c-Jun Is Required for Nuclear Factor-κB-Dependent, LPS-Stimulated Fos-Related Antigen-1 Transcription in Alveolar Macrophages.
Previously, we have reported that Fos-related antigen-1 (Fra-1) transcription factor promotes LPS-induced acute lung injury and mortality, and that LPS-induced Fra-1 expression in the lung occurs predominantly in alveolar macrophages. Nuclear factor-κB (NF-κB) and c-Jun transcription factors play key roles in modulating inflammatory and immune responses induced by infectious and non-infectious insults. Here, we report that NF-κB and c-Jun coregulate Fra-1 induction by LPS in alveolar macrophages and that this regulation occurs through both the NF-κB and the extracellular signal-regulated protein kinase (ERK) signaling pathways. Transient transfections with Fra-1 promoter-reporter constructs and inhibitor studies revealed that the transcriptional activation of Fra-1 by LPS in alveolar macrophages is mediated by NF-κB and ERK1/2 signaling. Importantly, chromatin immunoprecipitation assays revealed the recruitment of c-Jun and NF-κB to the endogenous Fra-1 promoter after LPS stimulation. We found that inhibition of ERK1/2 signaling reduced LPS-stimulated c-Jun and NF-κB recruitment to the promoter. Likewise, NF-κB inhibitor blocked LPS-induced NF-κB and c-Jun binding to the promoter. ERK1/2 inhibition had no effect on c-Jun activation but suppressed LPS-stimulated NF-κB phosphorylation. Finally, functional assays showed reduced levels of LPS-stimulated NF-κB regulated proinflammatory IL-1β and macrophage inflammatory protein-1α expression and increased antiinflammatory IL-10 expression in lung alveolar macrophages of Fra-1-null mice in vivo. Thus, our studies indicate that NF-κB and c-Jun coregulate LPS-induced Fra-1 transcription and that Fra-1 selectively modulates LPS-stimulated inflammatory cytokine expression in lung alveolar macrophages during inflammatory lung injury.


Does the approach influence the success rate for ultrasound-guided rectus sheath blocks? An anatomical case series.
The anterior cutaneous branches of the thoracolumbar spinal nerves enter the rectus sheath at its lateral border and perforate the muscle after travelling a short distance in the ventral direction. In this anatomical case series, we show that dye injection at the medial margin did not lead to reliable impregnation of the target nerves. The local anesthetic should therefore be injected at the lateral edge of the rectus sheath. Preceding surgical procedures to the ventral abdominal wall may affect the craniocaudal spread of local anesthetic.


Mitochondrial transplantation ameliorates ischemia/reperfusion-induced kidney injury in rat.
No real therapeutic modality is currently available for Acute kidney injury (AKI) and if any, they are mainly supportive in nature. Therefore, developing a new therapeutic strategy is crucial. Mitochondrial dysfunction proved to be a key contributor to renal tubular cell death during AKI. Thus, replacement or augmentation of damaged mitochondria could be a proper target in AKI treatment. Here, in an animal model of AKI, we auto-transplanted normal mitochondria isolated from healthy muscle cells to injured kidney cells through injection to renal artery. The mitochondria transplantation prevented renal tubular cell death, restored renal function, ameliorated kidney damage, improved regenerative potential of renal tubules, and decreased ischemia/reperfusion-induced apoptosis. Although further studies including clinical trials are required in this regard, our findings suggest a novel therapeutic strategy for treatment of AKI. Improved quality of life of patients suffering from renal failure and decreased morbidity and mortality rates would be the potential advantages of this therapeutic strategy.


South African Breast Cancer and HIV Outcomes Study: Methods and Baseline Assessment.
In low- and middle-income, HIV-endemic regions of sub-Saharan Africa, morbidity and mortality from the common epithelial cancers of the developed world are rising. Even among HIV-infected individuals, access to antiretroviral therapy has enhanced life expectancy, shifting the distribution of cancer diagnoses toward non-AIDS-defining malignancies, including breast cancer. Building on our prior research, we recently initiated the South African Breast Cancer and HIV Outcomes study. We will recruit a cohort of 3,000 women newly diagnosed with breast cancer at hospitals in high (average, 20%) HIV prevalence areas, in Johannesburg, Durban, Pietermaritzburg, and Empangeni. At baseline, we will collect information on demographic, behavioral, clinical, and other factors related to access to health care. Every 3 months in year 1 and every 6 months thereafter, we will collect interview and chart data on treatment, symptoms, cancer progression, comorbidities, and other factors. We will compare survival rates of HIV-infected and uninfected women with newly diagnosed breast cancer and their likelihood of receiving suboptimal anticancer therapy. We will identify determinants of suboptimal therapy and context-specific modifiable factors that future interventions can target to improve outcomes. We will explore molecular mechanisms underlying potentially aggressive breast cancer in both HIV-infected and uninfected patients, as well as the roles of pathogens, states of immune activation, and inflammation in disease progression. Our goals are to contribute to development of evidence-based guidelines for the management of breast cancer in HIV-positive women and to improve outcomes for all patients with breast cancer in resource-constrained settings.


Thermodynamic properties of He-H2 fluid mixtures over a wide range of temperatures and pressures.
The effect of pressure P and temperature T on the properties of mixing of helium-hydrogen (He-H2 ) fluid mixture is studied based on statistical mechanical perturbation theory. The constituent species are considered to be interacting via a pair potential consisting of short range repulsion and a long range attraction which has been included through a double Yukawa (DY) potential. He and H2 are the lightest elements; therefore, the quantum effect is included via first-order quantum correction in the framework of Wigner-Kirkwood expansion. The dimerization of the H2 molecule is treated as a hard convex body fluid for which the equation of state (EOS) can be derived from hard sphere system based on scaled particle theory. An advanced and most recent EOS has been used for our investigation. The use of the DY potential, which can readily be simulated to empirical potentials, has enabled us to obtain analytical expressions for attractive and quantum energy contributions in terms of Laplace transforms. With a view to ensure internal consistency of the various thermodynamic functions to extract information on segregation and order in the mixture, different functions, such as compressibility factor, Gibbs free energy of mixing, entropy of mixing, and concentration fluctuations in the long wavelength limit, have been calculated as functions of composition of the mixture over an extended region of P and T. The results suggest that segregation, heterocoordination, or both may occur in the He-H2 mixture depending upon its composition, pressure, and temperature.


