. The supracerebellar infratentorial approach can be technically challenging and a relative contraindication in cases where the angle of the straight sinus and tentorium is very steep. Similarly, an occipital transtentorial approach, which uses a low occipital craniotomy at the junction of the superior sagittal sinus and transverse sinus, may not provide the best trajectory to the pineal region in patients with a steep tentorium. In addition, this approach often necessitates retraction on the occipital lobe to access the tentorial incisura and pineal region, which can increase the risk of visual compromise. In this operative video, the author demonstrates an alternative route using an endoscopic-assisted interhemispheric parieto-occipital transtentorial approach to a pineal region tumor in a patient with a steep straight sinus and tentorium. The approach provided a shorter route and more direct trajectory to the tumor at the tentorial incisura, and avoided direct fixed retraction on the occipital lobe when performed using the lateral position, thereby minimizing visual complications. This video atlas demonstrates the operative technique and surgical nuances, including the application of endoscopic-assisted microsurgical resection and operative pearls for preservation of the deep cerebral veins. In summary, the parieto-occipital transtentorial approach with endoscopic assistance is an important approach in the armamentarium for surgical management of pineal region tumors. The video can be found here: https://youtu.be/Ph4veG14aTk .


Tear film lipids.
Human meibomian gland secretions (MGS, or meibum) are formed from a complex mixture of lipids of different classes such as wax esters, cholesteryl esters, (O-acyl)-ω-hydroxy fatty acids (OAHFA) and their esters, acylglycerols, diacylated diols, free fatty acids, cholesterol, and a smaller amount of other polar and nonpolar lipids, whose chemical nature and the very presence in MGS have been a matter of intense debates. The purpose of this review is to discuss recent results that were obtained using different experimental techniques, estimate limitations of their usability, and discuss their biochemical, biophysical, and physiological implications. To create a lipid map of MGS and tears, the results obtained in the author's laboratory were integrated with available information on chemical composition of MGS and tears. The most informative approaches that are available today to researchers, such as HPLC-MS, GC-MS, and proton NMR, are discussed in details. A map of the meibomian lipidome (as it is seen in reverse phase liquid chromatography/mass spectrometry experiments) is presented. Directions of future efforts in the area are outlined.


Cerebrospinal fluid Histoplasma antibodies in central nervous system histoplasmosis.
We have evaluated the Histoplasma antibody response in the cerebrospinal fluid (CSF) in nine patients with central nervous system histoplasmosis and 98 controls. While the CSF Histoplasma antibody response identified eight of the nine patients, CSF cultures were positive in only two. Of controls with histoplasmosis but without meningitis (13 patients), or without histoplasmosis (85 patients), elevated CSF antibodies were detected by complement fixation in seven, by IgG radioimmunoassay in 17, and by IgM radioimmunoassay in five. Measurement of the CSF Histoplasma antibody response appears useful for identifying meningitis in patients with histoplasmosis, although cross-reactions occur in half of patients with other forms of chronic fungal meningitis. Patients with these other infections can usually be identified by tests for CSF Coccidioides antibodies, or cryptococcal antigens.


