Reversible two-photon photoswitching and two-photon imaging of immunofunctionalized nanoparticles targeted to cancer cells.
Both photoswitchable fluorescent nanoparticles and photoactivatable fluorescent proteins have been used for super-resolution far-field imaging on the nanometer scale, but the photoactivating wavelength for such photochemical events generally falls in the near-UV (NUV) region (<420 nm), which is not preferred in cellular imaging. However, using two near-IR (NIR) photons that are lower in energy, we can circumvent such problems and replace NUV single-photon excitations (e.g., 390 nm) with NIR two-photon excitations (e.g., 780 nm). Thus, we have demonstrated that alternating 780 nm NIR two-photon and 488 nm single-photon excitations induces reversible on-off fluorescence switching of immunotargeted nanoparticles in the human breast cancer cell line SK-BR-3. Herein, two-photon absorption not only caused spiropyran-merocyanine photoisomerization within the particles but also imparted red fluorescence. In comparison with single-photon NUV excitations, two-photon NIR laser excitations can potentially reduce absorption-related photodamage to living systems because cellular systems absorb much more weakly in the NIR.


Improving the lives of ethnically diverse family carers and people living with dementia using digital media resources - Protocol for the Draw-Care randomised controlled trial.
Ethnically diverse family carers of people living with dementia (hereafter carers and people with dementia) experience more psychological distress than other carers. To reduce this inequality, culturally adapted, multilingual, evidence-based practical assistance is needed. This paper details the Draw-Care study protocol including a randomised control trial (RCT) to test the effectiveness of a digital intervention comprising a multilingual website, virtual assistant, animated films, and information, on the lives of carers and people with dementia in Australia. The Draw-Care intervention will be evaluated in a 12-week active waitlist parallel design RCT with 194 carers from Arabic, Cantonese, Greek, Hindi, Italian, Mandarin, Spanish, Tamil, and Vietnamese-speaking language groups. Our intervention was based on the World Health Organization's (WHO) iSupport Lite online carer support messages and was co-designed with carers, people with dementia, service providers, and clinicians. Culturally adapted multilingual digital resources were created in nine languages and English. In Phase I (2022), six co-design workshops with stakeholders and interviews with people with dementia informed the development of the intervention which will be trialled and evaluated in Phases II and III (2023 and 2024). Digital media content is a novel approach to providing cost-effective access to health care information. This study protocol details the three study phases including the RCT of a co-designed, culturally adapted, multilingual, digital intervention for carers and people with dementia to advance the evidence in dementia and digital healthcare research and help meet the needs of carers and people with dementia in Australia and globally.


Cognitive deficits characterization using the CogState Research Battery in first-episode psychosis patients.
The computer-based CogState Research Battery (CSRB) proposes a test structure which follows MATRICS recommended cognitive domains but lacks direct comparison to pen and paper batteries in first-episode psychosis (FEP). The aim of this study was to compare performances obtained with the CSRB and a pen and paper battery in a historical cohort of FEP patients. Among patients entering an early intervention program between 2003 and 2014, separate cohorts completed the traditional pen and paper cognitive battery (n = 182) and the CSRB (n = 97). Composite z-scores were derived using normative data of matched controls (n = 64 pen and paper, n = 69 CSRB) and were compared between the two batteries for the 7 cognitive domains. The cohort tested using the CSRB performed better on the domains of processing speed, attention, visual memory, and verbal memory than the cohort tested using the pen and paper battery (all p < 0.001). Performance did not differ between the two types of batteries for the working memory, executive functions, and social cognition domains. Cognitive profiles identified in the two patient cohorts were similar, with verbal memory being the most impaired domain. Better performances on the CSRB may be primarily due to the minimal demand of the computerized tests on graphomotor abilities and reading speed compared to the pen and paper tests. Our investigation offers a better understanding on how the results obtained with computerized batteries may compare to earlier work done with traditional tests.


[The knowledge of chagasic patients about their disease: collective construction of a research instrument and test of its applicability].
This article describes the collective construction of a research instrument (interview guideline) for investigating the knowledge of chagasic patients attended at the Chagas Disease Reference Center of the Oswaldo Cruz Foundation. A multi-professional team worked sequentially on six versions of the guideline for semi-structured interviews. The instrument aims collecting data for a qualitative approach to concepts and perceptions of the patients from the perspective of the human relationships in the context of life and health. It detects the individual experiences regarding the diseasing process, the knowledge about the disease (and the infection), the emotions, reactions, and affections. Some theoretical aspects were discussed based on sociological and anthropological practices used in public health actions. We performed a complete interview with a patient for testing and adjusting the instrument. The interview guideline was tested and showed to be a suitable instrument for investigating the knowledge of chagasic patients, covering many subjective and cognitive aspects. This knowledge can be a useful contribution to the development of strategies, actions and information material aimed at improving and humanizing the care delivered to Chagas disease patients.


An exploratory study of sodium, potassium, and fluid nutrition status of tube-fed nonambulatory children with severe cerebral palsy.
Children with severe cerebral palsy (CP) often have lower mineral intakes than healthy children. It is unknown if their lower nutrient intakes are adequate to meet their needs. The objective of this study was to examine the sodium, potassium, phosphate, and fluid status of primarily tube-fed nonambulatory children with severe CP. The design consisted of a cross-sectional exploratory study and a clinical trial of sodium supplementation. Nutritional status was determined among primarily tube-fed children (aged 2 to 17 years) with CP based on blood and urine samples, anthropometry, and 3-day food records. Mineral and fluid status was evaluated by a nephrologist blind to nutrient intakes. Twenty children supplied food records, blood samples, and anthropometric measurements, and 16 supplied urine samples. Six (37.5%) of those who provided urine samples were considered possibly dehydrated, as urine osmolality was >600 mmol·kg(-1). Six (60%) of the 10 children with satisfactory fluid status (low urine osmolality) were considered to have a possible dietary sodium deficiency based on a very low urine sodium concentration (<20 mmol·L(-1)). Those considered to have a possible dietary sodium deficiency had a significantly lower sodium intake (48% ± 15% Adequate Intake (AI)) compared with those considered sodium sufficient (73% ± 20% AI) (p = 0.031). One child was considered possibly phosphorus deficient, but none was assessed as likely potassium deficient. The conclusion was that sodium deficiencies were likely prevalent among the children. The findings from this small observational study suggest that sodium intakes for tube-fed children with CP should be maintained near the AI for their age. Hydration status of children receiving hypercaloric formulas should be monitored.


Conjunctival melanoma in a 55 year old male Nigerian: a case report.
Conjunctival melanoma is a rare occurrence in the Negroid race. To report a case of a 55 year old security man with right conjunctival melanoma. A 55 old man was operated on to remove a pigmented right bulbar conjuctival growth. The specimen was submitted to Lagos University Teaching Hospital Lagos and Harold Wood Hospital England for histopathologic examination and confirmation. Surgery was successful and histopathologic and immunohistochemical studies confirmed a diagnosis of a nodular malignant melanoma. The need for the provision of definitive investigative tool (immunohistochemical studies) to facilitate definitive diagnosis and management of such cases in some recognised centres in Nigeria cannot be overemphasised.


Single Thai women's interpersonal communication and mass media reception on AIDS.
This research examines young unmarried women's ways of talking about AIDS, AIDS prevention, and its relationship to mass media AIDS messages in Thailand. Data were derived from a survey conducted in four districts of Kanchanaburi province. Three hundred ninety-seven unmarried women were extracted from the approximately 1,800 original subjects for this analysis. Respondents were asked about the subjects and extent of their conversations about AIDS, the choice of discussion partners, considerations of social appropriateness in talking about the disease, as well as their risk perception. Important findings were that (a) women tend to talk about AIDS primarily with friends and siblings, (b) their reception level of mass media messages is related to the number of topics discussed and frequency of talks by the subjects, and (c) socioeconomic status and age are related to the variety and frequency of talking about AIDS. Implications for AIDS education are discussed.


Members of the methanotrophic genus Methylomarinum inhabit inland mud pots.
Proteobacteria capable of converting the greenhouse gas methane to biomass, energy, and carbon dioxide represent a small but important sink in global methane inventories. Currently, 23 genera of methane oxidizing (methanotrophic) proteobacteria have been described, although many are represented by only a single validly described species. Here we describe a new methanotrophic isolate that shares phenotypic characteristics and phylogenetic relatedness with the marine methanotroph Methylomarinum vadi. However, the new isolate derives from a terrestrial saline mud pot at the northern terminus of the Eastern Pacific Rise (EPR). This new cultivar expands our knowledge of the ecology of Methylomarinum, ultimately towards a fuller understanding of the role of this genus in global methane cycling.


Low levels of peripheral CD161++CD8+ mucosal associated invariant T (MAIT) cells are found in HIV and HIV/TB co-infection.
High expression of CD161 on CD8+ T cells is associated with a population of cells thought to play a role in mucosal immunity. We wished to investigate this subset in an HIV and Mycobacterium tuberculosis (MTB) endemic African setting. A flow cytometric approach was used to assess the frequency and phenotype of CD161++CD8+ T cells. 80 individuals were recruited for cross-sectional analysis: controls (n = 18), latent MTB infection (LTBI) only (n = 16), pulmonary tuberculosis (TB) only (n = 8), HIV only (n = 13), HIV and LTBI co-infection (n = 15) and HIV and TB co-infection (n = 10). The impact of acute HIV infection was assessed in 5 individuals recruited within 3 weeks of infection. The frequency of CD161++CD8+ T cells was assessed prior to and during antiretroviral therapy (ART) in 14 HIV-positive patients. CD161++CD8+ T cells expressed high levels of the HIV co-receptor CCR5, the tissue-homing marker CCR6, and the Mucosal-Associated Invariant T (MAIT) cell TCR Vα7.2. Acute and chronic HIV were associated with lower frequencies of CD161++CD8+ T cells, which did not correlate with CD4 count or HIV viral load. ART was not associated with an increase in CD161++CD8+ T cell frequency. There was a trend towards lower levels of CD161++CD8+ T cells in HIV-negative individuals with active and latent TB. In those co-infected with HIV and TB, CD161++CD8+ T cells were found at low levels similar to those seen in HIV mono-infection. The frequencies and phenotype of CD161++CD8+ T cells in this South African cohort are comparable to those published in European and US cohorts. Low-levels of this population were associated with acute and chronic HIV infection. Lower levels of the tissue-trophic CD161++ CD8+ T cell population may contribute to weakened mucosal immune defense, making HIV-infected subjects more susceptible to pulmonary and gastrointestinal infections and detrimentally impacting on host defense against TB.