Dose-response effect of sublingual captopril in hypertensive crises.
Forty-one patients, presenting in the Emergency Service of the Hospital General y Clinico, Tenerife, with symptoms of hypertensive crisis and supine diastolic blood pressure (DBP) greater than 120 mm Hg, were studied. They received 12.5 mg of sublingual captopril and 30 minutes later, if diastolic blood pressure (DBP) was not 100 mm Hg or less, the same dose was repeated by the same route. Supine systolic blood pressure (SBP), DBP and heart rate (HR) were monitored at 0, 5, 10, 15, 30, 45, 60, and 120 minutes after each administration of captopril. In 27 patients (66%) had a satisfactory response (DBP less than or equal to 100 mm Hg), after a single dose, less than 30 minutes after administration, which persisted at 120 minutes. In 14, a second administration was necessary after 30 minutes, and a satisfactory response to the second dose, defined again as DBP reaching values of 100 mm Hg or less, was achieved in 12 of them (29% of the total group). In two patients (5% of total) no full response was obtained. The observed pattern of response suggests that a sublingual dose of 25 mg of captopril is the minimum effective dose, but it is also possible that administration of 12.5 mg of sublingual captopril at 10 to 15 minute intervals, perhaps up to a maximum dose of 37.5 mg, might be considered as an alternative treatment in hypertensive crises.


[Perspectives on veterinary public health, food security, and the "One Health" joint initiative].
Veterinarians play a key role in food security. The health of millions of people, stimulation of national economies, development of sustainable livestock production related to this food source, and the different agricultural production systems that compose value chains, and access to more profitable international markets all depend on their efficient and transparent work. Shifting nutritional patterns globally, along with expected population growth, and the increase in marketable food commodity routes and volumes, forecast that demand for animal source food will steadily intensify over the coming decades. To successfully address these challenges, the veterinary profession should establish more practical and up-to-date conceptual and methodological frameworks for academic and professional profiles, focusing the profession on the different public health subject areas, in undergraduate and graduate courses. Furthermore, interdisciplinary alliances should also be developed--such as the "One Health" approach proposed by the United Nations Food and Agriculture Organization (FAO), the World Organization for Animal Health (OIE), and the World Health Organization (WHO)--to establish frameworks for joint work and public policies more in line with the domestic conditions of Latin American countries, using a collaborative, sustainable, and comprehensive approach to animal health, food security, and public health policy.


Multi-drug resistant typhoid fever with diarrhea.
To provide information about the characteristics of diarrheal stool in multi-drug resistant typhoid fever and observe the clinical course after treatment with furazolidone or ciprofloxacin. Hospital based. Twenty one male children who were positive for multi-drug resistant S. typhi by blood and stool cultures, having diarrhea at the time of hospitalization comprised the subjects. Serum and stool electrolytes were estimated. Stool samples were also processed to detect established enteropathogens, leukocytes and red blood cells. Children were treated either with furazolidone or ciprofloxacin and evaluated till recovery. Mean (+/- SD) pre-admission duration of fever and diarrhea of these cases were 19.1 (+/- 5.6) and 15.8 (+/- 4.6) days, respectively. Stool character in 81% of the patients was watery with mean (+/- SD) volume of stool 51.4 (+/- 25.1) ml per kg body weight in the first 24 hours of observation. Leukocyte count varied between 20-49 per high power field in 66.7% stool samples. Occult blood was present in only 19% cases. Fecal red blood cells in high power field were detected in 52.4% cases. Mean fecal electrolytes (mmol/liter) were as follows: sodium-53.8, potassium-51.4, chloride-41.6 and total CO2-24.3. Most of the children (71.4%) had no dehydration and had normal serum electrolytes. The isolated strains of S. typhi were multi-drug resistant. These children were treated successfully either with furazolidone or ciprofloxacin. The stools of multi-drug resistant typhoid fever patients were watery with little blood. Their electrolyte contents were more similar to the diarrheal stool seen in shigellosis rather than cholera. Uncontrolled observations revealed that children recovered with furazolidone or ciprofloxacin therapy.


Effective combinatorial immunotherapy for penile squamous cell carcinoma.
Penile squamous cell carcinoma (PSCC) accounts for over 95% of penile malignancies and causes significant mortality and morbidity in developing countries. Molecular mechanisms and therapies of PSCC are understudied, owing to scarcity of laboratory models. Herein, we describe a genetically engineered mouse model of PSCC, by co-deletion of Smad4 and Apc in the androgen-responsive epithelium of the penis. Mouse PSCC fosters an immunosuppressive microenvironment with myeloid-derived suppressor cells (MDSCs) as a dominant population. Preclinical trials in the model demonstrate synergistic efficacy of immune checkpoint blockade with the MDSC-diminishing drugs cabozantinib or celecoxib. A critical clinical problem of PSCC is chemoresistance to cisplatin, which is induced by Pten deficiency on the backdrop of Smad4/Apc co-deletion. Drug screen studies informed by targeted proteomics identify a few potential therapeutic strategies for PSCC. Our studies have established what we believe to be essential resources for studying PSCC biology and developing therapeutic strategies.


Monoclonal antibodies specific to native murine T-cell receptor gamma delta: analysis of gamma delta T cells during thymic ontogeny and in peripheral lymphoid organs.
Three hamster monoclonal antibodies (mAbs), all recognizing different epitopes present on the native form of the murine T-cell antigen receptor (TCR) gamma delta subunits, have been generated. mAb 3A10 is specific to a pan-murine TCR gamma delta, recognizing a C delta constant region determinant. mAb 8D6 is specific to a subset of T cells expressing V gamma 4- and V delta 5-encoded gamma delta TCR, and mAb 5C10 is clonotypic. Using these and other mAbs directed against a variety of T-cell surface markers, we quantitated and characterized gamma delta T cells present in developing thymuses as well as in the conventional lymphatic organs by flow cytometry. These studies revealed that (i) many gamma delta thymocytes and peripheral T cells bear CD4 and/or CD8 molecules, (ii) T cells bearing both alpha beta and gamma delta TCRs are scarce, and (iii) thymocyte subsets bearing TCR gamma delta encoded by different combinations of V gamma and V delta gene segments appear in waves during ontogeny.


DEPTOR-mTOR Signaling Is Critical for Lipid Metabolism and Inflammation Homeostasis of Lymphocytes in Human PBMC Culture.
Abnormal immune response of the body against substances and tissues causes autoimmune diseases, such as polymyositis, dermatomyositis, and rheumatoid arthritis. Irregular lipid metabolism and inflammation may be a significant cause of autoimmune diseases. Although much progress has been made, mechanisms of initiation and proceeding of metabolic and inflammatory regulation in autoimmune disease have not been well-defined. And novel markers for the detection and therapy of autoimmune disease are urgent. mTOR signaling is a central regulator of extracellular metabolic and inflammatory processes, while DEP domain-containing mTOR-interacting protein (DEPTOR) is a natural inhibitor of mTOR. Here, we report that overexpression of DEPTOR reduces mTORC1 activity in lymphocytes of human peripheral blood mononuclear cells (PBMCs). Combination of DEPTOR overexpression and mTORC2/AKT inhibitors effectively inhibits lipogenesis and inflammation in lymphocytes of PBMC culture. Moreover, DEPTOR knockdown activates mTORC1 and increases lipogenesis and inflammations. Our findings provide a deep insight into the relationship between lipid metabolism and inflammations via DEPTOR-mTOR pathway and imply that DEPTOR-mTOR in lymphocytes of PBMC culture has the potential to be as biomarkers for the detection and therapies of autoimmune diseases.


