Acute impact of erythromycin and tetracycline on the kinetics of nitrification and organic carbon removal in mixed microbial culture.
The study evaluated acute impact of erythromycin and tetracycline on nitrification and organic carbon removal kinetics in mixed microbial culture. Acclimated biomass was obtained from a fill and draw reactor fed with peptone mixture selected as synthetic substrate and operated at a sludge age of 10 days. Acute inhibition was tested in batch reactors involving a control unit started solely with substrate and the others with additional doses of each antibiotic. Modeling indicated that both steps of nitrification were totally blocked by erythromycin. Tetracycline inhibited and retarded nitrification kinetics at 50 mg/L and stopped nitrite oxidation at 200 mg/L, leading to nitrite accumulation. Both antibiotics also affected organic carbon removal by inducing partial inactivation of the heterotrophic community in the culture, increased substrate storage and accelerated endogenous respiration, with a relatively slight impact on heterotrophic growth. Major inhibitory effect was on process stoichiometry, leading to partial utilization of organic substrate.


Acetone-based cellulose solvent.
Acetone containing tetraalkylammonium chloride is found to be an efficient solvent for cellulose. The addition of an amount of 10 mol% (based on acetone) of well-soluble salt triethyloctylammonium chloride (Et3 OctN Cl) adjusts the solvent's properties (increases the polarity) to promote cellulose dissolution. Cellulose solutions in acetone/Et3 OctN Cl have the lowest viscosity reported for comparable aprotic solutions making it a promising system for shaping processes and homogeneous chemical modification of the biopolymer. Recovery of the polymer and recycling of the solvent components can be easily achieved.


Relationship between yeast polyribosomes and Upf proteins required for nonsense mRNA decay.
In yeast, the accelerated rate of decay of nonsense mutant mRNAs, called nonsense-mediated mRNA decay, requires three proteins, Upf1p, Upf2p, and Upf3p. Single, double, and triple disruptions of the UPF genes had nearly identical effects on nonsense mRNA accumulation, suggesting that the encoded proteins function in a common pathway. We examined the distribution of epitope-tagged versions of Upf proteins by sucrose density gradient fractionation of soluble lysates and found that all three proteins co-distributed with 80 S ribosomal particles and polyribosomes. Treatment of lysates with RNase A caused a coincident collapse of polyribosomes and each Upf protein into fractions containing 80 S ribosomal particles, as expected for proteins that are associated with polyribosomes. Mutations in the cysteine-rich (zinc finger) and RNA helicase domains of Upf1p caused loss of function, but the mutant proteins remained polyribosome-associated. Density gradient profiles for Upf1p were unchanged in the absence of Upf3p, and although similar, were modestly shifted to fractions lighter than those containing polyribosomes in the absence of Upf2p. Upf2p shifted toward heavier polyribosome fractions in the absence of Upf1p and into fractions containing 80 S particles and lighter fractions in the absence of Upf3p. Our results suggest that the association of Upf2p with polyribosomes typically found in a wild-type strain depends on the presence and opposing effects of Upf1p and Upf3p.


Preparation of developing Xenopus muscle for sarcomeric protein localization by high-resolution imaging.
Mutations in several sarcomeric proteins have been linked to various human myopathies. Therefore, having an in vivo developmental model available that develops quickly and efficiently is key for investigators to elucidate the critical steps, components and signaling pathways involved in building a myofibril; this is the pivotal foundation for deciphering disease mechanisms as well as the development of myopathy-related therapeutics. Although striated muscle cell culture studies have been extremely informative in providing clues to both the distribution and functions of sarcomeric proteins, myocytes in vivo develop in an irreproducible 3D environment. Xenopus laevis (frog) embryos are cost effective, compliant to protein level manipulations and develop relatively quickly (⩽ a week) in a petri dish, thus providing a powerful system for de novo myofibrillogenesis studies. Although fluorophore-conjugated phalloidin labeling is the gold standard approach for investigating actin-thin filament architecture, it is well documented that phalloidin-labeling can be challenging and inconsistent within Xenopus embryos. Therefore we highlight several techniques that can be utilized to preserve both antibody and fluorophore-conjugated phalloidin labeling within Xenopus embryos for high-resolution fluorescence microscopy.


Tunable ferroelectric capacitor-based voltage-controlled oscillator.
Ferroelectric capacitors made from Ba(1-0.5)Sr0.5TiO3 (BST) are applied as varactors in tunable, high-frequency circuit applications. In this context, a voltage-controlled oscillator (VCO) has been designed and implemented using discrete RF bipolar junction transistor (BJTs) and tunable ferroelectric capacitor. The designed VCO has a tuning range from 205 MHz to 216.3 MHz with a power dissipation of 5.1 mW. The measured phase noise is -90 dBc/Hz at 100 kHz and -140 dBc/Hz at 1 MHz offset.


[Psoas muscle abscess. Description of a series of 19 cases].
Abscess of the psoas muscle (PA) is every more frequently observed in recent years. The PA diagnosed in the authors' center over a period of 91 months are presented, analyzing the main clinical features, microbiologic causal agents, risk factors, treatment and the differences between primary and secondary PA. A total of 19 cases of which 14 were secondary PA (73.7%) and 5 primary PA (26.3%) were diagnosed. The main foci of infection of the former were the bone and the genitourinary tract, with intestinal infection being rare. The most frequent clinical data were lumbar pain with possible irradiation to the lower limb, fever, and leucocytosis with neutrophilia. Gram negative and enteric anaerobes were the bacteria most often identified, followed by Staphylococcus aureus and Mycobacterium tuberculosis. In a high percentage of patients (57.8%) a history of immunodeficiency was reported. In regard to treatment, surgical drainage was performed in 5 cases (26.3%), while ten cases (52.6%) were treated by DPCT. Four patients (21%) were exclusively treated with antibiotics. Recurrence was observed in three cases (15.3%) of the DPCT group requiring new drainage. Of all the cases, 18 were cured while one death occurred, being attributed to the underlying tumoral disease of advanced stage. The authors believe DPCT to be a good therapeutic option in both primary and secondary PA, thereby avoiding the risks of major surgery. In the cases with no underlying immunodeficiency the existence of secondary PA should be discarded as occurred in 7 out of 8 cases with no history of immunodeficiency in this series of patients.


Developing family rooms in mental health inpatient units: an exploratory descriptive study.
Family-friendly spaces for children and families to visit inpatient mental health units are recommended in international mental health guidelines as one way to provide service delivery that is responsive to the needs of parent-consumers and families. There is a lack of evidence on the implementation of family-friendly spaces or Family Rooms. This study aimed to explore the development, role, and function of Family Rooms in four mental health inpatient units in a local health district in NSW Australia. An exploratory descriptive inductive-deductive design using multiple data sources was employed. Methods included Family Room usage and parental status data over a 12 week period, an open-ended questionnaire, and semi-structured interviews with 20 nurses. Available parental status data indicated that between 8-14 % of inpatients were parents of dependent children under 18. Family Room usage was multipurpose and used specifically for children & families 29 % of the time. As spaces in the units, Family Rooms were perceived as acknowledging of the importance of family, and providing comfortable, secure spaces for parent-consumers and their children and family to maintain connections. Units did not have local policies or guidelines on the development, maintenance, and/or use of the rooms. Despite long-standing recognition of the need to identify consumers' parental status, there remains a lack of systematic processes for identifying parents in mental health inpatient services nationally. Family Rooms as spaces within inpatient units acknowledge the importance of families and are a step towards provision of family-focused mental health care. Recommendations for establishing and maintaining Family Rooms are outlined.


Opinions differ by expertise in Mycobacterium avium complex disease.
Pulmonary Mycobacterium avium complex treatment guidelines rely largely on expert opinion. The extent to which nonexperts agree with recommendations of experts in this clinical area is unknown. We sought to compare practices and perceptions of prognosis between experts and nonexperts. We surveyed respirologists (Ontario, Canada, "nonexperts") and experts from nontuberculous mycobacterial disease centers of excellence (Canada and United States). Forty-six Ontario respirologists (29% of 160) and 19 experts (73% of 26) participated. There was agreement between nonexperts and experts regarding disease duration before diagnosis (2 yr), likelihood of spontaneous remission (7-15%), typical duration of treatment (18 mo), first choice of therapy (guideline regimens), a subgroup of patients for whom less-intensive regimens are favored (10% after recurrence), likelihood of recurrence (30%), and median survival (10 yr in most patients). Noted differences were that nonexperts estimated fewer patients with a positive culture had disease (30% vs. 50%, P = 0.02), used intensive guidelines therapy less often in new cases (50% vs. 79%, P = 0.02), and perceived a slightly lower success rate with guidelines therapy (65% vs. 75%, P = 0.047). Response ranges were wider for nonexperts, significantly so for selection of intensive guidelines therapy in new (P = 0.01) and recurrent (P = 0.04) cases. Experts and nonexperts agreed on many issues. However, nonexperts perceived lower rates of disease among patients with isolates, tended to use less aggressive treatment approaches, and perceived lower success rates. Significant variability was observed in responses-often wider among nonexperts. Although these results are likely biased by referral, they may identify important areas for targeted education.


Long-term benzodiazepine use in patients with major depressive disorder in China.
There have been no data about long-term benzodiazepine (BZD) use and its correlates in patients with major depressive disorder (MDD) in China. This study aimed to examine the prevalence of long-term BZD use (more than three months) and its demographic and clinical correlates in Chinese patients with MDD. A total of 1,192 patients with MDD were examined in 10 mental health centers in China. Patients' socio-demographic and clinical characteristics and prescriptions for psychotropic drugs were recorded using a standardized form. A large portion of patients (36.2%) received long-term BZD treatment. Univariate analyses revealed that long-term BZD users were older, poorer, and had more impaired occupational functioning than patients not taking BZDs. Long-term BZD users had fewer psychotic symptoms and took less antipsychotic drugs. In multivariate analyses, long-term BZD use was independently associated with older age and more severe impaired occupational functioning; long-term BZD users were less likely to receive antipsychotic medications and traditional antidepressants (tricyclic antidepressants, tetracyclic antidepressant, and monoamine oxidase inhibitors). Long-term BZD use was common in patients with MDD in China. A host of demographic and clinical factors were independently associated with long-term BZD use.