Genetic evidence for role of integration of fast and slow neurotransmission in schizophrenia.
The most recent genome-wide association studies (GWAS) of schizophrenia (SCZ) identified hundreds of risk variants potentially implicated in the disease. Further, novel statistical methodology designed for polygenic architecture revealed more potential risk variants. This can provide a link between individual genetic factors and the mechanistic underpinnings of SCZ. Intriguingly, a large number of genes coding for ionotropic and metabotropic receptors for various neurotransmitters-glutamate, γ-aminobutyric acid (GABA), dopamine, serotonin, acetylcholine and opioids-and numerous ion channels were associated with SCZ. Here, we review these findings from the standpoint of classical neurobiological knowledge of neuronal synaptic transmission and regulation of electrical excitability. We show that a substantial proportion of the identified genes are involved in intracellular cascades known to integrate 'slow' (G-protein-coupled receptors) and 'fast' (ionotropic receptors) neurotransmission converging on the protein DARPP-32. Inspection of the Human Brain Transcriptome Project database confirms that that these genes are indeed expressed in the brain, with the expression profile following specific developmental trajectories, underscoring their relevance to brain organization and function. These findings extend the existing pathophysiology hypothesis by suggesting a unifying role of dysregulation in neuronal excitability and synaptic integration in SCZ. This emergent model supports the concept of SCZ as an 'associative' disorder-a breakdown in the communication across different slow and fast neurotransmitter systems through intracellular signaling pathways-and may unify a number of currently competing hypotheses of SCZ pathophysiology.


Melatonin Maintains Inner Blood-Retinal Barrier by Regulating Microglia via Inhibition of PI3K/Akt/Stat3/NF-κB Signaling Pathways in Experimental Diabetic Retinopathy.
Microglial activation and melatonin protection have been reported in diabetic retinopathy (DR). Whether melatonin could regulate microglia to protect the inner blood-retinal barrier (iBRB) remains unknown. In this study, the role of microglia in iBRB breakdown and the mechanisms of melatonin's regulation on microglia were explored. In diabetic rat retinas, activated microglia proliferated and migrated from the inner retina to the outer retina, accompanied by the obvious morphological changes. Meanwhile, significant leakage of albumin was evidenced at the site of close interaction between activated microglia and the damaged pericytes and endothelial cells. In vitro, inflammation-related cytokines, such as tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), interleukin (IL)-1β, and arginase-1 (Arg-1), were increased significantly in CoCl2-treated BV2 cells. The supernatant derived from CoCl2-treated BV2 cells significantly decreased the cell viability and disrupted the junctional proteins in both pericytes and endothelial cells, resulting in severe leakage. Melatonin suppressed the microglial overactivation, i.e., decreasing the cell number and promoting its anti-inflammatory properties in diabetic rat retinas. Moreover, the leakage of iBRB was alleviated and the pericyte coverage was restored after melatonin treatment. In vitro, when treated with melatonin in CoCl2-treated BV2 cells, the inflammatory factors were decreased, while the anti-inflammatory factors were increased, further reducing the pericyte loss and increasing the tight junctions. Melatonin deactivated microglia via inhibition of PI3K/Akt/Stat3/NF-κB signaling pathways, thus maintaining the integrity of iBRB. The present data support a causal role for activated microglia in iBRB breakdown and highlight the therapeutic potential of melatonin in the treatment of DR by regulating microglia.


Benefits and harms of doxycycline treatment for Gulf War veterans' illnesses: a randomized, double-blind, placebo-controlled trial.
It has been hypothesized that certain Mycoplasma species may cause Gulf War veterans' illnesses (GWVIs), chronic diseases characterized by pain, fatigue, and cognitive symptoms, and that affected patients may benefit from doxycycline treatment. To determine whether a 12-month course of doxycycline improves functional status in Gulf War veterans with GWVIs. A randomized, double-blind, placebo-controlled clinical trial with 12 months of treatment and 6 additional months of follow-up. 26 U.S. Department of Veterans Affairs and 2 U.S. Department of Defense medical centers. 491 deployed Gulf War veterans with GWVIs and detectable Mycoplasma DNA in the blood. Doxycycline, 200 mg, or matching placebo daily for 12 months. The primary outcome was the proportion of participants who improved more than 7 units on the Physical Component Summary score of the Veterans Short Form-36 General Health Survey 12 months after randomization. Secondary outcomes were measures of pain, fatigue, and cognitive function and change in positivity for Mycoplasma species at 6, 12, and 18 months after randomization. No statistically significant differences were found between the doxycycline and placebo groups for the primary outcome measure (43 of 238 participants [18.1%] vs. 42 of 243 participants [17.3%]; difference, 0.8 percentage point [95% CI, -6.5 to 8.0 percentage points]; P > 0.2) or for secondary outcome measures at 1 year. In addition, possible differences in outcomes at 3 and 6 months were not apparent at 9 or 18 months. Participants in the doxycycline group had a higher incidence of nausea and photosensitivity. Adherence to treatment after 6 months was poor. Long-term treatment with doxycycline did not improve outcomes of GWVIs at 1 year.


Revision Endoscopic Posterior Costal Cartilage Grafting: Is It Feasible?
The objective of this work is to examine the feasibility of revision endoscopic posterior costal cartilage graft (EPCCG) placement for posterior glottic stenosis (PGS) and bilateral vocal fold immobility (BVFI). Revision and primary cases were compared with respect to decannulation rates, and it was hypothesized that there would be no difference in outcomes. Twenty-one patients met inclusion criteria (14 primary, 7 revision). Thirteen (62%) had a primary indication of PGS, and 8 (42%) were for BVFI. There were no differences between revision and primary groups with respect to age, gender, or comorbidities (p > .05). There was no difference between groups with respect to decannulation rate (85% primary vs 100% revision, p = .32). Thus, revision EPCCG appears to have comparable results to primary EPCCG with respect to decannulation rate and time to decannulation. EPCCG may be a feasible alternative to open airway reconstruction for PGS and BVFI in selected patients.


Differential but direct abolishment of human regulatory T cell suppressive capacity by various TLR2 ligands.
CD4(+)CD25(high) regulatory T cells (Tregs) control cellular immune responses and maintain peripheral tolerance. We investigated whether TLR2 ligands are able to abrogate Treg-induced suppression in humans based on different reports about effects of triacylated lipopeptide Pam(3)CSK4 in mice. Pretreatment of human Tregs with a mixture of TLR2 ligands Pam(2)CSK4, FSL-1, and Pam(3)CSK4 reduced the Treg-mediated suppression of CD4(+)CD25(-) responder T cells in the majority of the analyzed donors. Differential effects of individual TLR2 ligands are explained by usage of different TLR2 heterodimers in the recognition of Pam(2)CSK4, FSL-1, and Pam(3)CSK4. In contrast to the murine system, TLR2 ligand-mediated abrogation of human Treg function was not associated with a downregulation of FoxP3 transcription factor. Furthermore, our results excluded an effect of TLR2 ligands on granzyme A/B release by human Tregs as a potential mechanism to abolish Treg-mediated suppression. Our data suggest that a downregulation of p27(Kip1) and restoration of Akt phosphorylation in human Tregs pretreated with TLR2 ligands result in a reversal of suppression on responder T cells. Moreover, our data indicate that a mixture of TLR2 ligands can be used to modulate human Treg activity.


Berberine inhibits the expression of TNFalpha, MCP-1, and IL-6 in AcLDL-stimulated macrophages through PPARgamma pathway.
Macrophages are the main source of cytokines in atherosclerotic plaques. Modified low-density lipoproteins may stimulate macrophages to produce large quantities of proinflammatory cytokines that promote atherosclerosis. Berberine is the main component of the traditional Chinese medicine umbellatine, which has a widespread effect and was used to treat many diseases clinically. Our previous study found that berberine could increase adipophilin expression in macrophages, which is a target gene of PPARgamma. PPARgamma agonist could decrease proinflammatory cytokines in macrophage. In this study, we investigated the effects and the mechanism of action of berberine on the expression and secretion of TNFalpha, MCP-1, and IL-6 in vitro to identify new pharmacological actions of berberine. The results of RT-PCR and ELISA shows that berberine may inhibit the expression and secretion of the tumor necrosis factor alpha (TNFalpha), monocyte chemoattractant protein 1 (MCP-1), and interleukin-6 (IL-6) in macrophages stimulated by acetylated low-density lipoprotein (AcLDL), whereas the peroxisome proliferator-activated receptor gamma (PPARgamma) inhibitor GW9662 could attenuate this effect of berberine. This study demonstrates that berberine may inhibit the expression and production of TNF-alpha, MCP-1, and IL-6 in AcLDL-stimulated macrophages. This effect might be partially mediated through PPARgamma activity.


The pivotal role of high-resolution mass spectrometry in the study of grape glycosidic volatile precursors for the selection of grapevines resistant to mildews.
A breeding program to produce new grape varieties tolerant to main vine fungal pathogens (Plasmopara viticola and Erysiphe necator) is carrying out by crossing Vitis vinifera cv. "Glera" with resistant genotypes such as "Solaris," "Bronner," and "Kunleany." Firstly, resistance gene-based markers analyses allowed the identification of five genotypes, which have inherited the resistance loci against mildews. To select those that also inherited the phenotype as close as possible to 'Glera' suitable to be introduced in the Prosecco wine production protocols, the grape glycosidic derivatives were studied by UHPLC/QTOF mass spectrometry. Targeted identification of the metabolites was performed using a database expressly constructed by including the glycosidic volatile precursors previously identified in grape and wine. A total of 77 glycosidic derivatives including many aroma precursors and some variety markers, were identified. Original resistant genotypes had distinct metabolomic profiles and different to 'Glera', while the crossings showed varying similarity degrees to V. vinifera parent. Findings demonstrated the Glera × Bronner and Glera × Solaris crossings are more suitable to produce high-sustainable Prosecco wines. Coupling of glycosidic volatile precursors profiling to multivariate statistical analysis was effective for phenotypic characterization of grapes and to evaluate their enological potential.