Quantum Slow Relaxation and Metastability due to Dynamical Constraints.
One of the general mechanisms that give rise to the slow cooperative relaxation characteristic of classical glasses is the presence of kinetic constraints in the dynamics. Here we show that dynamical constraints can similarly lead to slow thermalization and metastability in translationally invariant quantum many-body systems. We illustrate this general idea by considering two simple models: (i) a one-dimensional quantum analogue to classical constrained lattice gases where excitation hopping is constrained by the state of neighboring sites, mimicking excluded-volume interactions of dense fluids; and (ii) fully packed quantum dimers on the square lattice. Both models have a Rokhsar-Kivelson (RK) point at which kinetic and potential energy constants are equal. To one side of the RK point, where kinetic energy dominates, thermalization is fast. To the other, where potential energy dominates, thermalization is slow, memory of initial conditions persists for long times, and separation of timescales leads to pronounced metastability before eventual thermalization. Furthermore, in analogy with what occurs in the relaxation of classical glasses, the slow-thermalization regime displays dynamical heterogeneity as manifested by spatially segregated growth of entanglement.


Psychosocial competence of unselected young adults with sex chromosome abnormalities.
Very little is known about the adult adaptation of individuals with sex chromosome abnormalities (SCA) except for a few reports based upon biased samples of clinically identified patients. This first report from the Denver SCA study on the adult psychosocial adaptation of 36 unselected propositi, identified at birth, shows a continuation of mild psychological and social problems. Psychiatric interviews and self-reported information revealed that adaptation is quite variable, with many of the nonmosaic propositi not faring as well as their siblings, but in a few instances exceeding the success of brothers and sisters. Within this group of SCA subjects a subset demonstrated more marked pathology and a tendency to over-rate their social adaptation relative to the psychiatric interviewer, suggesting that the exclusive use of self-report questionnaires may not provide accurate assessment of psychological characteristics in this and other special populations. The full adult SCA behavioral phenotype has not yet been established but is emerging through additional reports from this and other studies of unselected SCA adults.


Gut microbes participate in food preference alterations during obesity.
Hypothalamic regulations of food intake are altered during obesity. The dopaminergic mesocorticolimbic system, responsible for the hedonic response to food intake, is also affected. Gut microbes are other key players involved in obesity. Therefore, we investigated whether the gut microbiota plays a causal role in hedonic food intake alterations contributing to obesity. We transferred fecal material from lean or diet-induced obese mice into recipient mice and evaluated the hedonic food intake using a food preference test comparing the intake of control and palatable diets (HFHS, High-Fat High-Sucrose) in donor and recipient mice. Obese mice ate 58% less HFHS during the food preference test (p < 0.0001) than the lean donors, suggesting a dysregulation of the hedonic food intake during obesity. Strikingly, the reduction of the pleasure induced by eating during obesity was transferable through gut microbiota transplantation since obese gut microbiota recipient mice exhibited similar reduction in HFHS intake during the food preference test (40% reduction as compared to lean gut microbiota recipient mice, p < 0.01). This effect was associated with a consistent trend in modifications of dopaminergic markers expression in the striatum. We also pinpointed a highly positive correlation between HFHS intake and Parabacteroides (p < 0.0001), which could represent a potential actor involved in hedonic feeding probably through the gut-to-brain axis. We further demonstrated the key roles played by gut microbes in this paradigm since depletion of gut microbiota using broad-spectrum antibiotics also altered HFHS intake during food preference test in lean mice. In conclusion, we discovered that gut microbes regulate hedonic aspects of food intake. Our data demonstrate that gut microbiota modifications associated with obesity participate in dysregulations of the reward and hedonic components of the food intake. These data provide evidence that gut microbes could be an interesting therapeutic target to tackle hedonic disorders related to obesity.


Profile of alisporivir and its potential in the treatment of hepatitis C.
Two classes of hepatitis C antiviral agents currently exist, i.e., direct-acting antivirals and host-targeting antivirals. Direct-acting antivirals target viral proteins including NS3/NS4A protease, NS5B polymerase and NS5A protein, while host-targeting antivirals target various host proteins critical for replication of the hepatitis C virus (HCV). Alisporivir is the most advanced host-targeting antiviral in clinical development. Alisporivir blocks HCV replication by neutralizing the peptidyl-prolyl isomerase activity of the abundant host cytosolic protein, cyclophilin A. Due to its unique mechanism of antiviral action, alisporivir is pangenotypic, provides a high barrier for development of viral resistance, and does not permit cross-resistance to direct-acting antivirals. Alisporivir has an excellent pharmacokinetic and safety profile. Phase I and II clinical studies have demonstrated that alisporivir causes a dramatic reduction in viral loads in HCV-infected patients. Alisporivir was shown to be highly potent in treatment-naïve and treatment-experienced patients with genotype 1 as well as in those with genotypes 2 or 3. Low viral breakthrough rates were observed and the most frequent clinical and laboratory adverse events associated with alisporivir in combination with pegylated interferon-alpha and ribavirin were similar to those associated with pegylated interferon-alpha and ribavirin used alone. A laboratory abnormality observed in some patients receiving alisporivir is hyperbilirubinemia, which is related to transporter inhibition and not to liver toxicity. The most recent clinical results suggest that alisporivir plus other direct-acting antivirals should provide a successful treatment option for difficult-to-treat populations, such as nonresponders to prior interferon-alpha therapy and patients with cirrhosis. In conclusion, alisporivir represents an attractive candidate component of future interferon-free regimens.


Controlled and sustained release of pharmaceuticals via single step solvent-free encapsulation.
Herein, we report a novel and solvent-free technique for the encapsulation of pharmaceuticals that allows achieving controllable release rates. This method utilizes the deposition of a plasma polymer coating of controlled chemistry and thickness on the outer surface of drug particles placed under continuous agitation.


Nuclear quantum effects of light and heavy water studied by all-electron first principles path integral simulations.
The isotopologs of liquid water, H2O, D2O, and T2O, are studied systematically by first principles PIMD simulations, in which the whole entity of the electrons and nuclei are treated quantum mechanically. The simulation results are in reasonable agreement with available experimental data on isotope effects, in particular, on the peak shift in the radial distributions of H2O and D2O and the shift in the evaporation energies. It is found that, due to differences in nuclear quantum effects, the H atoms in the OH bonds more easily access the dissociative region up to the hydrogen bond center than the D (T) atoms in the OD (OT) bonds. The accuracy and limitation in the use of the current density-functional-theory-based first principles PIMD simulations are also discussed. It is argued that the inclusion of the dispersion correction or relevant improvements in the density functionals are required for the quantitative estimation of isotope effects.