Enhancing biological stability of disinfectant-free drinking water by reducing high molecular weight organic compounds with ultrafiltration posttreatment.
The production of biologically stable drinking water is challenging in conventional surface water treatment plants. However, attainment of biological stability is essential to avoid regrowth in disinfectant-free distribution systems. A novel application of ultrafiltration as a posttreatment step to enhance biological stability of drinking water produced in an existing conventional surface water treatment plant was investigated. The conventional full-scale plant comprised coagulation/sedimentation/filtration, UV-disinfection, biological activated carbon filtration and chlorine dioxide post-disinfection. The produced water exhibited substantial regrowth of Aeromonads, invertebrates and colony counts in the distribution network. Recent literature attributes this phenomenon to the specific presence of slowly biodegradable, high molecular weight (MW) biopolymeric organic compounds. Hence, the aim of this study is to enhance the biological stability of conventionally treated surface water by reducing the concentration of high-MW organic compounds. For this purpose, biological active carbon filtrate was subjected to ultrafiltration with membrane pore sizes of 10 kDa, 150 kDa and 0.12 μm respectively, operating in parallel. The UF performance was evaluated in terms of the achieved reduction in particulate and high-MW organic carbon (PHMOC); the biopolymer fraction in Liquid Chromatography-Organic Carbon Detection; biomass (cells, ATP); Assimilable Organic Carbon (AOC) by the AOC-P17/NOX method for easily biodegradable, low-MW compounds and by the AOC-A3 method for slowly biodegradable, high-MW compounds; and overall microbial growth potential (MGP) as assessed by Biomass Production Potential (BPP) and Bacterial Growth Potential (BGP) bio-assays. Results showed increasing removal of high-MW organic carbon with decreasing UF pore size, i.e., 30%, 60% and 70% removal was observed for the 0.12 μm, 150 kDa and 10 kDa membranes, respectively. Biomass and particulates retention was more than 95% for all UF membranes. AOC-A3, BPP and BGP were substantially reduced by 90%, 70% and 50%, respectively. These respective reductions were similar for all three UF membranes despite their difference in pore size. Easily biodegradable organic compounds (as AOC-P17/NOX) were not reduced by any of the membranes, which was in accordance with expectations considering the low MW of the compounds involved. Based on the obtained results, growth potential appears to be largely attributable to high-MW organic compounds which are retained by a 0.12 μm UF membrane. Furthermore, the quality of all three UF permeates was equal to or better than in reference cases (literature data) which exhibit little regrowth in their disinfectant-free distribution networks. The results demonstrate that ultrafiltration posttreatment in conventional surface water treatment plants is a potentially promising approach to enhance the biological stability of drinking water.


Dorsal turning of motor corticospinal axons at the pyramidal decussation requires plexin signaling.
The development of the corticospinal tract (CST) in higher vertebrates relies on a series of axon guidance decisions along its long projection pathway. Several guidance molecules are known to be involved at various decision points to regulate the projection of CST axons. However, previous analyses of the CST guidance defects in mutant mice lacking these molecules have suggested that there are other molecules involved in CST axon guidance that are yet to be identified. In this study, we investigate the role of plexin signaling in the guidance of motor CST axons in vivo. Expression pattern studies show that plexin-A3, plexin-A4, and neuropilin-1 are expressed in the developing cerebral cortex when the motor CST axons originating from layer V cortical neurons are guided down to the spinal cord. By analyzing mutant mice, we show that motor CST axons that turn dorsally to cross the midline at the pyramidal decussation require plexin-A3 and plexin-A4 signaling. Although other CST guidance defects are found in neuropilin-1 mutants, this dorsal turning defect is not observed in either neuropilin-1 or neuropilin-2 mutants, suggesting that the local cues that activate plexin signaling at the dorsal turning point are membrane-bound semaphorins. Further expression pattern study and mutant analysis indicate that Sema6A is one of the local cues for motor CST axon turning at the pyramidal decussation. Dorsal turning and midline crossing at the pyramidal decussation is a crucial step to properly direct CST axons into the dorsal spinal cord. We show that the signaling of plexin-A3, plexin-A4, and Sema6A is at least partially required for dorsal turning of the CST axons, while neuropilin-1 is required for proper fasciculation of the tract at midline crossing. Together with previous reports, these results demonstrate that several guidance cues are specifically utilized to regulate the dorsal turning and midline crossing of developing CST axons.


COVIDSAVIOR: A Novel Sensor-Fusion and Deep Learning Based Framework for Virus Outbreaks.
The presented deep learning and sensor-fusion based assistive technology (Smart Facemask and Thermal scanning kiosk) will protect the individual using auto face-mask detection and auto thermal scanning to detect the current body temperature. Furthermore, the presented system also facilitates a variety of notifications, such as an alarm, if an individual is not wearing a mask and detects thermal temperature beyond the standard body temperature threshold, such as 98.6°F (37°C). Design/methodology/approach-The presented deep Learning and sensor-fusion-based approach can also detect an individual in with or without mask situations and provide appropriate notification to the security personnel by raising the alarm. Moreover, the smart tunnel is also equipped with a thermal sensing unit embedded with a camera, which can detect the real-time body temperature of an individual concerning the prescribed body temperature limits as prescribed by WHO reports. Findings-The investigation results validate the performance evaluation of the presented smart face-mask and thermal scanning mechanism. The presented system can also detect an outsider entering the building with or without mask condition and be aware of the security control room by raising appropriate alarms. Furthermore, the presented smart epidemic tunnel is embedded with an intelligent algorithm that can perform real-time thermal scanning of an individual and store essential information in a cloud platform, such as Google firebase. Thus, the proposed system favors society by saving time and helps in lowering the spread of coronavirus.