Algebraic second virial coefficient of the Mie m - 6 intermolecular potential based on perturbation theory.
We propose several simple algebraic approximations for the second virial coefficient of fluids whose molecules interact by a generic Mie m - 6 intermolecular pair potential. In line with a perturbation theory, the parametric equations are formulated as the sum of a contribution due to a reference part of the intermolecular potential and a perturbation. Thereby, the equations provide a convenient (low-density) starting point for developing equation-of-state models of fluids or for developing similar approximations for the virial coefficient of (polymeric-)chain fluids. The choice of Barker and Henderson [J. Chem. Phys. 47, 4714 (1967)] and Weeks, Chandler, and Andersen [Phys. Rev. Lett. 25, 149 (1970); J. Chem. Phys. 54, 5237 (1971); and Phys. Rev. A 4, 1597 (1971)] for the reference part of the potential is considered. Our analytic approximations correctly recover the virial coefficient of the inverse-power potential of exponent m in the high-temperature limit and provide accurate estimates of the temperatures for which the virial coefficient equals zero or takes on its maximum value. Our description of the reference contribution to the second virial coefficient follows from an exact mapping onto the second virial coefficient of hard spheres; we propose a simple algebraic equation for the corresponding effective diameter of the hard spheres, which correctly recovers the low- and high-temperature scaling and limits of the reference fluid's second virial coefficient.


Benign ethnic neutropenia.
Benign ethnic neutropenia (BEN) is one of the most common causes of chronic neutropenia seen in individuals of African, Middle Eastern and West Indian descent, affecting many individuals worldwide. Despite its prevalence, many physicians are not familiar with this benign condition, resulting in unnecessary evaluation and testing for neutropenia in otherwise healthy individuals. Clinically, patients with BEN are at no increased risk of infection despite their neutropenia. Implications of this condition are highlighted in those patients receiving therapies that have a known side effect of neutropenia, most commonly chemotherapy agents. Studies have suggested that disparities in survival among those patients receiving chemotherapy between patients of European decent and African decent may be attributed to measured neutropenia in these populations, questioning whether BEN could be an influential factor. This review encompasses all aspects of benign ethnic neutropenia, providing information about this condition and helping to guide clinical decision-making as to when an aggressive work up and referral are indicated and when it is appropriate to monitor. Additionally, we review the role of genetic studies in identifying the genes related to BEN, summarize the theories that offer the most accepted mechanisms behind the condition, and address the importance of pursuing larger studies to assess the implication of BEN in oncology patients as well as patients taking neutropenia-causing medications.


Some selected dental and jaw aberrations.
There is a close but separate interrelationship between the development of the teeth and jaws. Some principles of the biology of teeth and jaws are central to this presentation. The basic blueprints of both the tooth and jaws are inherent. Postnatal growth is but a continuation of prenatal growth interrupted by the event of birth. In utero, the fetus with its genetic beginnings is subjected to the vicissitudes of the maternal environment. After birth, the individual is subjected to the effects of the general environment. Development of facial form is related to the synchronous coordination of 3-dimensional, multiple, differential dental and jaw growth sites and centers and associated structure activities. This report deals with some selected unusual dental and jaw aberrations, some of which may have developed during the prenatal period and others during infancy and early childhood. However, they may not become significantly clinically manifest sometimes until late childhood or even early adulthood. Dental histogenesis is correlated in several instances (anodontia, ameloblastoma, hemifacial, atrophy) with jaw implications. Thus, this article is a synthesis of previous reports in which many included surgical treatment.


LEM Characterization of Synthetic Jet Actuators Driven by Piezoelectric Element: A Review.
In the last decades, Synthetic jet actuators have gained much interest among the flow control techniques due to their short response time, high jet velocity and absence of traditional piping, which matches the requirements of reduced size and low weight. A synthetic jet is generated by the diaphragm oscillation (generally driven by a piezoelectric element) in a relatively small cavity, producing periodic cavity pressure variations associated with cavity volume changes. The pressured air exhausts through an orifice, converting diaphragm electrodynamic energy into jet kinetic energy. This review paper considers the development of various Lumped-Element Models (LEMs) as practical tools to design and manufacture the actuators. LEMs can quickly predict device performances such as the frequency response in terms of diaphragm displacement, cavity pressure and jet velocity, as well as the efficiency of energy conversion of input Joule power into useful kinetic power of air jet. The actuator performance is also analyzed by varying typical geometric parameters such as cavity height and orifice diameter and length, through a suited dimensionless form of the governing equations. A comprehensive and detailed physical modeling aimed to evaluate the device efficiency is introduced, shedding light on the different stages involved in the process. Overall, the influence of the coupling degree of the two oscillators, the diaphragm and the Helmholtz frequency, on the device performance is discussed throughout the paper.


Amyloid-precursor Like Proteins APLP1 and APLP2 Are Dispensable for Normal Development of the Neonatal Respiratory Network.
Recent studies using animal models indicated that the members of the amyloid precursor protein (APP) gene family are important for the formation, maintenance, and plasticity of synapses. Despite this, the specific role of the APP homologs APLP1 and APLP2 within the CNS and PNS is still poorly understood. In contrast to the subtle phenotypes of single mutants, double knockout mice (DKO) lacking APP/APLP2 or APLP1/APLP2 die within the first day after birth. Whereas APP/APLP2-DKO mice show severe deficits of neuromuscular morphology and transmission, the underlying cause of lethality of APLP1/APLP2-DKO mice remains unclear. Since expression of both proteins was confirmed by in situ hybridization, we aimed to test the role of APLP1/APLP2 in the formation and maintenance of synapses in the brainstem, and assessed a potential dysfunction of the most vital central neuronal network in APLP1/APLP2-DKO mice by analyzing the respiratory network of the medulla. We performed in vivo unrestrained whole body plethysmography in newborn APLP1/APLP2-DKO mice at postnatal day zero. Additionally, we directly tested the activity of the respiratory network in an acute slice preparation that includes the pre-Bötzinger complex. In both sets of experiments, no significant differences were detected regarding respiratory rate and cycle variability, strongly arguing against central respiratory problems as the primary cause of death of APLP1/APLP2-DKO mice. Thus, we conclude that APLP1 and APLP2 are dispensable for the development of the network and the generation of a normal breathing rhythm.


Post-transplant Diabetes Mellitus in Kidney Transplant Recipients in Sudan: A Comparison Between Tacrolimus and Cyclosporine-Based Immunosuppression.
Hyperglycemia is a common complication among transplant patients without a history of diabetes mellitus (DM). Although new and potent immunosuppressants have improved short and long-term outcomes after transplantation, these drugs themselves may be associated with a greater risk of hyperglycemia. The present study aimed to determine the prevalence of post-transplant diabetes mellitus (PTDM) in post renal transplant patients in Sudan, and compare the effect of cyclosporine and tacrolimus-based immunosuppressive regimens. All adult kidney transplant recipients without pre-transplant diabetes who attended the transplant clinic at Ahmed Gasim Cardiac Surgery and Renal Transplant Center in Sudan were included. A total of 100 cases with functioning kidney allografts were enrolled in this study. The majority of cases were in the age range between 20 and 60 years (92%). Males and females were nearly equally distributed (56% vs 44%). Fifty-two percent of patients were on cyclosporine and 48% on tacrolimus. Overall, 18% of patients suffered from post-transplant diabetes mellitus. There was no statistically significant difference between tacrolimus and cyclosporine with regards to the prevalence of hyperglycemia (16.6% versus 13.4%; p>0.05).


Derandomizing Quantum Circuits with Measurement-Based Unitary Designs.
Entangled multipartite states are resources for universal quantum computation, but they can also give rise to ensembles of unitary transformations, a topic usually studied in the context of random quantum circuits. Using several graph state techniques, we show that these resources can "derandomize" circuit results by sampling the same kinds of ensembles quantum mechanically, analogously to a quantum random number generator. Furthermore, we find simple examples that give rise to new ensembles whose statistical moments exactly match those of the uniformly random distribution over all unitaries up to order t, while foregoing adaptive feedforward entirely. Such ensembles-known as t designs-often cannot be distinguished from the "truly" random ensemble, and so they find use in many applications that require this implied notion of pseudorandomness.


Electronic Cigarettes: Exposure to Secondhand Vapors at a Long-Term Healthcare Company.
Healthcare workers in long term care settings have limited control over their occupational secondhand exposure to electronic cigarettes and other tobacco products. The study aimed to identify the perceived frequency of exposure to exhaled electronic cigarette vapor on healthcare workers within two sites of a long-term healthcare company. An online survey was completed by 149 (out of approximately 500) employees that asked about electronic cigarette personal usage, concerns for exposure, exposure times, and demographic data. Twelve percent of all survey respondents expressed concerns related to second-hand exposure. Of those exposed, employee estimated exposure time was 2.1 minutes per shift for electronic cigarettes compared to 12.1 minutes per shift for cigarettes/cigars/pipes. Overall self-reported secondhand exposure to electronic cigarettes and cigarettes/cigars/pipes was low. To determine a definitive exposure level, quantitative sampling can be done related to chemical exposure via passive inhalation of the smoke and vapor cloud for cigarettes and electronic cigarettes, respectively. Education can be provided to healthcare workers and residents in long-term care facilities regarding risk of exposure to secondhand smoke to alleviate employees concerns with exposure.


Early recanalization and plasma brain natriuretic peptide as an indicator of left ventricular function after acute myocardial infarction.
Although plasma brain natriuretic peptide (BNP) levels have been widely measured in patients with acute myocardial infarction (AMI), it is still uncertain whether the early recanalization modulates the levels and whether the levels can predict chronic stage left ventricular function. This study was designed to elucidate these issues. In 80 consecutive patients with AMI, plasma BNP levels were measured at admission and at 4 hours, 24 hours, 48 hours, and 1 month after admission. In 35 of the 80 patients, the infarct-related artery was patent within 6 hours from the onset of MI (6-hour patency group), and in 27 patients, the artery was still occluded after 6 hours (6-hour occlusion group). The remaining 18 patients in whom it was unclear whether recanalization of the infarct-related artery had occurred within 6 hours or not were excluded from the analyses. In the 6-hour patency group, the BNP level gradually increased and reached a maximum value at 24 hours after admission. In the 6-hour occlusion group, the level increased more, with the values at 4 hours, 24 hours, and 48 hours significantly higher than those in the 6-hour patency group (86 +/- 18 pmol/L versus 35 +/- 8 pmol/L; P <.01; 112 +/- 13 pmol/L versus 74 +/- 9 pmol/L; P <.05; 102 +/- 15 pmol/L versus 53 +/- 11 pmol/L; P <.01). Chronic stage left ventricular function was correlated with not only the BNP level at same stage but also that at 24 hours and that at 48 hours after admission. Multiple regression analysis indicated that the BNP level at 24 hours was the most powerful predictor of chronic stage left ventricular function. Plasma BNP levels can predict subsequent cardiac function. In addition, the importance of early recanalization may also be supported with BNP kinetics.