Species-specific and inhibitor-dependent conformations of LpxC: implications for antibiotic design.
LpxC is an essential enzyme in the lipid A biosynthetic pathway in gram-negative bacteria. Several promising antimicrobial lead compounds targeting LpxC have been reported, though they typically display a large variation in potency against different gram-negative pathogens. We report that inhibitors with a diacetylene scaffold effectively overcome the resistance caused by sequence variation in the LpxC substrate-binding passage. Compound binding is captured in complex with representative LpxC orthologs, and structural analysis reveals large conformational differences that mostly reflect inherent molecular features of distinct LpxC orthologs, whereas ligand-induced structural adaptations occur at a smaller scale. These observations highlight the need for a molecular understanding of inherent structural features and conformational plasticity of LpxC enzymes for optimizing LpxC inhibitors as broad-spectrum antibiotics against gram-negative infections.


Gene expression in clonally derived cell lines produced by in vitro transformation of rat fetal hepatocytes: isolation of cell lines which retain liver-specific markers.
The pattern of gene expression in fetal hepatocytes transformed in culture with a hepatocarcinogen (FRL cells) is studied with respect to a range of markers which are either developmentally regulated and/or shown to be expressed at high levels in hepatoma cells. The relative abundance of the respective mRNAs is determined and immunocytochemistry is used to detect the respective proteins in cultured cells. When compared with its normal counterpart, FRL cells retain the expression of transferrin, alpha 1-acid glycoprotein, gamma-glutamyltranspeptidase, and tyrosine aminotransferase at near normal levels, while expression of the liver-specific isoenzymes of pyruvate kinase (L form) and aldolase (B form) is reduced. The cell lines are different in that they fail to express albumin, alpha-fetoprotein, thiostatin and alpha 2-macroglobulin, and they express high levels of M2-pyruvate kinase and aldolase A, markers often found in abundance in hepatoma cells. Therefore transformation has resulted in different effects on different genes. Furthermore, it is of interest to find that the cells coexpress both forms of the pyruvate kinase isoenzymes which does not occur in the normal developing hepatocyte. These results indicate that it is possible to use this model to study changes which accompany transformation of fetal rat hepatocytes. The resulting cell lines have a stable phenotype and retain the changes which result from transformation even after extended passaging. This facilitates comparisons between the precursor cell and the tumor cell, both of which can be maintained under controlled conditions which exist in culture.


Association between single limb standing test results and healthcare costs among community-dwelling older adults.
Identifying risks for older adults who will require healthcare resources is critical for the government, healthcare providers, and consumers. The objective of this study was to examine the relationship between the results of the single limb standing (SLS) test and healthcare costs among community-dwelling older adults. We used data obtained from a population-based prospective cohort study of the residents of Tadami town in Fukushima Prefecture, Japan. The participants were above 60 years of age and had undergone annual health check-ups, and data on their healthcare costs over the two-year study period were available. A censored regression model adjusted for potential confounders was used to estimate the mean difference in total healthcare costs between participants who could remain standing on a single limb for at least 30 s and those who could not. Healthcare costs of participants who passed the SLS test were significantly lower than those who did not. The mean difference between the two groups' healthcare costs was 4064 USD (95 % confidence interval: 2661-5467 USD, p < 0.05). After adjusting for potential confounders, the mean difference between the two groups was smaller (1686 USD) but remained statistically significant (95 % confidence interval: 125-3246 USD, p < 0.05). Among community-dwelling older adults, limited static balance (SLS time <30 s) was found to be associated with high healthcare costs in the two years after the SLS test. The SLS test may help identify individuals at high risk of becoming frequent users of healthcare services in the future.


Toxic shock syndrome associated with use of latex nasal packing.
We treated a previously healthy young man who developed toxic shock syndrome 2 days after elective septoplasty with nonabsorbent latex packing. This case emphasizes that non-menstrual wound-associated toxic shock syndrome can occur after surgery that does not involve absorbent splinting or packing and should be considered in patients who present within a few days after surgery with fever, sunburnlike rash, hypotension, and multisystem complaints and laboratory abnormalities.


Comparison of nanosecond and picosecond excitation for interference-free two-photon laser-induced fluorescence detection of atomic hydrogen in flames.
Two-photon laser-induced fluorescence (TP-LIF) line imaging of atomic hydrogen was investigated in a series of premixed CH4/O2/N2, H2/O2, and H2/O2/N2 flames using excitation with either picosecond or nanosecond pulsed lasers operating at 205 nm. Radial TP-LIF profiles were measured for a range of pulse fluences to determine the maximum interference-free signal levels and the corresponding picosecond and nanosecond laser fluences in each of 12 flames. For an interference-free measurement, the shape of the TP-LIF profile is independent of laser fluence. For larger fluences, distortions in the profile are attributed to photodissociation of H2O, CH3, and/or other combustion intermediates, and stimulated emission. In comparison with the nanosecond laser, excitation with the picosecond laser can effectively reduce the photolytic interference and produces approximately an order of magnitude larger interference-free signal in CH4/O2/N2 flames with equivalence ratios in the range of 0.5< or =Phi< or =1.4, and in H2/O2 flames with 0.3< or =Phi< or =1.2. Although photolytic interference limits the nanosecond laser fluence in all flames, stimulated emission, occurring between the laser-excited level, H(n=3), and H(n=2), is the limiting factor for picosecond excitation in the flames with the highest H atom concentration. Nanosecond excitation is advantageous in the richest (Phi=1.64) CH4/O2/N2 flame and in H2/O2/N2 flames. The optimal excitation pulse width for interference-free H atom detection depends on the relative concentrations of hydrogen atoms and photolytic precursors, the flame temperature, and the laser path length within the flame.


Umbrella Pine, Sciadopitys verticillata: Past and Present Distribution in Japan.
The umbrella pine, Sciadopitys verticillata S. and Z., a native Japanese conifer species and the only present member of the genus Sciadopitys, has become rapidly restricted in its geographic distribution since the beginning of intensified human activities. In Japan the genus was more widely distributed throughout the Pliocene and in the postglacial hypsithermal and slightly later times (R IIIa). In other parts of the world the genus has not appeared in the fossil record since the early Pleistocene. Conservation of this species is needed.


Household catastrophic health expenditure: a multicountry analysis.
Health policy makers have long been concerned with protecting people from the possibility that ill health will lead to catastrophic financial payments and subsequent impoverishment. Yet catastrophic expenditure is not rare. We investigated the extent of catastrophic health expenditure as a first step to developing appropriate policy responses. We used a cross-country analysis design. Data from household surveys in 59 countries were used to explore, by regression analysis, variables associated with catastrophic health expenditure. We defined expenditure as being catastrophic if a household's financial contributions to the health system exceed 40% of income remaining after subsistence needs have been met. The proportion of households facing catastrophic payments from out-of-pocket health expenses varied widely between countries. Catastrophic spending rates were highest in some countries in transition, and in certain Latin American countries. Three key preconditions for catastrophic payments were identified: the availability of health services requiring payment, low capacity to pay, and the lack of prepayment or health insurance. People, particularly in poor households, can be protected from catastrophic health expenditures by reducing a health system's reliance on out-of-pocket payments and providing more financial risk protection. Increase in the availability of health services is critical to improving health in poor countries, but this approach could raise the proportion of households facing catastrophic expenditure; risk protection policies would be especially important in this situation.


Proton Pump Inhibitors Do Not Increase Risk for Clostridium difficile Infection in the Intensive Care Unit.
Patients in the intensive care unit (ICU) frequently receive proton pump inhibitors (PPIs) and have high rates of Clostridium difficile infection (CDI). PPIs have been associated with CDI in hospitalized patients, but ICU patients differ fundamentally from non-ICU patients and few studies have focused on PPI use exclusively in the critical care setting. We performed a retrospective cohort study to determine the associations between PPIs and health-care facility-onset CDI in the ICU. We analyzed data from all adult ICU patients at three affiliated hospitals (14 ICUs) between 2010 and 2013. Patients were excluded if they had recent CDI or an ICU stay of <3 days. We parsed electronic medical records for ICU exposures, focusing on PPIs and other potentially modifiable exposures that occurred during ICU stays. Health-care facility-onset CDI in the ICU was defined as a newly positive PCR for the C. difficile toxin B gene from an unformed stool, with subsequent receipt of anti-CDI therapy. We analyzed PPIs and other exposures as time-varying covariates and used Cox proportional hazards models to adjust for demographics, comorbidities, and other clinical factors. Of 18,134 patients who met the criteria for inclusion, 271 (1.5%) developed health-care facility-onset CDI in the ICU. Receipt of antibiotics was the strongest risk factor for CDI (adjusted HR (aHR) 2.79; 95% confidence interval (CI), 1.50-5.19). There was no significant increase in risk for CDI associated with PPIs in those who did not receive antibiotics (aHR 1.56; 95% CI, 0.72-3.35), and PPIs were actually associated with a decreased risk for CDI in those who received antibiotics (aHR 0.64; 95% CI, 0.48-0.83). There was also no evidence of increased risk for CDI in those who received higher doses of PPIs. Exposure to antibiotics was the most important risk factor for health-care facility-onset CDI in the ICU. PPIs did not increase risk for CDI in the ICU regardless of use of antibiotics.


Recruitment of women research participants: the Women's Health Registry at the University of Michigan.
The goal was to develop the Women's Health Registry, a research participant database that prospectively collects detailed information on potential research subjects to assist in linking them with open research protocols and to assess investigator use and satisfaction with this Registry. The Women's Health Registry was launched in 1999. Women aged > or =18 years were recruited to enroll in a database of women with interest in research participation and to complete a health questionnaire. Women's health researchers with IRB-approved projects were encouraged to apply for access to the Registry participants. In 2003, the first 15 investigators to use the Women's Health Registry were asked to participate in a standardized open-ended interview to assess investigator satisfaction with this recruitment tool. The Women's Health Registry is currently populated with 2436 women: 36.8% aged 18-34, 39.9% aged 35-54, 16.8% aged 55-69, and 6.4% aged > or =70 years. Of these women, 84% are Caucasian and 8.5% are African American. Structured interviews with 13 of the 15 investigators contacted revealed that 36.4% of the total subject enrollment recruited by these investigators was recruited from the Women's Health Registry. In addition, Registry participants were more likely to enroll in their research protocols than women contacted through other methods. Most of the investigators' expectations from the Women's Health Registry were met, except for access to menopausal women. The Women's Health Registry was successfully developed, and the goal of linking women with appropriate protocols was met with significant investigator satisfaction.