Defining criteria to interpret multilocus variable-number tandem repeat analysis to aid Clostridium difficile outbreak investigation.
PFGE is currently the North American standard for surveillance for Clostridium difficile but lacks discriminatory power to aid outbreak investigation. A further limitation to PFGE is the high baseline rate of the epidemic North American pulsotype (NAP) 1 strain in hospitals. Multilocus variable-number tandem repeat analysis (MLVA) appears to have superior discriminatory power but criteria to define clonality have not been set. We conducted surveillance for toxin-positive C. difficile infection (CDI) at a single academic health sciences centre between September 2009 and April 2010. Seventy-four patient specimens resulting in 86 discrete CDI episodes were subjected to PFGE and MLVA. Results were analysed using Bionumerics software to generate phylogenetic trees and coupled to patient demographic data. Amongst the NAP1 strains, two distinct clusters were identified by MLVA using 90 % similarity as a cut-off by Manhattan distance-based clustering, four clusters using 95 % and seven clusters using 97 %. Population analysis conducted on multiple colonies (n = 25) demonstrated that 1-3 % difference in MLVA types was typical for a single individual. Typing was also conducted in the context of institutional outbreaks (n = 42, three outbreaks) in order to determine clusters within the NAP1 strain. By combining longitudinal surveillance with epidemiological information, single specimen population analysis and typing in the context of institutional outbreaks, we conclude that the use of the Manhattan distance-based clustering with a cut-off of 95-97 % is capable of distinguishing outbreak clones from sporadic isolates.


Propagating population activity patterns during spontaneous slow waves in the thalamus of rodents.
Slow waves (SWs) represent the most prominent electrophysiological events in the thalamocortical system under anesthesia and during deep sleep. Recent studies have revealed that SWs have complex spatiotemporal dynamics and propagate across neocortical regions. However, it is still unclear whether neuronal activity in the thalamus exhibits similar propagation properties during SWs. Here, we report propagating population activity in the thalamus of ketamine/xylazine-anesthetized rats and mice visualized by high-density silicon probe recordings. In both rodent species, propagation of spontaneous thalamic activity during up-states was most frequently observed in dorsal thalamic nuclei such as the higher order posterior (Po), lateral posterior (LP) or laterodorsal (LD) nuclei. The preferred direction of thalamic activity spreading was along the dorsoventral axis, with over half of the up-states exhibiting a gradual propagation in the ventral-to-dorsal direction. Furthermore, simultaneous neocortical and thalamic recordings collected under anesthesia demonstrated that there is a weak but noticeable interrelation between propagation patterns observed during cortical up-states and those displayed by thalamic population activity. In addition, using chronically implanted silicon probes, we detected propagating activity patterns in the thalamus of naturally sleeping rats during slow-wave sleep. However, in comparison to propagating up-states observed under anesthesia, these propagating patterns were characterized by a reduced rate of occurrence and a faster propagation speed. Our findings suggest that the propagation of spontaneous population activity is an intrinsic property of the thalamocortical network during synchronized brain states such as deep sleep or anesthesia. Additionally, our data implies that the neocortex may have partial control over the formation of propagation patterns within the dorsal thalamus under anesthesia.


A Qualitative Study Exploring the Experiences and Perceptions of Patients with Hemophilia Regarding Their Health-Related Well-Being, in Salamanca.
Hemophilia is a chronic, congenital/hereditary and X-linked disease, characterized by an insufficiency of factors VIII or IX, which are necessary for blood clotting. Those affected by hemophilia often suffer from particular psychosocial problems, both in the acceptance, coping, treatment and self-management of their disease and in their family and social relationships, which are often mediated by these circumstances. The aim of this study was to explore the experiences of people with hemophilia or their family members, of in a specific region of Spain, regarding the impact of having hemophilia. Structured interviews were conducted and developed, using the studies of the World Federation of Hemophilia and Osorio-Guzmán et al. as a guide, as well as a literature review of qualitative work on hemophilia. Data were analyzed using a six-step thematic analysis. A total of 34 interviews were thematically analyzed. The results showed that three key themes emerged from the data: (1) the daily impact of having hemophilia, (2) uncertainty about the disease, (3) the role of associations and (4) support from institutions. The results make it clear that the disease has a major impact on their lives (work, family, leisure and personal environment). The main conclusion is that hemophilia has a negative impact on the daily lives of patients, families and caregivers.