The effect of different fixatives on chromatin: cytochemical and ultrastructural approaches.
This study explores the effects of two types of fixative on chromatin. The first type (acrolein, glutaraldehyde) engenders a high degree of ultrastructural preservation. The other type are fixatives that are widely used in cytochemistry and cytogenetics (acetic acid, 3:1 by vol. methanol-acetic acid, methanol alone, formaldehyde). Lymphocytes of adult rats so-fixed in vitro were prepared for electron microscopy or microdensitometric evaluations of smears. Assessments were made of variations in their total protein, nuclear basic protein and DNA contents. DNA was determined both as Feulgen-positive material and by its binding of intercalating dyes (Methyl Green, specific for double-stranded polynucleotides). Our results showed that some fixatives break up the chromatin organization by acting on particular components of chromatin fibres. They can thus be considered to be destructive agents in situ. In addition, a revaluation of some aldehyde fixatives is proposed for both ultrastructural and cytochemical research.


Metagenome of Gut Microbiota Provides a Novel Insight into the Pathogenicity of Balantioides coli in Weaned Piglets.
Balantioides coli plays an important role in the diarrhea of weaned piglets, but its pathogenic potential and interaction with gut microbes remain unclear. To investigate the impact of B. coli colonization on the gut bacterial structure and function of weaned piglets, a metagenomic analysis based on shotgun sequencing was performed on fresh fecal samples collected from ten B. coli-colonized piglets and eight B. coli-free ones in this study. The results showed that decreasing diversity and shifted composition and function of the bacterial community were detected in the weaned piglets infected by B. coli. In contrast to the B. coli-negative group, the relative abundances of some members of the Firmicutes phylum including Clostridium, Ruminococcus species, and Intestinimonas butyriciproducens, which produce short-chain fatty acids, were significantly reduced in the B. coli-positive group. Notably, some species of the Prevotella genus (such as Prevotella sp. CAG:604 and Prevotella stercorea) were significantly increased in abundance in the B. coli-positive piglets. A functional analysis of the gut microbiota demonstrated that the differential gene sets for the metabolism of carbohydrates and amino acids were abundant in both groups, and the more enriched pathways in B. coli-infected piglets were associated with the sugar-specific phosphotransferase system (PTS) and the two-component regulatory system, as well as lipopolysaccharide (LPS) biosynthesis. Furthermore, several species of Prevotella were significantly positively correlated to the synthesis of lipid A, leading to the exporting of endotoxins and, thereby, inducing inflammation in the intestines of weaned piglets. Taken together, these findings revealed that colonization by B. coli was distinctly associated with the dysbiosis of gut bacterial structure and function in weaned piglets. Lower relative abundances of Clostridiaceae and Ruminococcaceae and higher abundances of Prevotella species were biomarkers of B. coli infection in weaned piglets.


[Epidemiological survey of a single-case focus of acute enteric infections].
The aim, tasks and stages of the epidemiological survey of a single-cased focus of infection, taking into account present-day specific features of the epidemiology of acute enteric infections, have been formulated. The technical approaches to the detection of the source, routes, factors and conditions of the causative agent transmission are given. The patterns of the conclusion on the epidemiological survey of the focus are given.


Recent developments in effector biology of filamentous plant pathogens.
Filamentous pathogens, such as plant pathogenic fungi and oomycetes, secrete an arsenal of effector molecules that modulate host innate immunity and enable parasitic infection. It is now well accepted that these effectors are key pathogenicity determinants that enable parasitic infection. In this review, we report on the most interesting features of a representative set of filamentous pathogen effectors and highlight recent findings. We also list and describe all the linear motifs reported to date in filamentous pathogen effector proteins. Some of these motifs appear to define domains that mediate translocation inside host cells.


Spontaneous remission of recurring disseminated intravascular coagulation associated with prostatic carcinoma.
A 58-year-old patient with metastatic prostatic carcinoma had two well-documented episodes of disseminated intravascular coagulation (DIC) occurring 1 year apart and resolving without heparin therapy. This case illustrates that DIC need not have a poor prognosis and may resolve spontaneously despite progressive cancer. The efficacy of heparin therapy is discussed.


In vitro treatment of human monocytes/macrophages with myristoylated recombinant Nef of human immunodeficiency virus type 1 leads to the activation of mitogen-activated protein kinases, IkappaB kinases, and interferon regulatory factor 3 and to the release of beta interferon.
The viral protein Nef is a virulence factor that plays multiple roles during the early and late phases of human immunodeficiency virus (HIV) replication. Nef regulates the cell surface expression of critical proteins (including down-regulation of CD4 and major histocompatibility complex class I), T-cell receptor signaling, and apoptosis, inducing proapoptotic effects in uninfected bystander cells and antiapoptotic effects in infected cells. It has been proposed that Nef intersects the CD40 ligand signaling pathway in macrophages, leading to modification in the pattern of secreted factors that appear able to recruit and activate T lymphocytes, rendering them susceptible to HIV infection. There is also increasing evidence that in vitro cell treatment with Nef induces signaling effects. Exogenous Nef treatment is able to induce apoptosis in uninfected T cells, maturation in dendritic cells, and suppression of CD40-dependent immunoglobulin class switching in B cells. Previously, we reported that Nef treatment of primary human monocyte-derived macrophages (MDMs) induces a cycloheximide-independent activation of NF-kappaB and the synthesis and secretion of a set of chemokines/cytokines that activate STAT1 and STAT3. Here, we show that Nef treatment is capable of hijacking cellular signaling pathways, inducing a very rapid regulatory response in MDMs that is characterized by the rapid and transient phosphorylation of the alpha and beta subunits of the IkappaB kinase complex and of JNK, ERK1/2, and p38 mitogen-activated protein kinase family members. In addition, we have observed the activation of interferon regulatory factor 3, leading to the synthesis of beta interferon mRNA and protein, which in turn induces STAT2 phosphorylation. All of these effects require Nef myristoylation.


[Antihistamine drugs in the treatment of allergic skin diseases].
Antihistaminic therapy is widely used in the treatment of allergic dermatoses. Second generation antihistamines due to their pharmacokinetic mechanism depending on the wide extra-receptor anti-inflammatory and anti-allergic actions are used in the treatment of diseases, in which the main pathogenetic role is played by various allergic mechanisms and inflammatory cellular processes. The modern views on etiopathogenesis and antihistaminic treatment of allergic skin diseases are presented in this paper. The course of allergic inflammation, role of histamine and its receptors, taking into consideration the biological effects of their suppression and influence on the course of early and late phase of allergic reaction, are discussed. A review of classical and second generation antihistamines has been done, taking into account their usefulness in the treatment of acute and chronic urticaria, angioedema, atopic dermatitis, different forms of eczema and various drug-induced reactions.


Effects of Oxysterols on Chondrogenesis of Human Adipose-derived Stem Cells.
Human adipose-derived stem cells (hADSCs) have been implicated as a high potency source of chondrocytes in cell therapy for cartilage defects. However, appropriate stimulators for the chondrogenesis of hADSCs are needed. Oxysterols have the potential to act as a stimulator. This study aims to investigate the effect of oxysterols on the chondrogenesis of hADSCs. hADSCs were collected from the abdominal subcutaneous tissue samples of patients undergoing caesarean section, and were cultured to passage 5. Mesenchymal stem cell markers were examined by flow cytometry. After the cells were subjected to adipogenic, osteogenic, and chondrogenic induction, the differentiation of each cell lineage was evaluated by RT-PCR and specific staining (Oil red O, Alizarin red S, and Alcian blue, respectively). The cell pellets of hADSCs were cultured in chondrogenic induced media containing 2μM 22(R)-hydroxycholesterol, 22(S)-hydroxycholesterol, or 25-hydroxycholesterol for 4 weeks. At 3 and 4 weeks of culture, the size and wet weight of the pellets were measured. The expressions of chondrogenesis-related genes and glycosaminoglycans production were examined by quantitative real-time PCR and Alcian blue staining. hADSCs were positive for the mesenchymal markers CD75, CD90, and CD105, while being negative for the hematopoietic markers CD31, CD34 and CD45. The multilineage potential of hADSCs was confirmed by the expression of adipogenic-, osteogenic-, and chondrogenic-specific genes, along with specific staining. 22(R)-hydroxycholesterol treatment significantly increased the size and wet weight of the pellet, glycosaminoglycans production, and expression of chondrogenic-related genes compared to the control group and other oxysterols (P<0.05). These results indicate that 22(R)-hydroxycholesterol can be effective as a stimulator for the chondrogenesis of hADSCs.


Factors Associated With Graft Rejection in the Cornea Preservation Time Study.
To identify factors related to graft rejection following Descemet stripping automated endothelial keratoplasty (DSAEK) in the Cornea Preservation Time Study (CPTS). Cohort study within a multicenter randomized clinical trial. A total of 1330 eyes of 1090 subjects undergoing DSAEK were randomized to receive a donor cornea with preservation time (PT) of 0-7 days (n = 675) or 8-14 days (n = 655) and followed for 3 years. Central endothelial cell density (ECD) was determined by a central image analysis reading center. Multivariable Cox models adjusted for PT, recipient diagnosis, and surgeon effect were used to identify factors associated with rejection. Cumulative probability of definite graft rejection was 3.6% (99% confidence interval 2.5%-5.3%). Younger recipient age was associated with graft rejection (P < .001; hazard ratio: 0.53 [0.33, 0.83] per decade). PT, donor-recipient sex mismatch, recipient diagnosis, recipient race, graft size, discontinuation of topical corticosteroids and immune-modulators, prior immunizations within 3 months, and prior glaucoma surgery were not associated with rejection (P > .01). Among clear grafts with an ECD measurement at baseline and 3 years (n = 913), endothelial cell loss (ECL) was greater in eyes that experienced a rejection episode (n = 27) than in those that did not (n = 886) (48% vs 38%, P = .03). Twelve of 44 eyes (27%) with definite graft rejection subsequently failed, comprising 15% of the 79 failures in the CPTS. Graft rejection is uncommon after DSAEK and more likely with younger age, in a study cohort mostly > 50 years old. Rejection increases ECL, but it is not a leading cause of DSAEK failure.