Effectiveness of switching between TNF inhibitors in patients with axial spondyloarthritis: is the reason to switch relevant?
To investigate whether the reason to discontinue the first TNF inhibitor (TNFi) affects the response to the second TNFi in axial spondyloarthritis (axSpA). Patients with axSpA from the Rheumatic Diseases Portuguese Register (ReumaPt), who discontinued their first TNFi and started the second TNFi between June 2008 and May 2018, were included. Response was assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS) clinically important improvement (ASDAS-CII), major important improvement (ASDAS-MI), low disease activity (ASDAS-LDA), and inactive disease (ASDAS-ID). The reason for discontinuation of the first TNFi was defined, according to ASDAS-CII as primary failure (no response ≤ 6 months), secondary failure (response ≤ 6 months but lost thereafter), adverse events, and others. The association between the reason for discontinuation of the first TNFi and response to the second TNFi over time was assessed in multivariable generalized equation (GEE) models. In total, 193 patients were included. The reason for discontinuation of the first TNFi did not influence the response to the second TNFi, according to the ASDAS-CII. However, a difference was found with more stringent outcomes, e.g., there was a higher likelihood to achieve ASDAS-ID with the second TNFi for patients discontinuing the first TNFi due to secondary failure (OR 7.3 [95%CI 1.9; 27.7]), adverse events (OR 9.1 [2.5; 33.3]), or other reasons (OR 7.7 [1.6; 37.9]) compared to primary failure. Patients with axSpA with secondary failure to their first TNFi, compared to those with primary failure, have a better response to the second TNFi according to stringent outcomes.


Structural plasticity in root-fungal symbioses: diverse interactions lead to improved plant fitness.
Root-fungal symbioses such as mycorrhizas and endophytes are key components of terrestrial ecosystems. Diverse in trophy habits (obligate, facultative or hemi-biotrophs) and symbiotic relations (from mutualism to parasitism), these associations also show great variability in their root colonization and nutritional strategies. Specialized interface structures such as arbuscules and Hartig nets are formed by certain associations while others are restricted to non-specialized intercellular or intracellular hyphae in roots. In either case, there are documented examples of active nutrient exchange, reinforcing the fact that specialized structures used to define specific mycorrhizal associations are not essential for reciprocal exchange of nutrients and plant growth promotion. In feremycorrhiza (with Austroboletus occidentalis and eucalypts), the fungal partner markedly enhances plant growth and nutrient acquisition without colonizing roots, emphasizing that a conventional focus on structural form of associations may have resulted in important functional components of rhizospheres being overlooked. In support of this viewpoint, mycobiome studies using the state-of-the-art DNA sequencing technologies have unearthed much more complexity in root-fungal relationships than those discovered using the traditional morphology-based approaches. In this review, we explore the existing literature and most recent findings surrounding structure, functioning, and ecology of root-fungal symbiosis, which highlight the fact that plant fitness can be altered by taxonomically/ecologically diverse fungal symbionts regardless of root colonization and interface specialization. Furthermore, transition from saprotrophy to biotrophy seems to be a common event that occurs in diverse fungal lineages (consisting of root endophytes, soil saprotrophs, wood decayers etc.), and which may be accompanied by development of specialized interface structures and/or mycorrhiza-like effects on plant growth and nutrition.


Current concepts in osteoarthritis.
Osteoarthritis (OA), the most common form of joint disease, affects mainly the hips, knees, hands and feet, leading to severe disability and loss of quality of life, particularly in the elderly population. Its importance grows every year with the aging of the population, with a large increase in the elderly population compared to younger patients. The progressive understanding of the pathophysiology of OA, the perception that the process is not purely mechanical and / or aging, and clarification of the inflammatory pathways involved led recently to the clinical application of various drugs and other measures. This update aims to expose the current concepts on the pathophysiology and treatment of OA.


Compression-induced damage in a muscle cell model in vitro.
Soft tissue breakdown can be initiated at the muscle layer associated with bony prominences, leading to the development of pressure ulcers. Both the magnitude and duration of pressure are important factors in this breakdown process. The present study utilizes a physical model, incorporating C2C12 mouse myoblasts in a homogeneous agarose gel, to examine the damaging effects of prolonged applied pressure. Identical cylindrical cores cut from the agarose/cell suspension were subjected to two separate compressive strains, of 10 and 20 per cent. The strain was applied for time periods ranging from 0.5 to 12 hours, using a specially designed loading apparatus. After each compression period, sections taken from the central horizontal plane of the individual constructs were stained using either haematoxylin and eosin or with the fluorescent probes, Calcein AM and ethidium homodimer-1, and assessed for cell damage. It was found that constructs subjected to the higher strain values demonstrated significantly higher values of non-viable cells for equivalent time points compared to the unstrained constructs. Further analysis on sections using the DNA nick-translation method suggested that this increase was primarily due to apoptosis. These findings imply a relationship between the duration of applied compression and damage to muscle cells seeded in the gel, which was particularly apparent at the strain level of 20 per cent, equivalent to a clinically relevant pressure of 32 mmHg (4.3 kPa). Such an approach might be useful in establishing damage threshold levels at a cellular level.


Single session of high-intensity focused ultrasound for localized prostate cancer: treatment outcomes and potential effect as a primary therapy.
To investigate the treatment outcomes of a single-session high-intensity focused ultrasound (HIFU) using the Sonablate(®) for patients with localized prostate cancer. Biochemical failure was defined according to the Stuttgart definition [a rise of 1.2 ng/ml or more above the nadir prostate-specific antigen (PSA)] and the Phoenix definition (a rise of 2 ng/ml or more above the nadir PSA). Disease-free survival rate was defined using the Phoenix criteria and positive follow-up biopsy. A total of 171 patients were identified. Fifty-two (30.4 %) patients were identified to be with D'Amico low risk, 47 (27.5 %) with intermediate risk, and 72 (42.1 %) with high risk. In the median follow-up time of 43 months, there was 44 (25.7 %) and 36 (21.1 %) patients experienced biochemical failure for Stuttgart and Phoenix definition with mean (±SD) time to failure of 17.8 ± 2.1 and 19.4 ± 2.3 months, respectively. A total of 44 (25.7 %) patients were diagnosed as disease failure. Cox multivariate analysis revealed PSA nadir level (PSA cutoff = 0.2 ng/ml; HR = 9.472, 95 % CI 4.527-19.820, p < 0.001) and D'amico risk groups [HR = 3.132 (95 % CI 1.251-6.389), p = 0.033] were the predictor for failure in single-session HIFU. Single-session HIFU treatment using the Sonablate(®) seems to be potentially curative approach. When treated carefully with neoadjuvant hormonal therapy or preoperative transurethral resection of the prostate, higher-risk disease might be able to choose this minimally invasive procedure as primary therapy.


Measurement of d+^{7}Be Cross Sections for Big-Bang Nucleosynthesis.
The cross sections of nuclear reactions between the radioisotope ^{7}Be and deuterium, a possible mechanism of reducing the production of mass-7 nuclides in big-bang nucleosynthesis, were measured at center-of-mass energies between 0.2 and 1.5 MeV. The measured cross sections are dominated by the (d,α) reaction channel, towards which prior experiments were mostly insensitive. A new resonance at 0.36(5) MeV with a strength of ωγ=1.7(5) keV was observed inside the relevant Gamow window. Calculations of nucleosynthesis outcomes based on the experimental cross section show that the resonance reduces the predicted abundance of primordial ^{7}Li, but not sufficiently to solve the primordial lithium problem.


Effects of chlorinated drinking water on human lipid metabolism.
Atherosclerosis with its complications is the most important health problem affecting American adults. The levels of serum cholesterol, of high and low density lipoproteins, and of apolipoproteins A1, A2, and B are major risk factors for the development of atherosclerotic lesions. Animal studies suggest that chlorinated drinking water may elevate the serum cholesterol. Studies are too limited to confirm or refute this effect in humans. Since millions of humans have and have had daily exposure to chlorinated drinking water, it is essential to study the effects of such exposure on human lipid metabolism. We have begun a protocol to discover whether consuming chlorinated drinking water elevates serum cholesterol and the other lipid components of blood known to be associated with atherosclerosis. This protocol has been designed to improve the chance of observing an effect while preserving the ability to generalize the data.


Modeling and Simulation for Individualized Therapy of Amisulpride in Chinese Patients with Schizophrenia: Focus on Interindividual Variability, Therapeutic Reference Range and the Laboratory Alert Level.
To explain the high inter-individual variability (IIV) and the frequency of exceeding the therapeutic reference range and the laboratory alert level of amisulpride, a population pharmacokinetic (PPK) model in Chinese patients with schizophrenia was built based on therapeutic drug monitoring (TDM) data to guide individualized therapy. Plasma concentration data (330 measurements from 121 patients) were analyzed using a nonlinear mixed-effects modeling (NONMEM) approach with first-order conditional estimation with interaction (FOCE I). The concentrations of amisulpride were detected by HPLC-MS/MS. Age, weight, sex, combination medication history and renal function status were evaluated as main covariates. The model was internally validated using goodness-of-fit, bootstrap and normalized prediction distribution error (NPDE). Recommended dosage regimens for patients with key covariates were estimated on the basis of Monte Carlo simulations and the established model. A one-compartment model with first-order absorption and elimination was found to adequately characterize amisulpride concentration in Chinese patients with schizophrenia. The population estimates of the apparent volume of distribution (V/F) and apparent clearance (CL/F) were 12.7 L and 1.12 L/h, respectively. Age significantly affected the clearance of amisulpride and the final model was as follows: CL/F=1.04×(AGE/32)-0.624 (L/h). To avoid exceeding the laboratory alert level (640 ng/mL), the model-based simulation results showed that the recommended dose of amisulpride was no more than 600 mg/d for patients aged 60 years, 800 mg/d for those aged 40 years and 1200 mg/d for those aged 20 years, respectively. Dosage optimization of amisulpride can be carried out according to age to reduce the risk of adverse reactions. The model can be used as a suitable tool for designing individualized therapy for Chinese patients with schizophrenia.


Implementing an electronic sideband offset lock for isotope shift spectroscopy in radium.
We demonstrate laser frequency stabilization with at least 6 GHz of offset tunability using an in-phase/quadrature (IQ) modulator to generate electronic sidebands (ESB) on a titanium sapphire laser at 714 nm and we apply this technique to perform isotope shift spectroscopy of 226Ra and 225Ra. By locking the laser to a single resonance of a high finesse optical cavity and adjusting the lock offset, we determine the frequency difference between the magneto-optical trap (MOT) transitions in the two isotopes to be 2630.0 ± 0.3 MHz, a factor of 29 more precise than the previously available data. Using the known value of the hyperfine splitting of the 3P1 level, we calculate the isotope shift for the 1S0 to 3P1 transition to be 2267.0 ± 2.2 MHz, a factor of 8 more precise than the best available value. Our technique could be applied to countless other atomic systems to provide unprecedented precision in isotope shift spectroscopy and other relative frequency comparisons.