Flux theory for Poisson distributed pores with Gaussian permeability.
The mean of the solute flux through membrane pores depends on the random distribution and permeability of the pores. Mathematical models including such randomness factors make it possible to obtain statistical parameters for pore characterization. Here, assuming that pores follow a Poisson distribution in the lipid phase and that their permeabilities follow a Gaussian distribution, a mathematical model for solute dynamics is obtained by applying a general result from a previous work regarding any number of different kinds of randomly distributed pores. The new proposed theory is studied using experimental parameters obtained elsewhere, and a method for finding the mean single pore flux rate from liposome flux assays is suggested. This method is useful for pores without requiring studies by patch-clamp in single cells or single-channel recordings. However, it does not apply in the case of ion-selective channels, in which a more complex flux law combining the concentration and electrical gradient is required.


Degradation of Polymer Films on Surfaces: A Model Study with Poly(sebacic anhydride).
There is compelling evidence that the degradation kinetics of thin polymer films differ significantly from those of bulk materials, as interfacial effects become dominant. Therefore, it is crucial to investigate these kinetics separately. Qualitative analytics of thin film degradation exist, e.g. by scanning electron microscopy or atomic force microscopy (AFM), but a quantitative study is so far missing. In this work, poly(sebacic anhydride) (PSA), an aliphatic polyanhydride, is used as a model system for a quantitative degradation study. PSA was spin-coated onto silicon or gold substrates. The degradation of these PSA films was monitored by ellipsometry, surface-plasmon resonance spectroscopy (SPR), and Fourier transform infrared spectroscopy (FTIR). Two kinetic regimes were observed when plotting the relative layer thickness determined by FTIR and SPR against the degradation time. The data obtained by FTIR showed a single process for the rate of ester bond cleavage. Overall, the degradation rate constants of PSA determined by the different methods were consistent. The degradation rate constants of PSA film up to 378 nm thickness were constant. Several thicker free-standing samples studied gravimetrically had a degradation rate constant that was one order of magnitude slower, thus confirming thickness-dependent degradation rate constants.


Implementing nursing clinical indicators.
Clinical indicators state desirable patient outcomes using evidence-based targets. Locally based indicators give professional staff ownership of the process of audit, and the programme can be adapted to the local circumstances.


Ascending projections from the caudal visceral nucleus of the solitary tract to brain regions involved in food intake and energy expenditure.
Metabolic homeostasis reflects the complex output of endocrine, autonomic, and behavioral control circuits that extend throughout the central nervous system. Brain regions that control food intake and energy expenditure are privy to continuous visceral sensory feedback signals that presumably modulate appetite, satiety, digestion, and metabolism. Sensory signals from the gastrointestinal tract and associated digestive viscera are delivered to the brain primarily by vagal afferents that terminate centrally within the caudal nucleus of the solitary tract (NST), with signals subsequently relayed to higher brain regions by parallel noradrenergic and peptidergic projection pathways arising within the NST. This article begins with an overview of these ascending pathways identified in adult rats using a standard anterograde tracer microinjected into the caudal visceral sensory region of the NST, and also by immunocytochemical localization of glucagon-like peptide-1. NST projection targets identified by these two approaches are compared to the distribution of neurons that become infected after inoculating the ventral stomach wall with a neurotropic virus that transneuronally infects synaptically-linked chains of neurons in the anterograde (i.e., ascending sensory) direction. Although the focus of this article is the anatomical organization of axonal projections from the caudal visceral NST to the hypothalamus and limbic forebrain, discussion is included regarding the hypothesized role of these projections in modulating behavioral arousal and coordinating endocrine and behavioral (i.e., hypophagic) responses to stress.


Optic neuritis following aseptic meningitis associated with modified measles: a case report.
In this study, we report the case of a 35-year-old woman with modified measles complicated by aseptic meningitis and subsequent optic neuritis. Although her initial manifestations were only flu-like symptoms without any Koplik's spots or skin rashes, virological testing confirmed an acute measles infection. Subsequently, right optic neuritis appeared after aseptic meningitis and was completely resolved following steroid pulse therapy. In general, modified measles is believed to be associated with mild symptoms and few neurological complications; however, our present observations demonstrated that modified measles can cause rapid neurological complications.


Determination of pantothenic acid in foods by optical biosensor immunoassay.
An optical biosensor inhibition immunoassay was developed using a specific pantothenic acid-binding protein for the quantitation of free pantothenic acid (vitamin B5) in foodstuffs. Samples were prepared by a simple extraction procedure in buffer, and vitamin content was estimated against authentic calibrants in the same buffer. Performance parameters included a working range of 10-5000 ng/mL, a limit of detection of 4.4 ng/mL, precision relative standard deviation of 5.4-7.1% over a range of concentrations, and recoveries > 95% in the matrixes tested. A wide range of foodstuffs, including National Institute of Standards and Technology reference samples, were tested in 3 independent laboratories and the results were compared with microbiological assay and liquid chromatography/mass spectrometry (LC/MS) methods. The results indicate that the biosensor technique is appropriate for the estimation of pantothenic acid in a wide range of foodstuffs.


Cardiac involvement in malignant syndrome in Parkinson's disease.
Little is known about cardiac abnormalities in neuroleptic malignant syndrome (NMS) in Parkinson's disease (PD), although high levels of serum creatine kinase (CK) suggest the presence of cardiac involvement. We have also been aware of elevated serum myosin light chain I (MLCI) in these patients with no clear evidence of an acute coronary syndrome. To evaluate cardiac involvement in NMS in PD, we recorded the electrocardiogram (ECG) and measured serum MLCI and CK-MB levels. Plasma levels of noradrenaline and adrenaline were also determined. The patients were classified based on the in-hospital outcome into 55 survivors and 5 nonsurvivors. Age- and gender-matched PD patients without NMS served as controls (n = 51). All patients had high serum concentrations of CK-MB and MLCI. The mean values of CK, CK-MB, MLCI, adrenaline and noradrenaline were higher in both patient groups as compared to control subjects, and the values in nonsurvivors were significantly higher than those in survivors. A positive correlation was observed between serum MLCI and CK levels (p < 0.01), and between serum MLCI levels and plasma noradrenaline concentrations (p < 0.01). ECG abnormalities such as prolonged QTc interval, abnormal Q wave, ST elevation and T wave inversion were observed in all nonsurvivors and 32 (58.2%) survivors. We conclude that myocardial involvement is common in patients with NMS even when they have no symptoms suggestive of myocardial injury, and MLCI and CK-MB as well as ECG are useful indicators of mortality.


Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: an emerging treatment option for advanced goblet cell tumors of the appendix.
The debate remains whether appendiceal goblet cell cancers behave as classical carcinoid or adenocarcinoma. Treatment options are unclear and reports of outcomes are scarce. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) is considered optimal treatment for peritoneal involvement of other epithelial appendiceal tumors. Prospective cohorts of patients treated for advanced appendiceal tumors from three peritoneal malignancy centres were collected (1994-2011). All patients underwent complete CRS+HIPEC, when possible, or tumor debulking. Demographic and outcome data for patients with goblet cell cancers were compared to patients with low- or high-grade epithelial appendiceal tumors treated during the same time period. Details on 45 goblet cell cancer patients were compared to 708 patients with epithelial appendix lesions. In the goblet cell group, 57.8 % were female, median age was 53 years, median peritoneal cancer index (PCI) was 24, and CRS+HIPEC was achieved in 71.1 %. These details were similar in patients with low- or high-grade epithelial tumors. Lymph nodes were involved in 52 % of goblet cell patients, similar to rates in high-grade cancers, but significantly higher than in low-grade lesions (6.4 %; p < 0.001). At 3 years, overall survival (OS) was 63.4 % for goblet cell patients, intermediate between that for high-grade (40.4-52.2 %) and low-grade (80.6 %) tumors. On multivariate analysis, tumor histology, PCI, and achievement of CRS+HIPEC were independently associated with OS. This data supports the concept that appendiceal goblet cell cancers behave more as high-grade adenocarcinomas than as low-grade lesions. These patients have reasonable long-term survival when treated using CRS+HIPEC, and this strategy should be considered.


A Mouse Model of Enterovirus D68 Infection for Assessment of the Efficacy of Inactivated Vaccine.
In recent years, enterovirus D68 (EVD68) has been reported increasingly to be associated with severe respiratory tract infections and acute flaccid myelitis (AFM) in children all over the world. Yet, no effective vaccines or antiviral drugs are currently available for EVD68. Although several experimental animal models have been developed, immunogenicity and protective efficacy of inactivated EVD68 vaccines has not been fully evaluated. To promote the development of vaccines, we established an Institute of Cancer Research (ICR) suckling mouse model of EVD68 infection in this study. The results showed that ICR neonatal mice up to about nine days of age were susceptible to infection with EVD68 clinical strain US/MO/14-18947 by intraperitoneal injection. The infected mice exhibited progressive limb paralysis prior to death and the mortality of mice was age- and virus dose-dependent. Tissue viral load analysis showed that limb muscle and spinal cord were the major sites of viral replication. Moreover, histopathologic examination revealed the severe necrosis of the limb and juxtaspinal muscles, suggesting that US/MO/14-18947 has a strong tropism toward muscle tissues. Additionally, β-propiolactone-inactivated EVD68 vaccine showed high purity and quality and induced robust EVD68-specific neutralizing antibody responses in adult mice. Importantly, results from both antisera transfer and maternal immunization experiments clearly showed that inactivated EVD68 vaccine was able to protect against lethal viral infection in the mouse model. In short, these results demonstrate the successful establishment of the mouse model of EVD68 infection for evaluating candidate vaccines against EVD68 and also provide important information for the development of inactivated virus-based EVD68 vaccines.


Left thoracoabdominal esophagogastrectomy: still a valid operation for carcinoma of the distal esophagus and esophagogastric junction.
The left thoraco-abdominal (LTA) esophago-gastrectomy is rarely performed and yet provides excellent exposure of the esophageal hiatus. The aim of this study was to review the outcome of LTA esophago-gastrectomy within a single unit. Patients were selected for an LTA esophago-gastrectomy (January 2000 - June 2003) based upon the presence of locally advanced tumors of the distal esophagus and cardia. These patients were identified from a prospective consultant database. LTA esophagogastrectomy was technically possible in all 38 patients (34 males; median age = 63 years). In-hospital mortality was 2.6% (1 patient). Four patients (10.5%) were admitted to the intensive care unit and three (7.9%) returned to theatre. Two patients developed clinically apparent anastomotic leaks (5.3%). A potentially curative resection was performed in 34 patients (89%) but 22 (57.8%) of these patients were subsequently found to have tumor cells at or within 2 mm from the circumferential resection margin. The 1-year and 2-year overall survival rates were 70% and 52%, respectively. Long-term complications included benign anastomotic stricture (24%), delayed gastric emptying (26%) and a persistent thoracic wound sinus (15%). LTA esophagogastrectomy remains a viable approach with an acceptably low incidence of short and long-term complications.


Mode of action of zorbamycin.
Zorbamycin (U-30,604E) induces rapid degradation of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) in Bacillus subtilis cells. DNA degradation is initiated first and is closely followed by the degradation of RNA. No interaction between isolated DNA and zorbamycin is observed. Nucleic acid and protein syntheses are not inhibited by zorbamycin in cell-free systems. Since the initial effect of the antibiotic is expressed at the level of the cellular DNA fraction, we assume that zorbamycin somehow induces a change in the structure or function of the cellular DNA fraction which results in rapid breakdown of this fraction.


Photophysical, photochemical, and tumor-selectivity properties of bromine derivatives of rhodamine-123.
The conceptual basis for the development of mitochondrial targeting as a novel therapeutic strategy for both chemotherapy and photochemotherapy of neoplastic diseases rests on the observation that enhanced mitochondrial membrane potential is a common tumor cell phenotype. The potential of this strategy is highlighted by the fact that the toxic effects associated with a number of cationic dyes known to localize in energized cell mitochondria are much more pronounced in tumor cells than in normal cells. Here we evaluate the phototoxic properties of four bromine derivatives of rhodamine-123 toward human uterine sarcoma (MES-SA) and green monkey kidney (CV-1) cells and compare the degrees of tumor cell selectivity associated with these dyes with those associated with two model mitochondrial triarylmethanes (crystal violet and ethyl violet). Selective phototoxicity toward tumor cells was found to be highly dependent upon the lipophilic/hydrophilic character of the cationic photosensitizer. Our experimental data have indicated that the probability of success of mitochondrial targeting in (photo)chemotherapy of neoplastic diseases is higher when the octan-1-ol/water partition coefficient of the drug candidate falls within approximately two orders of magnitude from that of the prototypical mitochondria-specific dye rhodamine-123.


Coordinated surgical and drug treatment of cancer.
Normal cells can proliferate to heal wounds while cancer cells die from chemotherapy with selected sulfhydryl (SH) inhibitors. Choice of the drugs is directed by sensitivity tests run immediately after surgery on each patient's own cancer. The SH-bearing nonhistone chromosomal proteins were predicted to play a major role in regulating genes. Much recent work now suggests that these proteins may play a key role in controlling gene expression.


Anesthesia for cesarean section in the dog and cat.
Anesthesia for cesarean section should ideally provide adequate muscle relaxation, analgesia, and narcosis or sedation for optimal operating conditions and safety to the dam. Since drugs that depress the dam must cross the blood-brain barrier, however, it is impossible to anesthetize the dam and not expose the fetuses to the anesthetic. No one agent or protocol is ideal for all dams, and satisfactory anesthesia for cesarean section can be induced in a number of ways. Cesarean section can be performed with either regional or general anesthesia.