A mobile clinical e-portfolio for nursing and medical students, using wireless personal digital assistants (PDAs).
This paper outlines the development and evaluation of a wireless personal digital assistant (PDA) based clinical learning tool designed to promote professional reflection for health professionals. The "Clinical e-portfolio" was developed at the University of British Columbia School of Nursing to enable students immediately to access clinical expertise and resources remotely, and record their clinical experiences in a variety of media (text, audio and images). The PDA e-portfolio tool was developed to demonstrate the potential use of mobile networked technologies to support and improve clinical learning; promote reflective learning in practice; engage students in the process of knowledge translation; help contextualize and embed clinical knowledge whilst in the workplace; and to help prevent the isolation of students whilst engaged in supervised clinical practice. The mobile e-portfolio was developed to synchronise wirelessly with a user's personal Web based portfolio from any remote location where a cellular telephone signal or wireless (Wi-Fi) connection could be obtained. An evaluation of the tool was undertaken with nurse practitioner and medical students, revealing positive attitudes to the use of PDA based tools and portfolios, but limits to the use of the PDA portfolio due to the inherent interface restrictions of the PDA.


Carcinoma of the male breast metastatic to both orbits.
We report the case of a 43-year-old man who presented with painless proptosis of the right eye of 6 weeks' duration. Examination demonstrated a tense right orbit and decreased vision and extraocular motility bilaterally. Diagnostic evaluation included computed tomographic imaging of the head and orbits, a therapeutic trial of high-dose systemic corticosteroids, and orbital biopsy, which revealed the presence of metastatic adenocarcinoma. The primary tumor was found to be an estrogen-receptor-positive, infiltrating ductal adenocarcinoma of the right breast. Therapy included lumpectomy of the breast mass, orbital irradiation, and hormonal therapy. Metastatic carcinoma of the breast should be considered in the differential diagnosis of orbital neoplastic disease in the male patient.


Dual channel RESOLFT nanoscopy by using fluorescent state kinetics.
We show that RESOLFT fluorescence nanoscopy, a low light level scanning superresolution technique employing reversibly switchable fluorescent proteins (rsFPs), is capable of dual-channel live-cell imaging that is virtually free of chromatic errors and temporal offsets. This is accomplished using rsEGFP and Dronpa, two rsFPs having similar spectra but different kinetics of switching and fluorescence emission. Our approach is demonstrated by imaging protein distributions and dynamics in living neurons and neuronal tissues.


Splenic abscess as a paradoxical response to chemotherapy in tuberculous pleural effusion.
We report a rare case of tuberculous pleural effusion that developed multiple splenic abscesses after antituberculosis chemotherapy. She responded to addition of oral corticosteroid to antituberculosis regimen. The relevant literature, regarding pathogenesis and clinical importance of recognizing a paradoxical response, is discussed.


Ammonia Fiber Expansion (AFEX) Pretreatment of Lignocellulosic Biomass.
Lignocellulosic materials are plant-derived feedstocks, such as crop residues (e.g., corn stover, rice straw, and sugar cane bagasse) and purpose-grown energy crops (e.g., miscanthus, and switchgrass) that are available in large quantities to produce biofuels, biochemicals, and animal feed. Plant polysaccharides (i.e., cellulose, hemicellulose, and pectin) embedded within cell walls are highly recalcitrant towards conversion into useful products. Ammonia fiber expansion (AFEX) is a thermochemical pretreatment that increases accessibility of polysaccharides to enzymes for hydrolysis into fermentable sugars. These released sugars can be converted into fuels and chemicals in a biorefinery. Here, we describe a laboratory-scale batch AFEX process to produce pretreated biomass on the gram-scale without any ammonia recycling. The laboratory-scale process can be used to identify optimal pretreatment conditions (e.g., ammonia loading, water loading, biomass loading, temperature, pressure, residence time, etc.) and generates sufficient quantities of pretreated samples for detailed physicochemical characterization and enzymatic/microbial analysis. The yield of fermentable sugars from enzymatic hydrolysis of corn stover pretreated using the laboratory-scale AFEX process is comparable to pilot-scale AFEX process under similar pretreatment conditions. This paper is intended to provide a detailed standard operating procedure for the safe and consistent operation of laboratory-scale reactors for performing AFEX pretreatment of lignocellulosic biomass.


Propofol Versus Midazolam/Fentanyl Sedation for Colonoscopy in the Elderly Patient Population.
Despite current literature, data on the most effective sedation and best patient outcomes are insufficient for providing recovery time recommendations for elderly patients undergoing colonoscopy with sedation. We sought to identify the best sedation practice for shorter recovery times. Therefore, a study was conducted to examine recovery times among patients older than 65 years undergoing elective colonoscopy with intravenous sedation with either propofol or the combination of midazolam/fentanyl. A retrospective descriptive, exploratory design was used. We retrospectively reviewed data from patients older than 65 years undergoing outpatient elective colonoscopy at our institution between January and December 2013. Recovery times were evaluated for those administered intravenous propofol or a combination of midazolam/fentanyl. Patient demographics and sedation medications were obtained from patient records. A modified Aldrete score greater than 8 was required for discharge. Recovery time was defined as the time from procedure completion to a modified Aldrete score greater than 8. Propofol sedation was associated with longer recovery times compared with sedation with a combination of midazolam and fentanyl (mean: 50 minutes versus 31 minutes, P < .001). Propofol sedation was not associated with shorter recovery times. Further studies are needed to validate these findings.


Peripheral Nerve Single-Cell Analysis Identifies Mesenchymal Ligands that Promote Axonal Growth.
Peripheral nerves provide a supportive growth environment for developing and regenerating axons and are essential for maintenance and repair of many non-neural tissues. This capacity has largely been ascribed to paracrine factors secreted by nerve-resident Schwann cells. Here, we used single-cell transcriptional profiling to identify ligands made by different injured rodent nerve cell types and have combined this with cell-surface mass spectrometry to computationally model potential paracrine interactions with peripheral neurons. These analyses show that peripheral nerves make many ligands predicted to act on peripheral and CNS neurons, including known and previously uncharacterized ligands. While Schwann cells are an important ligand source within injured nerves, more than half of the predicted ligands are made by nerve-resident mesenchymal cells, including the endoneurial cells most closely associated with peripheral axons. At least three of these mesenchymal ligands, ANGPT1, CCL11, and VEGFC, promote growth when locally applied on sympathetic axons. These data therefore identify an unexpected paracrine role for nerve mesenchymal cells and suggest that multiple cell types contribute to creating a highly pro-growth environment for peripheral axons.


Antidepressants in the treatment of psychosis with comorbid depression in Parkinson disease.
Psychotic symptoms are commonly associated with Parkinson disease and can be a source of significant morbidity. Depression has been reported as a comorbidity in patients with psychosis. We describe a patient with Parkinson disease with psychotic symptoms and comorbid depression whose treatment refractory delusions and hallucinations improved markedly only after antidepressant monotherapy was initiated. The phenomenology of the delusions was atypical for those found in Parkinson or in depression. Psychotic symptoms refractory or only partially responsive to conventional treatment should prompt a search for potential underlying psychiatric comorbidities. Given case reports of exacerbation of psychotic symptoms with antidepressants, we emphasize careful identification and active follow up of the comorbid depressive disorders in PD patients with psychosis. Potential mechanisms implicated in the response of psychosis to antidepressants are discussed.


Polymeric nanosponges as an alternative carrier for improved retention of econazole nitrate onto the skin through topical hydrogel formulation.
The present study was carried out to exploit the feasibility of using polymeric nanosponges as an alternative carrier for targeting econazole nitrate (EN) to the skin through topical hydrogel formulation. Nanosponges prepared by emulsion solvent diffusion method were evaluated for various physicochemical parameters and in vitro drug release. The nanosponges of EN were discrete free flowing nanosized particles with perforated orange peel like morphology as visualized by SEM. The nanosponge formulated using PVA:EC (3:2) displayed highest in vitro release after 12?h in phosphate buffer (pH 6.8) that fitted matrix model. Selected nanosponge was formulated as Carbopol 934 NF hydrogel using varying concentrations of permeation enhancers propylene glycol and N-methyl-2-pyrrolidone. The EN nanosponge-loaded hydrogels (F0?F7) were evaluated for pharmacotechnical properties and irritation studies on rat skin. On the basis of various evaluation parameters F7 with an equilibrium swelling of 0.944?g/g after 4?h, low firmness and high adhesiveness, a flux rate of 1540.2 (?g/cm(2).h) and that exhibited a controlled release of EN for 12?h was selected as best hydrogel. The DRS and DSC spectra of F7 confirmed stability of drug in the delivery system and absence of drug polymer interaction in nanosponges.


Characteristics of the Peripapillary Structure and Vasculature in Patients With Myopic Anisometropia.
To evaluate the interocular differences of the peripapillary structural and vascular parameters and that of association with axial length (AL) in participants with myopic anisometropia using swept-source optical coherence tomography. This prospective cross-sectional study included 90 eyes of 45 participants. Each participant's eyes were divided into the more and less myopic eye respectively according to spherical equivalent. The β- and γ-parapapillary atrophy (PPA) areas, Bruch's membrane opening distance, border length, and border tissue angle were measured manually. Peripapillary choroidal vascularity index and choroidal thickness (CT) values in superior, nasal, inferior, and temporal were calculated using a custom-built algorithm based on MATLAB. The interocular difference in AL and spherical equivalent was 0.62 ± 0.26 mm and -1.50 (-2.13, -1.25) diopters (D), respectively. The interocular difference in spherical equivalent was highly correlated with that of the AL. The β- and γ-PPA areas were significantly greater in more myopic eyes. The mean and inferior peripapillary choroidal vascularity index and all regions of peripapillary CT were significantly lower in the more myopic eyes. The interocular difference in AL was significantly positively correlated with the interocular differences in γ-PPA area and border length and negatively correlated with the interocular differences in temporal choroidal vascularity index and mean, inferior, and temporal peripapillary CT. There was an independent correlation between the interocular differences in AL and the interocular differences in γ-PPA area, inferior, and temporal peripapillary CT. Significant differences between both groups were detected in most peripapillary parameters, especially in peripapillary CT. The γ-PPA area, border length, and peripapillary CT were significantly correlated with the elongation of AL. The current study characterized and analyzed the peripapillary parameters in myopic anisometropia, which helped to monitor myopic progression.