Diet rich in high glucoraphanin broccoli reduces plasma LDL cholesterol: Evidence from randomised controlled trials.
Cruciferous-rich diets have been associated with reduction in plasma LDL-cholesterol (LDL-C), which may be due to the action of isothiocyanates derived from glucosinolates that accumulate in these vegetables. This study tests the hypothesis that a diet rich in high glucoraphanin (HG) broccoli will reduce plasma LDL-C. One hundred and thirty volunteers were recruited to two independent double-blind, randomly allocated parallel dietary intervention studies, and were assigned to consume either 400 g standard broccoli or 400 g HG broccoli per week for 12 weeks. Plasma lipids were quantified before and after the intervention. In study 1 (37 volunteers), the HG broccoli diet reduced plasma LDL-C by 7.1% (95% CI: -1.8%, -12.3%, p = 0.011), whereas standard broccoli reduced LDL-C by 1.8% (95% CI +3.9%, -7.5%, ns). In study 2 (93 volunteers), the HG broccoli diet resulted in a reduction of 5.1% (95% CI: -2.1%, -8.1%, p = 0.001), whereas standard broccoli reduced LDL-C by 2.5% (95% CI: +0.8%, -5.7%, ns). When data from the two studies were combined the reduction in LDL-C by the HG broccoli was significantly greater than standard broccoli (p = 0.031). Evidence from two independent human studies indicates that consumption of high glucoraphanin broccoli significantly reduces plasma LDL-C.


The effect of ozone fumigation on the biogenic volatile organic compounds (BVOCs) emitted from Brassica napus above- and below-ground.
The emissions of BVOCs from oilseed rape (Brassica napus), both when the plant is exposed to clean air and when it is fumigated with ozone at environmentally-relevant mixing ratios (ca. 135 ppbv), were measured under controlled laboratory conditions. Emissions of BVOCs were recorded from combined leaf and root chambers using a recently developed Selective Reagent Ionisation-Time of Flight-Mass Spectrometer (SRI-ToF-MS) enabling BVOC detection with high time and mass resolution, together with the ability to identify certain molecular functionality. Emissions of BVOCs from below-ground were found to be dominated by sulfur compounds including methanethiol, dimethyl disulfide and dimethyl sulfide, and these emissions did not change following fumigation of the plant with ozone. Emissions from above-ground plant organs exposed to clean air were dominated by methanol, monoterpenes, 4-oxopentanal and methanethiol. Ozone fumigation of the plants caused a rapid decrease in monoterpene and sesquiterpene concentrations in the leaf chamber and increased concentrations of ca. 20 oxygenated species, almost doubling the total carbon lost by the plant leaves as volatiles. The drop in sesquiterpenes concentrations was attributed to ozonolysis occurring to a major extent on the leaf surface. The drop in monoterpene concentrations was attributed to gas phase reactions with OH radicals deriving from ozonolysis reactions. As plant-emitted terpenoids have been shown to play a role in plant-plant and plant-insect signalling, the rapid loss of these species in the air surrounding the plants during photochemical pollution episodes may have a significant impact on plant-plant and plant-insect communications.


Development of an IoT-Based Sleep Apnea Monitoring System for Healthcare Applications.
Sleep is an essential and vital element of a person's life and health that helps to refresh and recharge the mind and body of a person. The quality of sleep is very important in every person's lifestyle, removing various diseases. Bad sleep is a big problem for a lot of people for a very long time. People suffering from various diseases are dealing with various sleeping disorders, commonly known as sleep apnea. A lot of people die during sleep because of uneven body changes in the body during sleep. On that note, a system to monitor sleep is very important. Most of the previous systems to monitor sleeping problems cannot deal with the real time sleeping problem, generating data after a certain period of sleep. Real-time monitoring of sleep is the key to detecting sleep apnea. To solve this problem, an Internet of Things- (IoT-) based real-time sleep apnea monitoring system has been developed. It will allow the user to measure different indexes of sleep and will notify them through a mobile application when anything odd occurs. The system contains various sensors to measure the electrocardiogram (ECG), heart rate, pulse rate, skin response, and SpO2 of any person during the entire sleeping period. This research is very useful as it can measure the indexes of sleep without disturbing the person and can also show it in the mobile application simultaneously with the help of a Bluetooth module. The system has been developed in such a way that it can be used by every kind of person. Multiple analog sensors are used with the Arduino UNO to measure different parameters of the sleep factor. The system was examined and tested on different people's bodies. To analyze and detect sleep apnea in real-time, the system monitors several people during the sleeping period. The results are displayed on the monitor of the Arduino boards and in the mobile application. The analysis of the achieved data can detect sleep apnea in some of the people that the system monitored, and it can also display the reason why sleep apnea happens. This research also analyzes the people who are not in the danger of sleeping problems by the achieved data. This paper will help everyone learn about sleep apnea and will help people detect it and take the necessary steps to prevent it.


[Technical specification for orthodontic transmission straight wire technique].
Malocclusion is an oral disease with a high prevalence. The goal of orthodontic treatment is health, aesthetics, function and stability. The transmission straight wire appliance and technique is an innovative orthodontic system with independent intellectual property rights invented by Professor Jiuxiang Lin's team based on decades of clinical experience, which provides a new solution for the non-surgical correction of skeletal malocclusions, especially Class Ⅲ, and it is also a good carrier for the implementation of the concept of healthy orthodontics. Due to the lack of guidelines, how to implement standardized application of transmission straight wire technique remains a problem to be solved. This technical specification was formed by combining the guidance from Professor Jiuxiang Lin and joint revision by a number of authoritative experts from the Orthodontic Special Committee, Chinese Stomatological Association, with reference to relevant literatures, and combined with abundant clinical experience of many experts. This specification aims to provide reference to standardize the clinical application of transmission straight wire technique, so as to reduce the risk and complications, and finally to improve the clinical application level of this technique.


Common gamma chain cytokines promote rapid in vitro expansion of allo-specific human CD8+ suppressor T cells.
Human CD8(+) regulatory T cells, particularly the CD8(+)CD28(-) T suppressor cells, have emerged as an important modulator of alloimmunity. Understanding the conditions under which these cells are induced and/or expanded would greatly facilitate their application in future clinical trials. In the current study, we develop a novel strategy that combines common gamma chain (γc) cytokines IL-2, IL-7 and IL-15 and donor antigen presenting cells (APCs) to stimulate full HLA-mismatched allogeneic human CD8(+) T cells which results in significant expansions of donor-specific CD8(+)CD28(-) T suppressor cells in vitro. The expanded CD8(+)CD28(-) T cells exhibit increased expressions of CTLA-4, FoxP3, and CD25, while down-regulate expressions of CD56, CD57, CD127, and perforin. Furthermore, these cells suppress proliferation of CD4(+) T cells in a contact-dependent and cytokine-independent manner. Interestingly, the specificity of suppression is restricted by the donor HLA class I antigens but promiscuous to HLA class II antigens, providing a potential mechanism for linked suppression. Taken together, our results demonstrate a novel role for common γc cytokines in combination with donor APCs in the expansion of donor-specific CD8(+)CD28(-) T suppressor cells, and represent a robust strategy for in vitro generation of such cells for adoptive cellular immunotherapy in transplantation.


Doublecortin-like, a microtubule-associated protein expressed in radial glia, is crucial for neuronal precursor division and radial process stability.
During corticogenesis, progenitors divide within the ventricular zone where they rely on radial process extensions, formed by radial glial cell (RG) scaffolds, along which they migrate to the proper layers of the cerebral cortex. Although the microtubule-associated proteins doublecortin (DCX) and doublecortin-like kinase (DCLK) are critically involved in dynamic rearrangement of the cytoskeletal machinery that allow migration, little is known about their role in early corticogenesis. Here we have functionally characterized a mouse splice-variant of DCLK, doublecortin-like (DCL), exhibiting 73% amino acid sequence identity with DCX over its entire length. Unlike DCX, DCL is expressed from embryonic day 8 onwards throughout the early neuroepithelium. It is localized in mitotic cells, RGs and radial processes. DCL knockdown using siRNA in vitro induces spindle collapse in dividing neuroblastoma cells, whereas overexpression results in elongated and asymmetrical mitotic spindles. In vivo knockdown of the DCLK gene by in utero electroporation significantly reduced cell numbers in the inner proliferative zones and dramatically disrupted most radial processes. Our data emphasize the unique role of the DCLK gene in mitotic spindle integrity during early neurogenesis. In addition, they indicate crucial involvement of DCLK in RG proliferation and their radial process stability, a finding that has thus far not been attributed to DCX or DCLK.


Minimally Invasive Surgery for Congenital Heart Disease.
Minimally invasive cardiac surgery for congenital heart disease has gained increasing acceptance within the specialty. However, most suitable candidates are still treated via a conventional median sternotomy. Adoption of minimally invasive techniques has proven essential in the surgical repair of acquired heart disease to increase patient satisfaction and to remain competitive in an ever-changing medical field. We herein summarize the currently available literature on minimally invasive congenital heart surgery. We describe available techniques and routes of access as well as the lesions amenable for minimally invasive repairs. Mainly derived from case series and smaller retrospective studies, we report available evidence on outcome especially in comparison to conventional repairs via median sternotomy. We highlight the unique challenges that arise from the wide range of lesions as well as from the spectrum of patients ranging from infant to adulthood and describe ways to mitigate those.


A role for transforming growth factor-beta 1 in regulating natural killer cell and T lymphocyte proliferative responses during acute infection with lymphocytic choriomeningitis virus.
The role of transforming growth factor beta 1 (TGF-beta 1) in regulating NK and T cell proliferation during acute viral infections was investigated. After infection of mice with lymphocytic choriomeningitis virus, NK cell proliferation peaks on day 3 and subsides by days 5 to 7 postinfection, whereas T cell proliferation peaks on day 7 and declines by days 9 to 14 postinfection. As TGF-beta 1 has been shown to inhibit lymphocyte proliferation in culture, the production and function of TGF-beta 1 during infection was evaluated in this model. Northern blot analysis demonstrated that the accumulation of TGF-beta 1 transcripts remained relatively constant in total splenic leukocytes during infection. The Mv 1 Lu mink lung cell bioassay was modified and used to evaluate the production of biologically active TGF-beta 1 during infection. Media conditioned with splenic leukocytes isolated from infected mice contained factors that inhibited DNA synthesis by the Mv 1 Lu cells. Low levels of inhibition were observed with conditioned media prepared on day 3 postinfection and high levels of inhibition were observed with conditioned media prepared on days 5 through 14 postinfection. Neutralization with antibodies specific for TGF-beta 1 demonstrated that TGF-beta 1 contributed to the inhibitory activity. As TGF-beta 1 was produced at times coinciding with the decline in NK cell proliferation, the TGF-beta 1 sensitivity of in vivo-elicited NK cells was evaluated. In vitro and in vivo studies demonstrated that NK cell proliferation was extremely sensitive to inhibition by TGF-beta 1. In culture, TGF-beta 1 had an ID50 of 8 pg/ml for inhibiting DNA synthesis by blast NK cells. In vivo, administration of a total of 0.18 micrograms of TGF-beta 1 resulted in a 93% inhibition of NK cell-mediated lytic units per spleen on day 3 postinfection. The inhibition was a result of a block in NK cell proliferation, as administration of TGF-beta 1 profoundly suppressed the appearance of blast size NK cells and the incorporation of [3H] thymidine by NK cell-enriched, blast lymphocyte populations on day 3 postinfection. In contrast to NK cell proliferation, T cell proliferation was not inhibited by up to 100-fold higher concentrations of the factor in vitro or in vivo. Taken together, these data demonstrate that TGF-beta 1 is an important regulator of NK cell proliferation in vivo. Furthermore, the results indicate that differential sensitivity to TGF-beta 1 may contribute to the coordination of NK and T cell responses during viral infections.