A critical role for the autophagy gene Atg5 in T cell survival and proliferation.
Macroautophagy (hereafter referred to as autophagy) is a well-conserved intracellular degradation process. Recent studies examining cells lacking the autophagy genes Atg5 and Atg7 have demonstrated that autophagy plays essential roles in cell survival during starvation, in innate cell clearance of microbial pathogens, and in neural cell maintenance. However, the role of autophagy in T lymphocyte development and survival is not known. Here, we demonstrate that autophagosomes form in primary mouse T lymphocytes. By generating Atg5-/- chimeric mice, we found that Atg5-deficient T lymphocytes underwent full maturation. However, the numbers of total thymocytes and peripheral T and B lymphocytes were reduced in Atg5 chimeras. In the periphery, Atg5-/- CD8+ T lymphocytes displayed dramatically increased cell death. Furthermore, Atg5-/- CD4+ and CD8+ T cells failed to undergo efficient proliferation after TCR stimulation. These results demonstrate a critical role for Atg5 in multiple aspects of lymphocyte development and function and suggest that autophagy may be essential for both T lymphocyte survival and proliferation.


[Pulmonary mycobacteriosis--the diagnostic challenge. The authors' experience].
The diagnosis of NTM-related pulmonary disease is based on clinical symptoms, radiological features and several positive cultures of one and the same NTM species from samples obtained from the respiratory tract. Short hospitalization usually does not enable sufficient diagnostic procedures to meet the diagnostic criteria, and this may lead to the reduction of diagnostic sensitivity. The aim of the study was to draw attention to NTM-related pulmonary disease, to share the authors' experience in the diagnosing of pulmonary mycobacteriosis and to indicate the possibilities of improving the diagnostic accuracy in this disease. A group of 31 patients with sputum, bronchial washing and/or bronchoalveolar lavage fluid (BALF) NTM-positive cultures was selected from a cohort of 245 patients evaluated for tuberculous and nontuberculous mycobacterial diseases (total number of 1277 specimens were invastigated). In two of them NTM related pulmonary disease was diagnosed (caused by M. kansasii and M. avium) at the course of initial evaluation. In the remaining 29 patients the microbiological data did not allow to establish the diagnosis of mycobacterial lung disease mainly due to a small number of samples from the respiratory tract. From this group 13 patients were reevaluated within 3 - 6 months from the initial investigation. This allowed to identify two new cases of mycobacteriosis (M. kansasii and M. avium). Thus among 31 patients with NTM positive cultures from respiratory tract specimens 4 patients (4/31, 12,9%) met the diagnostic criteria for mycobacterial disaease. Microbiological analysis of an adequate number of samples in symptomatic patients with radiological features suggestive for NTM-related pulmonary disease increses the diagnostic sensitivity in pulmonary mycobacteriosis. Identification of the species in positive cultures is of great importance.


Synthesis of organic-inorganic hybrid sols with nano silica particles and organoalkoxysilanes for transparent and high-thermal-resistance coating films using sol-gel reaction.
Organic-inorganic hybrid sols were synthesized from nano silica particles dispersed in water and from organoalkoxysilanes, using the sol-gel reaction. This work focuses on the effects of the three multifunctional organoalkoxysilanes dimethyldimethoxysilane (DMDMS), methyltrimethoxysilane (MTMS), and tetramethoxysilane (TMOS) to form a transparent and high-thermal-resistance coating film. The stability of the hybrid sol was evaluated as a function of the reaction time for 10 d through the variation of the viscosity. The viscosity of the silica/DMDMS and silica/MTMS sol was slightly increased for 10 d. The multifunctional organoalkoxysilanes formed dense silica networks through hydrolysis and condensation reaction, which enhanced the thermal resistance of the coating films. No thermal degradation of the silica/DMDMS sample occurred up to 600 degrees C, and none of the silica/MTMS and silica/TMOS samples occurred either up to 700 degrees C. The organic-inorganic hybrid sols were coated on the glass substrate using a spin-coating procedure. The organic-inorganic hybrid sols formed flat coating films without cracks. The transmittance of the hybrid sol coating films using MTMS and DMDMS was shown to be over 90%. The transmittance of the silica/TMOS sol coating film reacted for 10 d abruptly decreased due to faster gelation. The silica/DMDMS and silica/MTMS hybrid sols formed smooth coating films while the surface roughness of the silica/TMOS coating film markedly increased when the hybrid sol reacted for 10 d. The increase of the surface roughness of the silica/TMOS coating film can be attributed to the degradation of the stability of the hybrid sol and to the loss of transmittance of the coating film. It was confirmed in this study that the use of organic-inorganic hybrid sol can yield transparent and high-thermal-resistance coating films.


Lingual nerve deficit following mandibular third molar removal: review of the literature and medicolegal considerations.
The removal of mandibular third molars is probably the most frequently performed procedure in oral and maxillofacial surgery, and it is the most common surgical procedure associated with lingual nerve deficit. Lingual sensory impairment remains a clinical problem in oral and maxillofacial surgery and has serious medical and legal implications. In fact, damage to the lingual nerve is a common cause of litigation in dentistry. The purpose of this article was to review the literature about lingual nerve deficit following mandibular third molar removal and discuss the associated medicolegal aspects.


Fractures of the capitellum in adolescents.
Fractures of the capitellum are rare in children. The treatment of these injuries has been controversial. At a major pediatric trauma center, seven capitellar fractures were seen in children between 1988 and 1994. The average age of the children was 14.7 years (range, 11-17). Six of these fractures were type I injuries, with large anterosuperior fragments that required operative reduction and internal fixation in five cases. Internal fixation methods used were K wires in three patients, Herbert screws in one patient, and cannulated screws in one patient. The remaining type I fracture was treated with a closed reduction. The seventh fracture was a type II fracture, treated nonoperatively. Five children did well with their respective treatments, but one required reoperation to remove an exostosis block to flexion. Accurate open reduction and internal fixation for the displaced capitellar fracture in children is an effective treatment to restore normal elbow function.


Flexible calibration method for microscopic structured light system using telecentric lens.
This research presents a novel method to calibrate a microscopic structured light system using a camera with a telecentric lens. The pin-hole projector calibration follows the standard pin-hole camera calibration procedures. With the calibrated projector, the 3D coordinates of those feature points used for projector calibration are then estimated through iterative Levenberg-Marquardt optimization. Those 3D feature points are further used to calibrate the camera with a telecentric lens. We will describe the mathematical model of a telecentric lens, and demonstrate that the proposed calibration framework can achieve very high accuracy: approximately 10 μm with a volume of approximately 10(H) mm × 8(W) mm × 5(D) mm.