How Do I Review Thee? Let Me Count the Ways: A Comparison of Research Grant Proposal Review Criteria Across US Federal Funding Agencies.
While Elizabeth Barrett Browning counted 25 ways in which she loves her husband in her poem, "How Do I Love Thee? Let me Count the Ways," we identified only eight ways to evaluate the potential for success of a federal research grant proposal. This may be surprising, as it seems upon initial glance of the review criteria used by various federal funding agencies that each has its own distinct set of "rules" regarding the review of grant proposals for research and scholarship. Much of the grantsmanship process is dependent upon the review criteria, which represent the funders' desired impact of the research. But since most funders that offer research grants share the overarching goals of supporting research that (1) fits within its mission and (2) will bring a strong return on its financial investment, the review criteria used to evaluate research grant proposals are based on a similar set of fundamental questions. In this article, we compare the review criteria of 10 US federal agencies that support research through grant programs, and demonstrate that there are actually only a small and finite number of ways that a grant proposal can be evaluated. Though each funding agency may use slightly different wording, we found that the majority of the agencies' criteria address eight key questions. Within the highly competitive landscape of research grant funding, new researchers must find support for their research agendas and established investigators and research development offices must consider ways to diversify their funding portfolios, yet all may be discouraged by the apparent myriad of differences in review criteria used by various funding agencies. Guided by research administrators and research development professionals, recognizing that grant proposal review criteria are similar across funding agencies may help lower the barrier to applying for federal funding for new and early career researchers, or facilitate funding portfolio diversification for experienced researchers. Grantmakers are furthermore provided valuable guidance to develop and refine their own proposal review criteria.


Inhibition of NF-kappa B activation through targeting I kappa B kinase by celastrol, a quinone methide triterpenoid.
Celastrol, a quinone methide triterpenoid, was isolated as an inhibitor of NF-kappaB from Celastrus orbiculatus. This compound dose-dependently inhibited a variety of stimuli-induced NF-kappa B-regulated gene expression and the DNA-binding of NF-kappa B in different cell lines without affecting DNA-binding activity of AP-1. Preincubation of celastrol completely blocked the LPS-, TNF-alpha-, or PMA-induced degradation and phosphorylation of I kappa B alpha. Importantly, celastrol inhibited IKK activity and the constitutively active IKK beta activity in a dose-dependent manner without either affecting the NF-kappa B activation induced by RelA over-expression or directly suppressing the DNA-binding of activated NF-kappa B. However, mutation of cysteine 179 in the activation loop of IKK beta abolished sensitivity towards to celastrol, suggesting that celastrol suppressed the NF-kappa B activation by targeting cysteine 179 in the IKK. To verify that celastrol is a NF-kappa B inhibitor, we investigated its effect on some NF-kappa B target genes expressions. Celastrol prevented not only LPS-induced mRNA expression of iNOS and TNF-alpha, but also TNF-alpha-induced Bfl-1/A1 expression, a prosurvival Bcl-2 homologue. Consistent with these results, celastrol significantly suppressed the production of NO and TNF-alpha in LPS-stimulated RAW264.7 cells, and increased the cytotoxicity of TNF-alpha in HT-1080 cells. We also demonstrated that celastrol showed anti-inflammatory and anti-tumor activities in animal models. Taken together, this study extends our understanding on the molecular mechanisms underlying the anti-inflammatory and anti-cancer activities of celastrol and celastrol-containing medicinal plant, which would be a valuable candidate for the intervention of NF-kappa B-dependent pathological conditions.


Development and evaluation of drop-in centers operated by mental health consumers.
As part of a statewide initiative begun in 1989 to promote consumer involvement, the Pennsylvania Office of Mental Health initially funded the development of nine consumer-operated drop-in centers. This paper describes some of the programs and services developed by the centers and presents results of a survey of consumers' use of and satisfaction with services. During the six-month survey period, a total of 478 consumers used services; average daily attendance at each center was 28. Most centers had one paid position supplemented by heavy use of volunteers. Most projects had collaborative relationships with a few providers who maintained a low profile in daily operations. Although consumers were highly satisfied with the drop-in centers, they desired improvements in the number of paid staff, hours of operation, management, and transportation.


Draft Whole-Genome Sequences of 16 Campylobacter jejuni Isolates Obtained from Wild Birds.
The draft genome sequences of 16 Campylobacter jejuni isolates obtained from wild birds are presented in this study. These genomes provide insights into the genetic features of C. jejuni isolates from wild birds, which are considered common hosts of this microorganism but have scarcely been investigated to date.


Iatrogenic tracheobronchial rupture.
Iatrogenic tracheobronchial ruptures most frequently occur during tracheal intubation, but they can also be produced during tracheobronchial endoscopy or thoracic surgery. The clinical presentation can be brutal, with respiratory failure, cervical emphysema, pneumothorax and hemoptysis. There are also less symptomatic presentations. The diagnosis is confirmed by bronchoscopy. The therapeutic approach can be differentiated, surgical or conservative, although the criteria are not universally accepted. This article aims to review the indications and therapeutic options.


Transport studies of doxorubicin in model membranes indicate a difference in passive diffusion across and binding at the outer and inner leaflets of the plasma membrane.
The kinetics of passive transport of the anticancer drug doxorubicin were analyzed in relation to membrane composition in large unilamellar vesicles in which DNA was enclosed. Special attention was paid to lipids that are typical for the inner and outer leaflet of the plasma membrane of mammalian cells: Phosphatidylethanolamine and anionic phosphatidylserine versus phosphatidylcholine, sphingomyelin, and cholesterol, respectively. The presence of anionic phospholipids results in a highly efficient incorporation of the drug into biological and model membranes [de Wolf, F. A., et al. (1993) Biochemistry 32, 6688-6695]. Therefore, the effect of drug binding on the amount of free, transportable drug was explicitly taken into account. However, even after correction for binding the permeability coefficient was about 35% lower in membranes containing 50 mol % of the anionic phosphatidylserine than in membranes consisting only of zwitterionic phospholipids (0.71-0.79 versus 1.18-1.25 microns s-1). This shows that drug binding and insertion also affect the intrinsic transport characteristics of the membranes. As compared to pure phosphatidylcholine, binding was not influenced by the incorporation of sphingomyelin or cholesterol, but equimolar amounts of sphingomyelin and cholesterol in phosphatidylcholine membranes decreased the rate of doxorubicin transport by 60% and 80%, respectively. The inhibitory effect of these two lipids is probably due to a closer packing of the membranes. In accordance, after the acyl chain order was decreased by adding the anaesthetic-like phenethyl alcohol (0.5% v/v), transport was stimulated more than 4-fold. The implications of our findings for the functioning and rate of drug pumping by the multidrug resistance-conferring P-glycoprotein in cancer cells are discussed.


The Saccharomyces cerevisiae COQ10 gene encodes a START domain protein required for function of coenzyme Q in respiration.
Deletion of the Saccharomyces cerevisiae gene YOL008W, here referred to as COQ10, elicits a respiratory defect as a result of the inability of the mutant to oxidize NADH and succinate. Both activities are restored by exogenous coenzyme Q2. Respiration is also partially rescued by COQ2, COQ7, or COQ8/ABC1, when these genes are present in high copy. Unlike other coq mutants, all of which lack Q6, the coq10 mutant has near normal amounts of Q6 in mitochondria. Coq10p is widely distributed in bacteria and eukaryotes and is homologous to proteins of the "aromatic-rich protein family" Pfam03654 and to members of the START domain superfamily that have a hydrophobic tunnel implicated in binding lipophilic molecules such as cholesterol and polyketides. Analysis of coenzyme Q in polyhistidine-tagged Coq10p purified from mitochondria indicates the presence 0.032-0.034 mol of Q6/mol of protein. We propose that Coq10p is a Q6-binding protein and that in the coq10 mutant Q6 it is not able to act as an electron carrier, possibly because of improper localization.


Dose-dependent kinetics of probenecid in rhesus monkeys--infusion studies.
14 infusion studies to steady state with probenecid were carried out in 2 monkeys. Plasma clearance decreased with increasing rate of infusion. The urinary excretion data showed a decrease in the fraction of the dose excreted as probenecid conjugate, an increase in the total N-depropyl metabolites, and no change in the 2-hydroxy metabolites with increasing probenecid dose. Pooled Michaelis-Menten constants for probenecid metabolism were estimated from a plot of the linearized Michaelis-Menten equation using infusion rates of probenecid versus the plasma clearances of the drug.


Enhancement of hemostatic property of plant derived oxidized nanocellulose-silk fibroin based scaffolds by thrombin loading.
To combat post-surgical and traumatic bleeding conditions effective hemostasis is of great importance. The study was designed to investigate the effect of thrombin (Th) loading on hemostatic performance of TEMPO-oxidized cellulose nanofiber (TOCN)-silk fibroin (SF) scaffolds. Addition of SF with TOCN significantly (***P < 0.001) increased blood absorption capacity and improved biocompatibility of TOCN. Thrombin loading potentiated platelet activation and hemostatic property of scaffolds (TOCN-SF-Th) compared to samples without thrombin (TOCN-SF). The hemostatic time of TOCN-SF5-Th in rabbit ear artery bleeding model was reduced (*** P < 0.001) to 114 s from 220 s of TOCN-SF5. Reduction in bleeding time and blood loss of TOCN-SF5-Th in rat tail amputation and liver avulsion model was comparable to commercial hemostat (Floseal). Surface morphology (SEM) of samples applied on bleeding site showed that RBCs and fibrin fiber could strongly interact with TOCN-SF and TOCN-SF-Th scaffolds. The result suggests that TOCN-SF-Th can be a promising candidate for designing hemostatic agents.


Laparoscopic port-site metastases: etiology and prevention.
The purpose of this article is to summarize current hypotheses for the possible sources of laparoscopic port-site metastasis, to review the results of experimental models that support such hypotheses, and to discuss the potential options for preventing these metastases. We performed a Medline search to identify in vitro and in vivo studies and clinical trials that analyzed port-site metastases associated with laparoscopic surgery. We report the incidence of port-site metastases and causative factors associated with this condition. The estimated incidence of port-site metastases in all patients undergoing laparoscopic surgery for malignant disease is approximately 1-2%. Multiple factors are associated with this complication. Among the most common proposed etiologies are the wound implantations caused by the surgical technique and instrumentation; the leakage of insufflation gas through the ports, known as the "chimney effect"; and the impact of pneumoperitoneum on local immune reactions. Several preventive measures, have been suggested, including careful patient selection, lavage of the peritoneal cavity as well as of the port wounds with cytotoxic agents, and modifications of surgical technique. Only through the results of well-conducted large multi-institutional prospective randomized trials will we learn not only the true incidence of port-site metastases, but also the potential factors that lead to the occurrence of this complication.