David on Neutrality of NAS, PSAC.
The two most significant conduits through which scientific advice is channeled to government are the National Academy of Sciences (NAS)and the President's Science Advisory Committee (PSAC). The neutrality of these two bodies has on occasion been called into question by their critics, but seldom from within. In a philosophic but candid interview published in a recent issue of Mosaic, house organ of the National Science Foundation, Edward E. David, the President's science adviser and chairman of PSAC, suggests that the Academy and PSAC may behindered by their government links from offering scientific advice in an unbiased and credible way.


Facial skin pores: a multiethnic study.
Skin pores (SP), as they are called by laymen, are common and benign features mostly located on the face (nose, cheeks, etc) that generate many aesthetic concerns or complaints. Despite the prevalence of skin pores, related literature is scarce. With the aim of describing the prevalence of skin pores and anatomic features among ethnic groups, a dermatoscopic instrument, using polarized lighting, coupled to a digital camera recorded the major features of skin pores (size, density, coverage) on the cheeks of 2,585 women in different countries and continents. A detection threshold of 250 μm, correlated to clinical scorings by experts, was input into a specific software to further allow for automatic counting of the SP density (N/cm(2)) and determination of their respective sizes in mm(2). Integrating both criteria also led to establishing the relative part of the skin surface (as a percentage) that is actually covered by SP on cheeks. The results showed that the values of respective sizes, densities, and skin coverage: 1) were recorded in all studied subjects; 2) varied greatly with ethnicity; 3) plateaued with age in most cases; and 4) globally refected self-assessment by subjects, in particular those who self-declare having "enlarged pores" like Brazilian women. Inversely, Chinese women were clearly distinct from other ethnicities in having very low density and sizes. Analyzing the present results suggests that facial skin pore's morphology as perceived by human eye less result from functional criteria of associated appendages such as sebaceous glands. To what extent skin pores may be viewed as additional criteria of a photo-altered skin is an issue to be further addressed.


NDX-1 protein hydrolyzes 8-oxo-7, 8-dihydrodeoxyguanosine-5'-diphosphate to sanitize oxidized nucleotides and prevent oxidative stress in Caenorhabditis elegans.
8-oxo-dGTP is generated in the nucleotide pool by direct oxidation of dGTP or phosphorylation of 8-oxo-dGDP. It can be incorporated into DNA during replication, which would result in mutagenic consequences. The frequency of spontaneous mutations remains low in cells owing to the action of enzymes degrading such mutagenic substrates. Escherichia coli MutT and human MTH1 hydrolyze 8-oxo-dGTP to 8-oxo-dGMP. Human NUDT5 as well as human MTH1 hydrolyze 8-oxo-dGDP to 8-oxo-dGMP. These enzymes prevent mutations caused by misincorporation of 8-oxo-dGTP into DNA. In this study, we identified a novel MutT homolog (NDX-1) of Caenorhabditis elegans that hydrolyzes 8-oxo-dGDP to 8-oxo-dGMP. NDX-1 did not hydrolyze 8-oxo-dGTP, 2-hydroxy-dATP or 2-hydroxy-dADP. Expression of NDX-1 significantly reduced spontaneous A:T to C:G transversions and mitigated the sensitivity to a superoxide-generating agent, methyl viologen, in an E. coli mutT mutant. In C. elegans, RNAi of ndx-1 did not affect the lifespan of the worm. However, the sensitivity to methyl viologen and menadione bisulfite of the ndx-1-RNAi worms was enhanced compared with that of the control worms. These facts indicate that NDX-1 is involved in sanitization of 8-oxo-dGDP and plays a critical role in defense against oxidative stress in C. elegans.


Neutrophil maturation of CD34+ cells from peripheral blood and bone marrow in serum-free culture medium with PIXY321 and granulocyte-colony stimulating factor (G-CSF).
Bone marrow (BM) or peripheral blood (PB) CD34+ cells were cultured for 12 days in serum-free culture medium containing PIXY321 (IL-3/ GM-CSF fusion protein) with or without periodic supplements of granulocyte-colony stimulating factor (G-CSF). The cultures were evaluated at day 12 for total cell proliferation (fold increase from day 0), neutrophil differentiation by flow cytometry, using dual staining with CD15-FITC and CD11b-PE, and morphology using Wright-Giemsa and granule staining. In cultures containing PIXY321 where 6000 U/ml of G-CSF was added days 0 and 6, there was no significant difference (p > or = 0.05) in cell proliferation or the percent of CD15+/CD11b+ cells when compared with cultures with PIXY321 alone. ELISA analysis showed G-CSF levels had declined by 90% after 3 days of culture. Further studies were performed to assess the benefit of supplementing lower concentrations of G-CSF (600 U/ml) at more frequent intervals. A significant increase (p < or = 0.05) in cell proliferation and percent CD15+/CD11b+ was observed when G-CSF was added on days 0, 3, 6, and 9 (every 3 days) as compared with those cultures with PIXY321 alone. CD34+ cell proliferation without G-CSF was 19.6 +/- 4.8-fold, with G-CSF added on days 0 and 6 was 28.7 +/- 6.4-fold, and with G-CSF added on days 0, 3, 6, and 9 was 45.9 +/- 10.6-fold. Percent of CD15+/CD11b+ cells was 19.0 +/- 4.6%, 38.2 +/- 7.2%, and 58.5 +/- 6.5%, respectively, in these cultures. We observed more CD15+/CD11b+ cells, myelocytes/metamyelocytes, and secondary granule staining in cultures with G-CSF added on day, 0, 3, 6, and 9 as compared with cultures with G-CSF added on days 0 and 6 or no G-CSF added. We conclude that PIXY321 and G-CSF act synergistically on the in vitro proliferation and neutrophil differentiation of BM and PB CD34+ cells and that frequent supplements of G-CSF facilitate neutrophil differentiation.


Absolute Configurations of Naturally Occurring [5]- and [3]-Ladderanoic Acids: Isolation, Chiroptical Spectroscopy, and Crystallography.
We have isolated mixtures of [5]- and [3]-ladderanoic acids 1a and 2a from the biomass of an anammox bioreactor and have separated the acids and their phenacyl esters for the first time by HPLC. The absolute configurations of the naturally occurring acids and their phenacyl esters are assigned as R at the site of side-chain attachment by comparison of experimental specific rotations with corresponding values predicted using quantum chemical (QC) methods. The absolute configurations for 1a and 2a were independently verified by comparison of experimental Raman optical activity spectra with corresponding spectra predicted using QC methods. The configurational assignments of 1a and 2a and of the phenacyl ester of 1a were also confirmed by X-ray crystallography.


Mycosis fungoides. Small-bowel involvement complicated by perforation and peritonitis.
Mycosis fungoides (MF) is a malignant lymphoma that arises in the skin and subsequently may involve lymph nodes and viscera as part of the natural course of the disease. The disease has distinct histologic characteristics that may be recognized in extracutaneous tissues. A patient who had MF with ulcerating cutaneous nodules is presented herein. Death resulted from perforation of the small bowel involved by the disease and consequent peritonitis.


Phenotypic and Functional Consequences of PLT Binding to Monocytes and Its Association with Clinical Features in SLE.
Platelets (PLTs) can modulate the immune system through the release of soluble mediators or through interaction with immune cells. Monocytes are the main immune cells that bind with PLTs, and this interaction is increased in several inflammatory and autoimmune conditions, including systemic lupus erythematosus (SLE). Our aim was to characterize the phenotypic and functional consequences of PLT binding to monocytes in healthy donors (HD) and in SLE and to relate it to the pathogenesis of SLE. We analyzed the phenotypic and functional features of monocytes with non-activated and activated bound PLTs by flow cytometry. We observed that monocytes with bound PLTs and especially those with activated PLTs have an up-regulated HLA-DR, CD86, CD54, CD16 and CD64 expression. Monocytes with bound PLTs also have an increased capacity for phagocytosis, though not for efferocytosis. In addition, monocytes with bound PLTs have increased IL-10, but not TNF-α, secretion. The altered phenotypic and functional features are comparable in SLE and HD monocytes and in bound PLTs. However, the percentages of monocytes with bound PLTs are significantly higher in SLE patients and are associated with undetectable levels of anti-dsDNA antibodies and hematuria, and with normal C3 and albumin/creatinine levels. Our results suggest that PLTs have a modulatory influence on monocytes and that this effect may be highlighted by an increased binding of PLTs to monocytes in autoimmune conditions.


Bayesian asymmetric regression as a means to estimate and evaluate oral reading fluency slopes.
Bayesian techniques have become increasingly present in the social sciences, fueled by advances in computer speed and the development of user-friendly software. In this paper, we forward the use of Bayesian Asymmetric Regression (BAR) to monitor intervention responsiveness when using Curriculum-Based Measurement (CBM) to assess oral reading fluency (ORF). An overview of Bayesian methods and their application to the problem-solving model is first presented, which is further illustrated by a case example. We conclude the paper with a Monte Carlo simulation study demonstrating the validity of BAR, as compared to the current standard of practice for CBM decision-making, ordinary least squares (OLS) regression. Results suggest that BAR is most advantageous with studies using small-to-moderate sample sizes, and when distributional information (such as the probability of intervention success) is of interest. (PsycINFO Database Record


Genetic heterogeneity of yellow fever virus strains from Africa and the Americas.
Isolates of yellow fever (YF) virus from Africa (Senegambia, Central African Republic, Ivory Coast, Burkina Faso) and from South America (Panama, Ecuador, Trinidad) were examined by oligonucleotide fingerprinting of the 40S genome RNA. Geographically isolated and epidemiologically unrelated viruses were very distinct. On the basis of the T1 oligonucleotide fingerprints of each isolate, four geographical variants (topotypes) of YF virus isolated within the same period of time have been established. The Ivory Coast and Burkina Faso topotypes were similar. In the Central African Republic, two variants could be found exhibiting 70 to 75% homology to one another. In South America, the three analysed strains exhibited only about 70% homology, but could be classified in the same topotype. The oligonucleotide fingerprints of the genome RNA offered a useful tool for the understanding of YF virus variability.