Activity-Induced Pain as a Predictor of Sedentary Behavior Among Midlife Adults.
Purpose: Midlife adults have been estimated to spend over half of their waking time engaging in sedentary behavior, and greater sedentary behavior has been associated with a reduced likelihood of successful aging. Moreover, more than one-quarter of midlife adults report chronic pain, and there is reason to believe that pain may contribute to sedentary behavior among this population. The goal of these analyses was to test associations between self-reported increases in pain during activity and subsequent sedentary behavior among a sample of midlife adults with chronic pain. Methods: Participants included 200 midlife adults (age 50-64) who reported chronic pain and completed an online prospective survey. Activity-induced pain was assessed at baseline and total time spent engaging in sedentary behavior was assessed at baseline, 1-week, and 4-week follow-up assessments. Results: Activity-induced pain predicted greater sedentary behavior at 1-week (p < .05) and 4-week (p < .01) follow-up assessments, even after controlling for chronic pain intensity and baseline sedentary behavior. Conclusions: Activity-induced pain may represent an important mechanism underlying sedentary behavior among midlife adults with chronic pain, and programs designed to reduce sedentary behavior among this population may benefit from tailoring to account for the antithetical influence of activity-induced pain. Indeed, the current findings suggest that mitigating the extent to which pain increases during activity may be more important than reducing overall pain intensity when attempting to decrease sedentary behavior among this population. This and future work have the potential to inform the refinement of tailored interventions.


Microbial control of the production of hydrogen sulfide by sulfate-reducing bacteria.
A sulfide-resistant ctrain of Thiobacillus denitrificans, strain F, prevented the accumulation of sulfide by Desulfovibrio desulfuricans when both organisms were grown in liquid medium or in Berea sandstone cores. The wild-type strain of T. denitrificans did not prevent the accumulation of sulfide produced by D. desulfuricans. Strain F also prevented the accumulation of sulfide by a mixed population of sulfate-reducing bacteria enriched from an oil field brine. Fermentation balances showed that strain F stoichiometrically oxidized the sulfide produced by D. desulfuricans and the oil field brine enrichment to sulfate. These data suggest that strain F would be effective in controlling sulfide production in oil reservoirs and other environments.


Synthesis, hydrolysis kinetics and pharmacological evaluation of aceclofenac prodrugs.
The mutual prodrugs of aceclofenac with various naturally available antioxidants; menthol, thymol, eugenol, guiacol and vanillin have been synthesized by the DCC coupling method, purified and characterized by spectral data, as well as, partition coefficient, solubility and hydrolytic studies. The title compounds have more lipophilic character as compared to the parent moieties and good stability in acidic environment, which is prerequisite for the oral absorption of the drug. Under gastric as well as intestinal pH conditions these prodrugs showed variable susceptibility towards hydrolysis. The synthesized derivatives were evaluated for antiinflammatory, analgesic activities and ulcerogenic potential. Prodrug showed improved solubility in organic solvents, which implies lipophilic character of ester prodrugs and were also found to be chemically stable in acidic environment. The aceclofenac mutual prodrugs showed improved analgesic and anti-inflammatory activities with reduced ulcerogenicity.


Tolerance, hospital stay, and recovery after uterine artery embolization for fibroids: the Ontario Uterine Fibroid Embolization Trial.
Uterine artery embolization (UAE) is gaining popularity as an alternative to hysterectomy for the treatment of fibroids. Although minimally invasive treatments such as UAE offer the potential of fewer complications, shorter hospital stay, and quicker recovery than surgery, there have been few published data on tolerance and recovery in patients undergoing UAE. This was a multicenter prospective single-arm clinical treatment trial involving the practices of 11 interventional radiologists in eight Ontario university-affiliated and community hospitals. Between November 1998 and November 2000, 555 women underwent UAE for symptomatic uterine fibroids. Follow-up included ultrasound examinations and telephone interviews. UAE was performed under conscious sedation. Polyvinyl alcohol particles (355-500 micro m) were the primary embolic agent, and the procedural endpoint involved stasis in the uterine arteries. Pain protocols included antiinflammatory medications and narcotics and a planned overnight hospital admission. Tolerance and recovery were measured by patient-reported pain intensity (10-point numeric rating and five-point descriptor scale), hospital length of stay (LOS), and time until return to work. Intraprocedural pain was reported by 30% of patients and postprocedural pain was reported by 92% of patients (mean pain rating +/- SD, 7.0 +/- 2.47). The mean hospital LOS was 1.3 nights. Postprocedural pain was the most common indication for an LOS greater than 1 night (18%) or 2 nights (5%). Return visits to the hospital (10%) and readmissions (3%) were primarily for pain. The overall postprocedural complication rate was 8.0% (95% CI: 5.9%-10.6%). Of the 44 complications, 32 (73%) were pain-related. The mean recovery time after UAE was 13.1 days (median, 10.0 d). The majority of patients had a 1-night LOS after UAE and recovered within 2 weeks. Postprocedural pain varied considerably and was the major indication for extended hospital stay and recovery.


Iterative chromosome mutation and selection as a mechanism of complete transformation of human diploid fibroblasts by SV40 T antigen.
The acquisition of an extended lifespan and of neoplastic properties, including anchorage independence, ability to grow in low serum-containing media, morphological transformation, immortalization and tumorigenicity in nude mice were studied in 31 human fibroblast lineages transfected with plasmids containing the SV40 early genes. Plasmids were used that contained sequences for large T alone, or large T plus small t or large T plus small t plus the SV40 origin. Cells expressing large T antigen gradually acquired the ability to form colonies in low serum or to form anchorage-independent colonies. Large T antigen was sufficient to cause complete transformation to tumorigenicity if multi-step lineage evolution was obtained by prolonged serial passage and if in vivo progression was assisted by means of a gelatin sponge implantation technique. Cells derived from progressive tumors initiated in sponges showed enhanced tumorigenicity as measured by ability to obtain tumors without using sponges and with reduced latent period, higher incidence and with fewer cells inoculated. Multiple lineages of human fibroblasts have been converted to tumorigenicity without additional treatments such as transfection with activated oncogenes or exposure to carcinogens. These data, taken in conjunction with earlier studies showing that T antigen causes chromosome mutation preceding and accompanying the accumulation of the neoplastic phenotype, suggests that the T protein drives the transformation process by acting as a mutagen and cells with growth advantages were selected for in vitro and in vivo. With the possible exception of morphological transformation, the presence or absence of genes for small t and the SV40 origin were not critical for the process.


Increased phencyclidine-induced hyperactivity following cortical cholinergic denervation.
Altered cholinergic function is considered as a potential contributing factor in the pathogenesis of schizophrenia. We hypothesize that cortical cholinergic denervation may result in changes in glutamatergic activity. Therefore, we lesioned the cholinergic corticopetal projections by local infusion of 192 IgG-saporin into the nucleus basalis magnocellularis of rats. Possible effects of this lesion on glutamatergic systems were examined by phencyclidine-induced locomotor activity, and also by N-methyl-D-aspartate receptor binding. We find that cholinergic lesioning of neocortex leads to enhanced sensitivity to phencyclidine in the form of a dramatic increase in horizontal activity. Further, N-methyl-D-aspartate receptor binding is unaffected in denervated rats. These results suggest that aberrations in cholinergic function might lead to glutamatergic dysfunctions, which might be of relevance for the pathophysiology for schizophrenia.