Evidence of a genetic contribution to lung function decline in asthma.
There has been great progress in identifying new asthma susceptibility genes. In asthmatic subjects there is variable airway remodeling that includes features such as smooth muscle hypertrophy/hyperplasia, basement membrane thickening, and increased extracellular matrix deposition. Does airway remodeling have a genetic contribution in asthma? Data from different murine strains suggest there is a genetic contribution to the development and progression of airway remodeling. In human subjects it is important to consider what surrogate markers of remodeling have been used in genetic studies. Baseline FEV(1) and airway hyperresponsiveness are determined by a complex interplay of factors, including nonremodeling mechanisms; however, we consider a decline in FEV(1) as a robust marker of remodeling. To date, single nucleotide polymorphisms spanning ADAM33, ESR1, PLAUR, and VEGF have been associated with an excess decline in lung function in asthmatic subjects carrying the rare alleles (FEV(1), -13.0 to 55.2 mL/y excess). Interestingly these genes have overlapping functions in proteolytic pathways in the airways. There is accumulating evidence that genetic factors are important in the development of airway remodeling in asthmatic subjects, and further longitudinal studies with additional remodeling phenotypes and genome-wide association studies will identify novel susceptibility genes, leading to new approaches to target remodeling in asthmatic subjects.


Activation of blood clotting factors by microbial proteinases.
There are very few reports on the involvement of bacterial proteinases on the blood clotting system using both human plasma and purified clotting factors. We studied whether microbial proteinases from the opportunistic pathogens Candida albicans, Pseudomonas aeruginosa and Serratia marcescens activate the blood clotting cascade by using normal human plasma, human plasmas deficient in clotting factor XII or X, and also by using purified clotting factors XII, X and prothrombin. All proteinases tested activated either clotting factor XII or prothrombin in vitro, thus resulting in generation of thrombin. Clotting factor X was converted to the active form (Xa) by both Candida and Pseudomonas proteinases, but not by Serratia proteinase. These results suggest that peripheral and systemic blood circulation may be impaired by activation of the blood clotting cascade by microbial infections, especially in septic patients, which would enhance disseminated intravascular coagulation and multi-organ failure.


Muscarinic cholinergic receptor binding in rat brain at 15 days following traumatic brain injury.
Laboratory studies indicate that activation of muscarinic cholinergic receptors (mAChRs) at or soon after traumatic brain injury (TBI) significantly contributes to behavioral morbidity. Recent research has demonstrated that pre-injury treatment with the muscarinic antagonist scopolamine significantly reduces spatial memory deficits at 11-15 days post-TBI. In the present study, we examined mAChR binding kinetics in brain regions at 15 days after moderate (1.95 atm) fluid percussion TBI in untreated and scopolamine-treated rats. Three groups were examined: untreated TBI (n = 8), TBI with pre-injury scopolamine treatment (1.0 mg/kg, i.p., 15 min prior to injury) (n = 11), and sham-injury (n = 7). The affinity (Kd) and maximum number of binding sites (Bmax) of mAChRs in hippocampus, neocortex, and brainstem were determined by [3H]QNB binding. Bmax values in TBI animals were significantly higher in hippocampus (4061 +/- 494 fmol/mg protein) and neocortex (4272 +/- 640 fmol/mg protein), but not in brainstem (833 +/- 39 fmol/mg protein) compared to sham-injured controls (hipp. 2812 +/- 218 fmol/mg/protein; neoctx. 2850 +/- 129 fmol/mg protein; brainstem 794 +/- 26 fmol/mg protein) (P < 0.05). At 15 days after injury, Bmax values of mAChRs in TBI animals with pre-injury scopolamine treatment (hipp. 2850 +/- 129 fmol/mg protein; neoctx. 2948 +/- 123 fmol/mg protein) did not differ from control. In all brain regions, Kd values did not differ between groups. These results demonstrate that TBI significantly alters the binding sites of mAChRs in hippocampus and neocortex for as long as 15 days after TBI. Furthermore, these results indicate that a pharmacological treatment that improves motor and memory function outcome also normalizes aspects of mAChRs physiology. These data suggest that excessive activation of mAChRs at or soon after TBI impact contributes to long-term pathophysiological processes in TBI.


Competency assessment and development among health-care leaders: results of a cross-sectional survey.
In light of the challenges involved in leading a health care organization, it is important that the executives and managers charged with doing so are competent in a variety of areas. However, leading at all organizational levels does not necessarily require the same levels and types of competencies. The purpose of this research is to determine how well competency training works in health care organizations, and to obtain a better understanding of the competencies needed for leaders at different points of their careers and at various organizational levels. Ten health care management competency domains thought to positively influence job performance for health care executives are presented. The study seeks to answer four hypotheses related to self-perceptions of competencies and training opportunities at various hierarchical levels. A survey method was used to sample a subset of the healthcare executive population in the USA, based on three variables of interest, competency training opportunities, self-reported level of competency and hierarchical level. A series of Kruskal-Wallis and Mann-Whitney U tests were conducted to identify perceived differences in both competency level and training opportunities among respondents of various hierarchical levels. The most significant result of our research is that competency training is effective in health care organizations. The implications and need for additional research are discussed.


MAPK signaling pathways mediate AMPA receptor trafficking in an in vitro model of classical conditioning.
The mitogen-activated protein kinase (MAPK) signal transduction pathways have been implicated in underlying mechanisms of synaptic plasticity and learning. However, the differential roles of the MAPK family members extracellular signal-regulated kinase (ERK) and p38 in learning remain to be clarified. Here, an in vitro model of classical conditioning was examined to assess the roles of ERK and p38 MAPK in this form of learning. Previous studies showed that NMDA-mediated trafficking of synaptic glutamate receptor 4 (GluR4)-containing AMPA receptors (AMPARs) underlies conditioning in this preparation and that this is accomplished through GluR4 interactions with the immediate-early gene protein Arc and the actin cytoskeleton. Here, it is shown that attenuation of conditioned responses (CRs) by ERK and p38 MAPK antagonists is associated with significantly reduced synaptic localization of GluR4 subunits. Western blotting reveals that p38 MAPK significantly increases its activation levels during late stages of conditioning during CR expression. In contrast, ERK MAPK activation is enhanced in early conditioning during CR acquisition. The results suggest that MAPKs have a central role in the synaptic delivery of GluR4-containing AMPARs during in vitro classical conditioning.


Effects of dietary protein concentration and ractopamine hydrochloride on performance and carcass characteristics of finishing beef steers.
Ractopamine hydrochloride (RAC) is used in the feedlot industry to increase daily gain, improve feed efficiency, and increase HCW. However, little work has been done to determine whether additional protein is needed in the diet to maximize the benefit of RAC in beef cattle. Objectives of our experiment were to determine if feeding additional CP in conjunction with RAC would improve animal performance and carcass characteristics. Therefore, an experiment was conducted using finishing diets containing 13.5 or 17.5% CP with 0 or 300 mg of RAC for 30 to 33 d at the end of the finishing period. Beef steers ( = 438; 387.8 ± 1.9 kg initial BW) were randomly assigned to 1 of 4 treatments in a 2 × 2 factorial arrangement (16 pens total, 4 pens/treatment). No interactions between feeding RAC and CP level were detected ( > 0.19) for animal performance or carcass traits. Final BW did not differ among treatment ( = 0.37); however, final BW had a tendency to be 2% greater ( = 0.07) when the 13.5% CP diet was fed. Dry matter intake was not different between steers fed 0 or 300 mg/d of RAC ( = 0.20), yet DMI was 12% greater for cattle fed the 13.5% CP compared with steers fed the 17.5% CP diet ( < 0.01). Daily gain did not differ for cattle fed different levels of RAC or CP ( > 0.16). The G:F was 3.6% greater for cattle fed 300 vs. 0 mg/d of RAC ( = 0.04). The G:F was 8.7% greater for cattle fed the 17.5% diet vs. the 13.5% CP diet ( < 0.01), which can be attributed to the decreased DMI for cattle fed the 17.5% CP diet. Hot carcass weight was not different for steers fed 0 or 300 mg/d of RAC ( = 0.36) or for steers fed the 13.5% diet vs. 17.5% CP diet ( = 0.93). Dressing percentage was 1.5% greater for cattle fed 300 vs. 0 mg/d of RAC ( = 0.05) but was not different between cattle fed the different CP levels in the diet ( = 0.16). Longissimus area, adjusted 12th-rib fat, and marbling score did not differ across RAC or CP treatments ( > 0.26). Additionally, no differences in USDA yield grade or percentage of cattle grading USDA Choice were detected for RAC or CP treatments ( > 0.26), which also supports the idea that quality grade of cattle fed RAC at the same level of fatness is not impacted. Our data indicate excess protein did not enhance the response to RAC, and furthermore, the improved performance from RAC reported by others was not observed other than a small increase in G:F.


Relation between CarS expression and activation of carotenogenesis by stress in Fusarium fujikuroi.
Fusarium fujikuroi, a model organism for secondary metabolism in fungi, produces carotenoids, terpenoid pigments with antioxidant activity. Previous results indicate that carotenoid synthesis in F. fujikuroi is stimulated by light or by different stress conditions and downregulated by a RING finger protein encoded by carS gene. Here, we have analyzed the effects of three stressors, nitrogen scarcity, heat shock, and oxidative stress. We compared them with the effect of light in the wild type, a carS mutant that overproduces carotenoids, and its complemented strain. The assayed stressors increase the synthesis of carotenoids in the three strains, but mRNA levels of structural genes of carotenogenesis, carRA and carB, are only enhanced in the presence of a functional carS gene. In the wild-type strain, the four conditions affect in different manners the mRNA levels of carS: greater in the presence of light, without significant changes in nitrogen starvation, and with patent decreases after heat shock or oxidative stress, suggesting different activation mechanisms. The spores of the carS mutant are more resistant to H2O2 than those of the wild type; however, the mutant shows a greater H2O2 sensitivity at the growth level, which may be due to the participation of CarS in the regulation of genes with catalase domains, formerly described. A possible mechanism of regulation by heat stress has been found in the alternative splicing of the intron of the carS gene, located close to its 3' end, giving rise to the formation of a shorter protein. This action could explain the inducing effect of the heat shock, but not of the other inducing conditions, which may involve other mechanisms of action on the CarS regulator, either transcriptionally or post-transcriptionally.