Facing the threat of equine parasitic disease.
Horses worldwide are exposed to a complex mixture of intestinal parasitic helminths. When burdens are high, these parasites can seriously compromise health and welfare. Some helminth species have an extremely high prevalence and are difficult to control, not least because there is a limited understanding of their most basic biology. Furthermore, levels of resistance to some of the commonly used anthelmintics are widespread and increasing. The cyathostomins are the most common nematode species affecting equids worldwide. Within this group of parasites are more than 50 different species. Until recent research activities, little was known about the contribution that individual species make to clinical disease, parasite epidemiology and anthelmintic resistance. This review describes some of the recent research advances in the understanding of cyathostomins in these areas. As part of the research effort, molecular tools were developed to facilitate identification of the non-parasitic stages of cyathostomins. These tools have proved invaluable in the investigation of the relative contributions that individual species make to the pathology and epidemiology of mixed infections. At the more applied level, research has also progressed in the development of a diagnostic test that will allow numbers of cyathostomin encysted larvae to be estimated. This test utilises cyathostomin-specific serum antibody responses as markers of infection. As anthelmintic resistance will be the major constraint on parasite control in future, researchers are actively investigating mechanisms of drug resistance and how to improve the detection of resistance in the field. Recent developments in these areas are also outlined.


Protection of privacy and confidentiality.
A multistate, cooperative program seeking to develop better methods for the effective and efficient gathering. storing, analyzing, and utilizing of mental patient records has made a comprehensive effort to protect the confidentiality and privacy of these psychiatric patient records. Administrative, technical, and legal safeguards have been implemented. The discussion of legal safeguards involves two areas: the protection of the system itself, located at Rockland State Hospital; and the specific legal environment of confidentiality and privacy of mental health records and information in the group of cooperating jurisdictions. On the whole, adequate legal and administrative protection can be afforded the confidentiality and privacy of an electronic data system in the mental health field, and access to the records can be restricted for the welfare of the patients. At the same time, access to aggregate data in the system can be allowed, under proper standards, for important research and planning purposes. The methods adopted by MSIS to preserve confidentiality and privacy by limiting access to such records could well prove an important model for the development of protective methods in other electronic data programs-not only those in psychiatry, but those in other fields where the data collected are sensitive and confidential.


Prevention and intervention research with Latino families: a translational approach.
The present paper takes a translational approach in applying the themes of the current special section to prevention and intervention science in Latino families. The paper reviews the current literature on cultural processes in prevention and intervention research with Latino families. Overall, many prevention and intervention programs have either been developed specifically for Latino families or have been modified for Latino families with great attention paid to the socio-cultural needs of these families. Nevertheless, few studies have tested the role of cultural values or acculturation processes on outcomes. We make recommendations based on findings within basic science and in particular this special section on the incorporation of these values and processes into prevention and intervention science with Latino families.


In vitro detection of calcium in bone by modified carbon dots.
This article depicts a simple and novel approach to locate calcium deposits in bone using modified carbon dots (CDs) through fluorescence imaging. Amino-functionalized CDs along with glutamic acid, a naturally-occurring ligand for calcium ions, were conjugated onto hyaluronic acid using EDC chemistry. The ability of the probe to recognise Ca ions was demonstrated using polymer strips doped with Ca ions and freshly collected bones. The probe was found to bind more at bone cracks, reflecting its potential to locate micro-cracks in bone as well as to map Ca deposits. The bound portions can be visualized through a fluorescence microscope or by illumination by a UV source (365 nm). The components used to generate the probes, namely CD, glutamic acid and hyaluronic acid, are well known for their non-toxicity and biocompatibility. It appears, therefore, that the probe could be used for in vivo applications.


Cadherin-11-mediated interactions with bone marrow stromal/osteoblastic cells support selective colonization of breast cancer cells in bone.
Cell adhesion molecules have been implicated in the selective colonization of cancer in distant organs. Breast cancer has a strong predilection for spreading to bone. Cadherin-11, which is one of the classical type-2 cadherin family members and mediates homophilic cell-cell adhesion, is constitutively expressed in stromal and osteoblastic cells in bone marrow. Elevated cadherin-11 expression is also found in aggressive human breast cancers. Here, we investigated the role of the interactions between breast cancer cells and bone marrow stromal/osteoblastic cells via cadherin-11 in the selective spread to bone. The bone-seeking clone of the MDA-MB-231 human breast cancer cells showed greater cadherin-11 expression than the parental and the brain-seeking clone. Cadherin-11 overexpression in MDA-MB-231 cells increased bone metastases with promoted bone resorption, while the natural variant form of cadherin-11 that is unable to establish cell-cell adhesion did not. Of note, introduction of cadherin-11 showed no effects on lung metastases. Fluorescence-activated cell sorter analysis using the fluorescent dye-labeled cancer cells showed that early colonization in bone marrow was increased by cadherin-11. Co-cultures with the MC3T3-E1 osteoblastic cells that constitutively expressed cadherin-11 caused an up-regulation of parathyroid hormone-related protein (PTH-rP) production in MDA-MB-231 cells overexpressing cadherin-11. The conditioned medium of the co-cultures increased osteoclastogenesis, which was blocked by a neutralizing antibody to PTH-rP. In conclusion, our results suggest that cadherin-11 promotes homing and migration to bone and osteoclastogenesis through mediating the homophilic interactions of breast cancer cells with marrow stromal/osteoblastic cells, thereby enhancing bone metastases.


Morphological Effects and In Vitro Biological Mechanisms of Radiation-Induced Cell Killing by Gold Nanomaterials.
Gold nanomaterials have been shown to augment radiation therapy both in vitro and in vivo. However, studies on these materials are mostly phenomenological due to nanoparticle heterogeneity and the complexity of biological systems. Even accurate quantification of the particle dose still results in bulk average biases; the effect on individual cells is not measured but rather the effect on the overall population. To perform quantitative nanobiology, we coated glass coverslips uniformly at varying densities with Au nanoparticle preparations with different morphologies (45 nm cages, 25 nm spheres, and 30 nm rods). Consequently, the effect of a specific number of particles per unit area in contact with breast cancer cells growing on the coated surfaces was ascertained. Gold nanocages showed the highest degree of radiosensitization on a per particle basis, followed by gold nanospheres and gold nanorods, respectively. All three materials showed little cytotoxic effect at 0 Gy, but clonogenic survival decreased proportionally with the radiation dose and particle coverage density. A similar trend was seen in vivo in the combined treatment antitumor response in 4T1 tumor-bearing animals. The presence of gold affected the type and quantity of reactive oxygen species generated, specifically superoxide and hydroxyl radicals, and the concentration of nanocages correlated with the development of more numerous double-stranded DNA breaks and increased protein oxidation as measured by carbonylation. This work demonstrates the dependence on morphology and concentration of radiation enhancement by gold nanomaterials and may lead to a novel method to differentiate intra- and extracellular functionalities of gold nanomedicine treatment strategies. It further provides insights that can guide the rational development of gold nanomaterial-based radiosensitizers for clinical use.


Effect of respiratory acidosis on intracellular pH of the proximal tubule.
In contrast to chronic metabolic acidosis, chronic respiratory acidosis does not result in an adaptation in either renal ammonia or glucose production. To examine the possibility that this might be explained by a difference in proximal tubule intracellular pH, the response of two pH-sensitive metabolites, citrate and alpha-ketoglutarate, were assessed. Metabolic acidosis of 3 days duration, induced by drinking 1.5% NH4Cl, significantly reduced urinary citrate excretion (172 to 15 mumol/day) and renal cortical citrate (1.33 to 0.88 mumol/g) and alpha-ketoglutarate (0.90 to 0.46 mumol/g) concentrations in comparison with normal rats. Chronic respiratory acidosis, produced by 3 days in a 10% CO2 environment, lowered systemic pH similar to metabolic acidosis but had no effect on either urinary citrate excretion or renal cortical citrate and alpha-ketoglutarate concentrations. By contrast, acute respiratory acidosis (3, 6, or 24 h duration) reduced urinary citrate excretion and renal cortical citrate and alpha-ketoglutarate concentrations in a fashion similar to acute metabolic acidosis. These data suggest that acute acidosis of either respiratory or metabolic origin lowers the intracellular pH of the proximal tubule. However, when the acid-base abnormality enters the chronic phase, proximal tubular intracellular pH remains low with metabolic acidosis but returns to normal values with respiratory acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)


Control of cell proliferation and apoptosis by mob as tumor suppressor, mats.
Appropriate cell number and organ size in a multicellular organism are determined by coordinated cell growth, proliferation, and apoptosis. Disruption of these processes can cause cancer. Recent studies have identified the Large tumor suppressor (Lats)/Warts (Wts) protein kinase as a key component of a pathway that controls the coordination between cell proliferation and apoptosis. Here we describe growth inhibitory functions for a Mob superfamily protein, termed Mats (Mob as tumor suppressor), in Drosophila. Loss of Mats function results in increased cell proliferation, defective apoptosis, and induction of tissue overgrowth. We show that mats and wts function in a common pathway. Mats physically associates with Wts to stimulate the catalytic activity of the Wts kinase. A human Mats ortholog (Mats1) can rescue the lethality associated with loss of Mats function in Drosophila. As Mats1 is mutated in human tumors, Mats-mediated growth inhibition and tumor suppression is likely conserved in humans.


Characterization of CHAT and Cox type 1 live-attenuated poliovirus vaccine strains.
CHAT and Cox type 1 live-attenuated poliovirus strains were developed in the 1950s to be used as vaccines for humans. This paper describes their characterization with respect to virulence, sensitivity for growth at high temperatures, and complete nucleotide and amino acid sequences. The results are compared to those for their common parental wild virus, the Mahoney strain, and to those for two other poliovirus strains derived from Mahoney, the Sabin 1 vaccine strain and the mouse-adapted LS-a virus. Analysis of four isolates from cases of vaccine-associated paralytic poliomyelitis related to the CHAT vaccine revealed genetic and phenotypic properties of the CHAT strain following replication in the human gut. CHAT-VAPP strain 134 contained a genome highly evolved from that of CHAT (1.1% nucleotide differences), suggesting long-term circulation of a vaccine-derived strain in the human population. The molecular mechanisms of attenuation and evolution of poliovirus in humans are discussed in the context of the global polio eradication initiative.


Development of a rhenium-186-labeled MAG3-conjugated bisphosphonate for the palliation of metastatic bone pain based on the concept of bifunctional radiopharmaceuticals.
Rhenium-186-1-hydroxyethylidene-1,1-diphosphonate (186Re-HEDP) has been used for the palliation of metastatic bone pain. Delayed blood clearance and high gastric uptake of radioactivity have been observed upon injection, due to the instability of (186)Re-HEDP in vivo. In this study, on the basis of the concept of bifunctional radiopharmaceuticals, we designed a stable 186Re-mercaptoacetylglycylglycylglycine (MAG3) complex-conjugated bisphosphonate, [[[[(4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl]carbamoylmethyl]carbamoylmethyl]carbamoylmethanethiolate]oxorhenium(V) (186Re-MAG3-HBP). As a precursor, [1-hydroxy-1-phosphono-4-[2-[2-[2-(2-tritylmercaptoacetylamino)acetylamino]acetylamino]acetylamino]butyl]phosphonic acid (Tr-MAG3-HBP) was synthesized by the conjugation of N-[(tritylmercapto)acetyl]glycylglycylglycine (Tr-MAG3) with the bisphosphonate analogue. After deprotection of the trityl group of Tr-MAG3-HBP, 186Re-labeling was performed by reacting 186ReO4- with SnCl2 in citrate buffer. After purification by HPLC, 186Re-MAG3-HBP showed a radiochemical purity of over 95%. To compare the stability of 186Re-MAG3-HBP and 186Re-HEDP, these (186)Re complexes were incubated in phosphate buffer. No measurable decomposition of 186Re-MAG3-HBP occurred over a 24-h period, while only approximately 30% of 186Re-HEDP remained intact 24 h postincubation. In biodistribution experiments, the radioactivity level of 186Re-MAG3-HBP in bone was significantly higher than that of (186)Re-HEDP. Blood clearance of 186Re-MAG3-HBP was faster than that of 186Re-HEDP. In addition, the gastric accumulation of 186Re-MAG3-HBP radioactivity was lower than that of 186Re-HEDP. In conclusion, 186Re-MAG3-HBP is expected to be a useful radiopharmaceutical for the palliation of metastatic bone pain.


Data mining: Potential applications in research on nutrition and health.
Data mining enables further insights from nutrition-related research, but caution is required. The aim of this analysis was to demonstrate and compare the utility of data mining methods in classifying a categorical outcome derived from a nutrition-related intervention. Baseline data (23 variables, 8 categorical) on participants (n = 295) in an intervention trial were used to classify participants in terms of meeting the criteria of achieving 10 000 steps per day. Results from classification and regression trees (CARTs), random forests, adaptive boosting, logistic regression, support vector machines and neural networks were compared using area under the curve (AUC) and error assessments. The CART produced the best model when considering the AUC (0.703), overall error (18%) and within class error (28%). Logistic regression also performed reasonably well compared to the other models (AUC 0.675, overall error 23%, within class error 36%). All the methods gave different rankings of variables' importance. CART found that body fat, quality of life using the SF-12 Physical Component Summary (PCS) and the cholesterol: HDL ratio were the most important predictors of meeting the 10 000 steps criteria, while logistic regression showed the SF-12PCS, glucose levels and level of education to be the most significant predictors (P ≤ 0.01). Differing outcomes suggest caution is required with a single data mining method, particularly in a dataset with nonlinear relationships and outliers and when exploring relationships that were not the primary outcomes of the research.


[Epidemiological study of pediculosis capitis and scabies in schoolchildren from Antofagasta, Chile, 1995].
In order to contribute to a better knowledge of the pediculosis capitis and scabies during March-December 1995, 1122 primary schoolchildren under 14 years of age in the city-port of Antofagasta in northern Chile (20 degrees South lat.), were examined. A total of 285 (25.4%) were found to be infested with Pediculus humanus capitis and only 20 (1.8%) with Sarcoptes scabiei. In general the rates of infestation to both ectoparasitic diseases were higher in groups of younger schoolchildren, also higher in women than in men and in those groups with high indexes of crowding and ignorance of the transmission mechanism of pediculosis capitis and scabies.


Juvenile hormone differentially regulates two Grp78 genes encoding protein chaperones required for insect fat body cell homeostasis and vitellogenesis.
Juvenile hormone (JH) has a well known role in stimulating insect vitellogenesis (i.e. yolk deposition) and oocyte maturation, but the molecular mechanisms of JH action in insect reproduction are unclear. The 78-kDa glucose-regulated protein (Grp78) is a heat shock protein 70-kDa family member and one of the most abundant chaperones in the endoplasmic reticulum (ER) where it helps fold newly synthesized peptides. Because of its prominent role in protein folding, and also ER stress, we hypothesized that Grp78 might be involved in fat body cell homeostasis and vitellogenesis and a regulatory target of JH. We report here that the migratory locust Locusta migratoria possesses two Grp78 genes that are differentially regulated by JH. We found that Grp78-1 is regulated by JH through Mcm4/7-dependent DNA replication and polyploidization, whereas Grp78-2 expression is directly activated by the JH-receptor complex comprising methoprene-tolerant and Taiman proteins. Interestingly, Grp78-2 expression in the fat body is about 10-fold higher than that of Grp78-1 Knockdown of either Grp78-1 or Grp78-2 significantly reduced levels of vitellogenin (Vg) protein, accompanied by retarded maturation of oocytes. Depletion of both Grp78-1 and Grp78-2 resulted in ER stress and apoptosis in the fat body and in severely defective Vg synthesis and oocyte maturation. These results indicate a crucial role of Grp78 in JH-dependent vitellogenesis and egg production. The presence and differential regulation of two Grp78 genes in L. migratoria likely help accelerate the production of this chaperone in the fat body to facilitate folding of massively synthesized Vg and other proteins.


Use of somatosensory evoked potentials to evaluate the peripheral nervous system.
Somatosensory evoked potentials (SEPs) are being used increasingly to evaluate peripheral somatosensory pathways. They have been used in patients with plexus lesions but may provide misleading information when multiple lesions are present, demonstrating only the electrophysiologic consequences of the most distal lesion that is present. Ulnar SEPs can be abnormal in neurogenic thoracic outlet syndrome, whereas they are normal in the nonneurogenic variety. SEPs to nerve trunk stimulation are generally not helpful in patients with isolated radiculopathies, and SEPs elicited by dermatomal or cutaneous nerve stimulation have provided conflicting results. SEPs may be important in evaluating conduction along inaccessible proximal segments of limb nerves. Their value in Guillain-Barré syndrome, in which pathology may be predominantly proximal, is unclear. In evaluating peripheral neuropathies, SEPs can sometimes be useful when peripheral sensory nerve action potentials are unobtainable; sometimes, however, SEPs provide misleading information concerning conduction velocity. The SEP findings should not be relied on to determine whether sensory loss is organic or nonorganic, although they are one factor to consider in making this determination.


Inhibition of prolyl 4-hydroxylase by hydroxyanthraquinones.
Prolyl 4-hydroxylase (EC 18.104.22.168) is an essential enzyme in the post-translational modification of collagen. Inhibitors of this enzyme are of potential interest for the treatment of diseases involving excessive deposition of collagen. We have found that anthraquinones with at least two hydroxy groups ortho to each other are potent inhibitors of this enzyme. Kinetic studies revealed that 2,7,8-trihydroxyanthraquinone (THA) competitively inhibited the co-substrate, 2-oxoglutarate, but was non-competitive with regard to ascorbate and was tentatively considered to be uncompetitive with regard to protocollagen. The inhibition by THA was greatly enhanced in the absence of added Fe2+ and was partially reversed by the addition of concentrations of Fe2+ in excess of the optimum for the enzymic reaction. Binding studies indicated that THA is an effective chelating agent for Fe2+. Several non-quinoidal compounds bearing the catechol moiety also inhibited the enzyme. The results suggest that THA inhibited prolyl 4-hydroxylase by binding to the enzyme at the site for 2-oxoglutarate possibly involving the Fe2+ atom, rather than by complexing with Fe2+ in free solution. The inhibition of prolyl 4-hydroxylase by THA exhibited strong positive co-operativity and may involve three distinct but non-independent binding sites.


Intraoperative Neurological Monitoring With Evoked Potentials During Carotid Endarterectomy Versus Cooperative Patients Under General Anesthesia Technique: A Retrospective Study.
The best technique to evaluate contralateral carotid flow during carotid endarterectomy (CEA) is still debated; an accurate detection of efficient contralateral blood flow can avoid unnecessary shunt placement and its complications. The aim of this retrospective observational study was to evaluate and compare the safety and efficacy of general anesthesia with motor-evoked potential and somatosensory-evoked potentials (mSSEP and tcMEP) versus cooperative patients under general anesthesia (CPGA) technique for CEA. Primary outcome was the rate of technical failure. The procedural time and shunt incidence between the 2 neuromonitoring strategies were also analyzed. A total of 331 patients who consecutively underwent CEA were included (100 patients in the CPGA group and 231 in the mSSEP+tcMEP group). The anesthesia technique was customized according to the cerebral monitoring needs. Comparison between groups was performed along with risk analysis. Electrophysiological monitoring seems to be a safe and effective strategy of neuromonitoring during CEA. Compared with the CPGA technique, it ensures fewer technical failures, reduces surgical and anesthesiological time and, moreover, it may reduce shunt risk/incidence. The incidence of shunt between the CPGA group and mSSEP+tcMEP was statistically different (CPGA 12%, mSSEP+tcMEP 5.2%; P=0.02), and the relative risk reduction in the mSSEP+tcMEP group, compared with the CPGA group, was 0.57. mSSEP and tcMEP neuromonitoring was associated with less technical failure and procedural time than asleep-awake-asleep strategy. The evoked potential neuromonitoring may be an alternative technique to awake clinical assessment during CEA.