Nonalcoholic fatty liver disease in patients with inflammatory bowel disease: Beyond the natural history.
Nonalcoholic fatty liver disease (NAFLD) is a frequently reported condition in patients with inflammatory bowel disease (IBD). Both intestinal inflammation and metabolic factors are believed to contribute to the pathogenesis of IBD-associated NAFLD. To evaluate the prevalence of steatosis and liver fibrosis (LF) in a cohort of IBD patients and the identification of metabolic- and IBD-related risk factors for NAFLD and LF. IBD patients were consecutively enrolled from December 2016 to January 2018. Demographic, anthropometric and biochemical data were collected so as eating habits. Abdominal ultrasound and transient elastography were performed to evaluate the presence of NAFLD and LF respectively. A total of 178 consecutive patients were enrolled and included in the analysis (95 Ulcerative colitis, 83 Crohn's disease). NAFLD was detected by imaging in 72 (40.4%) patients. Comparison between patients with and without NAFLD showed no significant differences in terms of IBD severity, disease duration, location/extension, use of IBD-related medications (i.e., steroids, anti-TNFs, and immunomodulators) and surgery. NAFLD was significantly associated with the presence of metabolic syndrome [MetS; odds ratio (OR): 4.13, P = 0.001] and obesity defined by body mass index (OR: 9.21, P = 0.0002). IBD patients with NAFLD showed higher caloric intake and lipid consumption than those without NAFLD, regardless disease activity. At the multivariate analysis, male sex, advanced age and high lipid consumption were independent risk factors for the development of NAFLD. An increased liver stiffness was detected in 21 patients (16%) and the presence of MetS was the only relevant factor associated to LF (OR: 3.40, P = 0.01). In this study, we demonstrate that risk factors for NAFLD and LF in the IBD population do not differ from those in the general population.


Roller massage: is the numeric pain rating scale a reliable measurement and can it direct individuals with no experience to a specific roller density?
This investigation measured the reliability of the numeric pain rating scale (NPRS) for roller massage (RM) over two sessions and compared it to pressure pain threshold (PPT) during a third session. Twenty-five subjects participated. Session one, subjects rolled on 3 different rollers and filled out the NPRS for each roller then chose their preferred roller. Session two, subjects repeated the testing blind-folded to eliminate visual biases. Session three, subjects repeated testing but were measured with PPT. For the NPRS, there was poor to moderate reliability for the soft roller (ICC=0.60) and good reliability for the moderate (ICC=0.82) and hard density (ICC= 0.90) rollers. For preferred roller, there was no significant difference between sessions (t (24) =.00, p=1.00). For NPRS and PPT, there was a fair relationship for all rollers (Rho=0.34-0.49, p = 0.11-0.28). The NPRS appears to be a reliable measure and may help direct individuals to a specific roller. The NPRS and PPT should be used independently.


Lead-contaminated drinking water in bulk-water storage tanks--Arizona and California, 1993.
Lead poisoning is a major environmental health problem for children in the United States (1,2): during 1988-1991, approximately 1.7 million U.S. children aged 1-5 years had elevated blood lead levels (BLLs) (> or = 10 micrograms/dL) (3). To determine the source of lead exposure for children with BLLs > or = 20 micrograms/dL, the Arizona Department of Health Services (ADHS) conducts environmental investigations. In 1993, as a result of investigations of increased BLLs in two children in southwestern Arizona, ADHS detected lead levels approximately 30 times the Environmental Protection Agency (EPA) action level of 15 parts per billion (ppb) in bulk-delivered drinking water in the homes of these children. Because two of the three companies that supplied bulk water to southwestern Arizona were based in California, ADHS notified the California State Department of Health Services (CSDHS) about the problem. As a result, CSDHS conducted a separate investigation and identified one child with an elevated BLL whose drinking water sources included bulk-delivered water with lead levels exceeding EPA standards. This report summarizes the investigations of elevated BLLs in these three children and high lead levels in bulk-delivered drinking water in Arizona and California.


[Study on the genetic damage in mice induced by the volatile organic compounds of decoration materials].
To study genetic damage of mice caused by the volatile organic compounds (VOC) of decoration materials. Fifty-five hotel guest rooms newly decorated within 6 months and 18 hotel guest rooms not decorated within 3 years were selected to determine the concentrations of 6 main VOC (benzene, methylbenzene, dimethylbenzene, ethyl acetate, butyl acetate, formaldehyde) in the air. Mice were exposed to VOC with the concentrations of 5, 10, 20, 40 times respectively as high as those present in the newly decorated rooms in an exposure cabinet for 15 days. DNA damage of peripheral lymphocytes of the mice was determined by single cell gel electrophoresis (SCGE) and bone marrow micronucleus test. The concentrations of benzene, methylbenzene, dimethylbenzene, ethyl acetate, butyl acetate and formaldehyde in the rooms newly decorated within 6 months (6.50, 3.00, 6.70, 41.33, 1.70 and 0.14 mg/m(3) respectively) were significantly higher than those in rooms not decorated within 3 years (0.08, 0.94, 1.38, 0.25, 0.25, 0.01 mg/m(3), P < 0.01). DNA damage rates of peripheral lymphocytes in the concentrations of 10, 20, 40 times of exposure groups were significantly higher than those in the control groups (P < 0.05 or P < 0.01), and the frequencies of micronucleus in the mice exposed to 40 times of concentration was significantly higher than that in control group. High concentrations of the volatile organic chemical compounds may cause genetic damage in mice. SCGE test is more sensitive than micronucleus test.


Evaluation of circulating tumor DNA as a biomarker in pancreatic cancer with liver metastasis.
Pancreatic cancer is an aggressive, solid tumor, with a grave prognosis. Despite surgical treatment in patients with pancreatic cancer, the rate of recurrence is high. In addition, although tumor biomarkers are frequently used to confirm advanced pancreatic cancer, this is not accurate and the biomarkers currently used cannot indicate prognosis. This study sought to evaluate circulating tumor DNA as a tumor biomarker to prognosticate pancreatic cancer. Patients with advanced pancreatic cancer and liver metastasis (N = 104) were included, and blood samples were collected from all patients. The mutant allele frequency was measured using amplicon-based deep sequencing on a cell-free DNA panel covering 14 genes with > 240 hot spots. In patients with advanced pancreatic cancer, 50% (N = 52) had detectable ctDNA levels, with TP53 (45%, N = 47) and KRAS (42.3%, N = 44) mutations the most common. Patients with detectable circulating tumor DNA levels also had significantly worse overall survival and progression free survival than ctDNA negative patients (8.4 vs 16 months, P<0.0001 for overall survival; 3.2 vs 7.9 months, P<0.0001 for progression-free survival). In a multivariate analysis, ctDNA status was independently associated with overall survival and progression-free survival (HR = 3.1, 95%CI = 1.9-5.0, P<0.0001; HR 2.6, 95%CI = 1.7-4.0, P<0.0001, respectively). Moreover, circulating tumor DNA significantly correlated with a higher number of liver metastases, the presence of lung and/or peritoneal metastases, tumor burden, and higher carbohydrate antigen 19-9 levels. This study supports the use of circulating tumor DNA as an independent prognostic marker for advanced pancreatic cancer.


Delineation of diverse macrophage activation programs in response to intracellular parasites and cytokines.
The ability to reside and proliferate in macrophages is characteristic of several infectious agents that are of major importance to public health, including the intracellular parasites Trypanosoma cruzi (the etiological agent of Chagas disease) and Leishmania species (etiological agents of Kala-Azar and cutaneous leishmaniasis). Although recent studies have elucidated some of the ways macrophages respond to these pathogens, the relationships between activation programs elicited by these pathogens and the macrophage activation programs elicited by bacterial pathogens and cytokines have not been delineated. To provide a global perspective on the relationships between macrophage activation programs and to understand how certain pathogens circumvent them, we used transcriptional profiling by genome-wide microarray analysis to compare the responses of mouse macrophages following exposure to the intracellular parasites T. cruzi and Leishmania mexicana, the bacterial product lipopolysaccharide (LPS), and the cytokines IFNG, TNF, IFNB, IL-4, IL-10, and IL-17. We found that LPS induced a classical activation state that resembled macrophage stimulation by the Th1 cytokines IFNG and TNF. However, infection by the protozoan pathogen L. mexicana produced so few transcriptional changes that the infected macrophages were almost indistinguishable from uninfected cells. T. cruzi activated macrophages produced a transcriptional signature characterized by the induction of interferon-stimulated genes by 24 h post-infection. Despite this delayed IFN response by T. cruzi, the transcriptional response of macrophages infected by the kinetoplastid pathogens more closely resembled the transcriptional response of macrophages stimulated by the cytokines IL-4, IL-10, and IL-17 than macrophages stimulated by Th1 cytokines. This study provides global gene expression data for a diverse set of biologically significant pathogens and cytokines and identifies the relationships between macrophage activation states induced by these stimuli. By comparing macrophage activation programs to pathogens and cytokines under identical experimental conditions, we provide new insights into how macrophage responses to kinetoplastids correlate with the overall range of macrophage activation states.


Temperature Dependence of Static Structure Factor Peak Intensities for a Pyrrolidinium-Based Ionic Liquid.
Static structure factors ( S( q)) for many ionic liquids show low-wavenumber peaks whose intensities increase with increasing temperature. The greater peak intensities might seem to imply increasing intermediate-range order with increasing temperature. Molecular dynamics (MD) simulations for a representative ionic liquid, 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide (C4C1pyrrTFSI), were used to calculate S( q) and partial S( q) (cation-cation, anion-anion, and cation-anion) at 298, 363, and 500 K. S( q) and partial S( q) were further decomposed into positive and negative components (which each indicate structural ordering) by separately summing positive and negative Fourier transform summands. Increasing temperature causes the negative components of each partial S( q) to decrease in magnitude more than the positive components, causing the total S( q) to increase in magnitude. Thus, structural ordering with periodicities corresponding to observed peaks in S( q) does not increase but instead decoheres with increasing temperature, even though S( q) peak heights increase. Fourier transform summands also show where in real space the positive and negative component contributions to S( q) change when the temperature increases. This new, detailed analysis based on Fourier transform summands comprising S( q) argues for great caution when interpreting S( q) intensities and highlights the value of simulations as a complement to X-ray (or neutron) scattering experiments.