Radiation-induced adaptive response is not seen in cell lines showing a bystander effect but is seen in lines showing HRS/IRR response.
A previous study comparing the bystander effect and low-dose hypersensitivity found that they were inversely correlated. In the current study seven cell lines with established bystander effect and hyper-radiosensitivity/increased radioresistance (HRS/IRR) were further screened for the presence of an adaptive response. Cell survival after exposure to direct radiation with or without a 0.1 Gy priming dose, was determined using the colony forming assay for seven human cell lines (HaCAT, HPV-G, SW48, T98G, U373, HGL21 and HT29). Furthermore, the impact of the bystander effect on cell survival after exposure to irradiated cell culture medium was measured concurrently. An adaptive response was induced in four cell lines (U373, T98G, HGL21 and HT29) causing increased cell survival. In agreement with previous publications, a bystander effect was induced in three cell lines (HPV-G, HaCAT and SW48); while no bystander effect was seen in U373, T98G, HGL21 and HT29. An adaptive response was detected in cell lines known to produce hypersensitive response, and was inversely correlated with the bystander effect. These results suggest that for the cell lines tested the ability to induce an adaptive response may be mutually exclusive to the bystander effect.


Optical tracking of phenotypically diverse individual synapses on solitary tract nucleus neurons.
The solitary tract nucleus (NTS) is the termination site for cranial visceral afferents-peripheral primary afferent neurons which differ by phenotype (e.g. myelinated and unmyelinated). These afferents have very uniform glutamate release properties calculated by variance mean analysis. In the present study, we optical measured the inter-terminal release properties across individual boutons by assessing vesicle membrane turnover with the dye FM1-43. Single neurons were mechanically micro-harvested from medial NTS without enzyme treatment. The TRPV1 agonist capsaicin (CAP, 100 nM) was used to identify afferent, CAP-sensitive terminals arising from unmyelinated afferents. Isolated NTS neurons retained both glutamatergic and inhibitory terminals that generated EPSCs and IPSCs, respectively. Visible puncta on the neurons were stained positively with monoclonal antibody for synaptophysin, a presynaptic marker. Elevating extracellular K(+) concentration to 10 mM increased synaptic release measured at individual terminals by FM1-43. Within single neurons, CAP destained some but not other individual terminals. FM1-43 positive terminals that were resistant to CAP could be destained with K(+) solution. Individual terminals responded to depolarization with similar vesicle turnover kinetics. Thus, vesicular release was relatively homogenous across individual release sites. Surprisingly, conventionally high K(+) concentrations (>50 mM) produced erratic synaptic responses and at 90 mM K(+) overt neuron swelling--results that suggest precautions about assuming consistent K(+) responses in all neurons. The present work demonstrates remarkably uniform glutamate release between individual unmyelinated terminals and suggests that the homogeneous EPSC release properties of solitary tract afferents result from highly uniform release properties across multiple contacts on NTS neurons.


The cranial osteology of Tyrannoneustes lythrodectikos (Crocodylomorpha: Metriorhynchidae) from the Middle Jurassic of Europe.
Tyrannoneustes lythrodectikos is one of numerous metriorhynchid crocodylomorph species known from the Oxford Clay Formation of England (Callovian-Oxfordian; Middle-Late Jurassic). This taxon is of evolutionary importance, as it is the oldest and most basal known macrophagous metriorhynchid. It has a mosaic of plesiomorphic and derived feeding related characteristics, including: teeth with microscopic, poorly formed and non-contiguous denticles; increased tooth apicobasal length; ventrally displaced dentary tooth row (increased gape); reduced dentary tooth count; and a proportionally long mandibular symphysis. However the type specimen, and current referred specimens, all lack a preserved cranium. As such, the craniofacial morphology of this taxon, and its potential feeding ecology, remains poorly understood. Here we describe two skulls and two lower jaws which we refer to T. lythrodectikos. Previously these specimens were referred to 'Metriorhynchus' brachyrhynchus. They share with the T. lythrodectikos holotype: the in-line reception pits on the dentary, dorsal margin of the surangular is strongly concave in lateral view, and the most of the angular ventral margin is strongly convex. Based on our description of these specimens, the skull of T. lythrodectikos has three autapomorphies: very long posterior processes of the premaxilla terminating in line with the 4th or 5th maxillary alveoli, deep lateral notches on the lateral surface of the maxillary with reception pits for dentary teeth, and the premaxilla forms the anterior margin of the first maxillary alveoli. Our description of the cranial anatomy of Tyrannoneustes lythrodectikos confirms that some macrophagous characteristics evolved during the Middle Jurassic, and were not exclusive to the clade Geosaurini. Moreover, the skulls further highlight the mosaic nature of Tyrannoneustes lythrodectikos and wide-gape macrophagous evolution in Geosaurinae.


[Upper-limb work-related musculoskeletal disorders (UL-WMSDs) and latency of effect].
Trends in work-related upper limb musculoskeletal disorders appear to be in constant increase in industrialized countries. In Europe claims and compensation for these disorders have significantly increased. The aim of this study was to investigate the temporal relationship between the beginning of occupational exposure to repetitive movements and exertions of upper limbs, assessed through the OCRA index, and the manifestation of the disorders. Clinical and questionnaire information about 557 cases of UL-WMSDs in the upholstered furniture industry were analyzed in order to investigate the mean latency period of the disorders and to verify to what extent different levels of exposure influence the latency time. The latency of UL-WMSDs is influenced by the level of exposure to risk, measured by means of the OCRA index. Shorter latency times were found for wrist/hand tendonitis, with a mean latency time of 5.4 years and with a greater sensitivity to the level of exposure assessed with the OCRA index value. This might support a sort of predictive value with reference to other UL-WMSDs with longer latency. Probably a latency period of 12 years may be suggested as the cut-off limit to assess a causal relationship between tendon or canalicular WMISDs and occupational exposure to repetitive movements and exertions of upper limbs.


The relationship between nonalcoholic fatty liver disease and pediatric congenital hypothyroidism patients.
Previous studies have shown hypothyroidism was independently associated with nonalcoholic fatty liver disease (NAFLD) in adults, but few studies examined their relationships in pediatric populations. This study aimed to investigate the prevalence of NAFLD in pediatric congenital hypothyroidism (CHT) patients and to identify the association between CHT and NAFLD. This study enrolled pediatric CHT patients receiving levothyroxine treatment at one medical center from 2013 to 2014. Euthyroid subjects (ET) and transient hypothyroidism (THT) patients weaned off medication successfully after age 3 were selected for further comparison. Laboratory data including thyroid functions, liver functions, and metabolic profiles were obtained. The major outcome was the occurrence of NAFLD, diagnosed based on the findings of abdominal ultrasonography. One-hundred and twenty-nine subjects (47 in CHT, 47 in THT, and 35 in ET groups) were enrolled. The analysis showed higher fasting serum glucose, insulin, thyroxine (T4), and mean thyroid-stimulating hormone (TSH) levels in the CHT group. NAFLD prevalence was higher in the CHT (23.4%) group than in the THT (8.5%) and the ET (5.7%) groups, demonstrating an increasing trend across three strata (X2 linear-by-linear = 5.9, P < .05). The multivariate regression analysis showed obesity (β-coefficient = 5.52, P < .05), CHT (β-coefficient = 2.92, P < .05) and mean TSH levels (β-coefficient = 0.24, P < .05) were independent risk factors for NAFLD. A positive correlation was found between TSH level and lipid profiles. CHT patients had higher risk of NAFLD despite treatment being initiated early in life. Close monitoring of metabolic profiles is warranted. Further research should examine ways to optimize the treatment for CHT patients in terms of prevention against NAFLD.


CS-Symmetric Pyridine(diimine) Iron Methyl Complexes for Catalytic [2+2] Cycloaddition and Hydrovinylation: Metallacycle Geometry Determines Selectivity.
A series of CS-symmetric (aryl,alkyl)-substituted pyridine(dimine) iron methyl (CyARPDI)FeCH3 complexes have been prepared, characterized, and evaluated as precatalysts for the [2+2]-cycloaddition of butadiene and ethylene. Mixtures of vinylcyclobutane and (Z)-hexa-1,4-diene were observed in each case. By comparison, C2v-symmetric, arylated (PDI) iron catalysts are exclusively selective for reversible [2+2]-cycloaddition to yield vinylcyclobutane. The alteration in the chemoselectivity of the catalytic reaction was investigated through a combination of precatalyst stability studies, identification of catalytic resting state(s), and 2H and 13C isotopic labeling experiments. While replacement of an aryl-imine substituent with an N-alkyl group decreases the stability of the formally iron(0) dinitrogen and butadiene complexes, two diamagnetic metallacycles were identified as catalyst resting states. Deuterium labeling and NOESY/EXSY NMR experiments support 1,4-hexadiene arising from catalytic hydrovinylation involving reversible oxidative cyclization leading to accessible cis-metallacycle. Cyclobutane formation proceeds by irreversible C(sp3)-C(sp3) bond-forming reductive elimination from a trans-metallacycle. These studies provide key mechanistic understanding into the high selectivity of bis(arylated) pyridine(diimine) iron catalysts for [2+2]-cycloaddition, unique, thus far, to this class of iron catalysts.


New treatment for IgA nephropathy: enteric budesonide targeted to the ileocecal region ameliorates proteinuria.
Systemic corticosteroid treatment has been shown to exert some protection against renal deterioration in IgA nephropathy (IgAN) but is not commonly recommended for long-term use due to the well-known systemic side effects. In this study, we investigated the efficacy and safety of a new enteric formulation of the locally acting glucocorticoid budesonide (Nefecon®), designed to release the active compound in the ileocecal region. The primary objective was to evaluate the efficacy of targeted release budesonide on albuminuria. Budesonide 8 mg/day was given to 16 patients with IgAN for 6 months, followed by a 3-month follow-up period. The efficacy was measured as change in 24-h urine albumin excretion, serum creatinine and estimated glomerular filtration rate (eGFR). The median relative reduction in urinary albumin excretion was 23% during the treatment period (interquartile range: -0.36 to -0.04, P = 0.04) with pretreatment values ranging from 0.3 to 6 g/24 h (median: 1.5 g/24 h). The median reduction in urine albumin peaked at 40% (interquartile range: -0.58 to -0.15) 2 months after treatment discontinuation. Serum creatinine was reduced by 6% (interquartile range: -0.12 to -0.02; P = 0.003), and eGFR [Modification of Diet in Renal Disease (MDRD)] increased ∼8% (interquartile range: 0.02-0.16, P = 0.003) during treatment. No major corticosteroid-related side effects were observed. In the present pilot study, enteric budesonide targeted to the ileocecal region had a significant effect on urine albumin excretion, accompanied by a minor reduction of serum creatinine and a modest increase of eGFR calculated by the MDRD equation, while eGFR calculated from Cockcroft-Gault equation and cystatin C was not changed. Enteric budesonide may represent a new treatment of IgAN warranting further investigation.