Comparison of the effects of desflurane and total intravenous anesthesia on the optic nerve sheath diameter in robot assisted laparoscopic radical prostatectomy: A randomized controlled trial.
Optic nerve sheath diameter (ONSD) is a well-known surrogate marker for intracranial pressure during robot-assisted laparoscopic radical prostatectomies (RALP). ONSD during RALP is known to increase due to elevated intracranial pressure as a result of the steep Trendelenburg position and carbon dioxide pneumoperitoneum. We aimed to compare the effects of total intravenous anesthesia (TIVA) and desflurane anesthesia (DES) on ONSD during RALP. Patients scheduled for RALP were enrolled and randomly assigned to the TIVA (propofol and remifentanil) or DES (desflurane and remifentanil) group in this randomized trial. Ultrasonographic measurements of ONSD were conducted before administration of anesthesia (T0), 10 minutes after the Trendelenburg position (T1), 1 hour after the Trendelenburg position (T2), 2 hours after the Trendelenburg position (T3), 10 minutes after resuming the supine position (T4), and at the time of arrival in the post-anaesthetic care unit (T5). The primary outcome measure was the mean ONSD at T2 of the TIVA and DES group during RALP. A total of 56 patients were analysed in this study. The mean ONSD at T1, T2, T3, and T4 were significantly lower for patients in the TIVA group compared with those in the DES group (P = .023, .000, .000, and .003, respectively). The mean ONSD for patients in the TIVA group was significantly lower than that in the DES group during the RALP procedure. Our findings suggest that TIVA may be a more suitable anesthetic option for patients at risk of cerebral hypoperfusion.


Predictors of cognitive change from preclinical to clinical Alzheimer's disease.
We examined individual-difference variables in relation to the rate of change in global cognitive performance, measured by the MMSE, from 3 years prior to diagnosis of Alzheimer's disease (AD) to the time of diagnosis. The population-based sample consisted of 230 incident AD persons who were followed over a 3-year interval. The average annual decline in MMSE was 1.81 points. Being older and acquiring additional diseases during the 3 years preceding diagnosis predicted a faster rate of decline in global cognitive functioning. However, other individual difference variables such as sex, education, depression, vitamin levels (vitamin B12 and folic acid), apolipoprotein status, and social network did not precipitate the rate of decline in the preclinical phase of AD.


Review of antidiabetic fruits, vegetables, beverages, oils and spices commonly consumed in the diet.
Type 2 diabetes is the most common type of diabetes and its prevalence is rapidly increasing throughout the world. Modifications of lifestyle such as suitable diet and exercise programs along with pharmacotherapy and education of patients are beneficial therapies for patients with type 2 diabetes. The ethnopharmacological use of herbal medicines, many of them part of our diet as spices, vegetables and fruits, has been developed for the treatment of diabetes due to inexpensiveness, easy availability and few side effects. Our aim is to present a review for researchers who are interested in the biologically active dietary plants traditionally utilized in the treatment of diabetes. Information was obtained from a literature search of electronic databases such as Google Scholar, Pubmed, Sci Finder and Cochrane. Common and scientific name of the fruits, vegetables, beverages, oils and spices and the words 'antidiabetic', 'hypoglycemic', 'anti-hyperglycemic', 'type 2 diabetes' were used as keywords for search. Certain fruits and vegetables are functional foods and their consumption reduces the incidence of type 2 diabetes. Hypoglycemic effects of fruits and vegetables may be due to their inducing nature on pancreatic β-cells for insulin secretion, or bioactive compounds such as flavonoids, alkaloids and anthocyanins, which act as insulin-like molecules or insulin secretagogues. This write-up covers hypoglycemic, anti-hyperglycemic and anti-diabetic activities of some dietary fruits, vegetables, beverages, oils and spices and their active hypoglycemic constituents. Including such plant species in the diet might improve management of type 2 diabetes.


Tren centered tris-macrocycles as polytopic ligands for Cu(II) and Ni(II).
Two novel symmetric polytopic ligands L(1) and L(2) have been synthesized. They are composed of three 1,4,8,11-tetraazacyclotetradecane macrocycles which are connected to a central tren moiety via an ethylene and a trimethylene bridge, respectively. The complexation potential and the speciation diagrams of L(1) and L(2) towards Cu(2+) and Ni(2+) were determined by spectrophotometric and potentiometric titrations. Insight into the geometry of the Cu(2+) complexes is provided by UV-VIS and EPR spectroscopy. The simplified ligands L(3) and L(4) are utilized as references for an aminoethyl- and a tren-substituted tetraaza macrocycle to help assign the EPR spectra of the polytopic ligands L(1) and L(2). At a metal-to-ligand ratio of 3 : 1, the metal cations are preferentially bound to the tetraaza macrocycles of L(1) and L(2) in a square planar geometry. At high pH values, a nitrogen atom of the tren moiety in L(1) serves as an additional ligand in an axial position leading to a square pyramidal coordination around Cu(2+), whereas in L(2) no such geometry change is observed. At a metal-to-ligand ratio of 4 : 1, the additional metal cation resides in the central tren moiety of L(1) and L(2). However, in contrast to the typical trigonal bipyramidal geometry found in the [Cutren](2+) complex, the fourth Cu(2+) has a square pyramidal coordination caused by the interaction with the Cu(2+) cations in the macrocycles (as evidenced by EPR spectra). Since the sequence of metal complexation is such that the first three metal ions always bind to the three macrocycles of L(1) and L(2) and the fourth to the tren unit, it is possible to prepare heteronuclear complexes such as [Cu(3)NiL](8+) or [Ni(3)CuL](8+), which can be unambiguously identified by their spectral properties.


Complete genome sequencing and comparative genome analysis of the extremely halophilic archaea, Haloterrigena daqingensis.
In the present study, we report the complete genome sequencing of Haloterrigena daqingensis species. The genome of H. daqingensis JX313T consisted of a circular chromosome with three plasmids. The genome size and G+C content were estimated to be 3835796 bp and 61.7%, respectively. A total of 4158 genes were predicted with six rRNAs and 45 tRNAs. Metabolic pathway analysis suggests that H. daqingensis JX313T codes for all the necessary genes responsible to sustain its life at saline environment. The pan-genome analysis suggests that the number of singleton-gene between H. daqingensis and other Haloterrigena species varied. The study not only helps us understand H. daqingensis strategy for dealing with high stress, but it also provides an overview of its genomic makeup.


Comparison of the effects of 3-isobutyl-1-methylxanthine and adenosine cyclic 3':5'-monophosphate on the induction of skin tumors by the initiation-promotion protocol and by the complete carcinogenesis process.
Topical application of either 5 mumols of 3-isobutyl-1-methylxanthine (IBMX) or 0.25 mumol of adenosine cyclic 3':5'-monophosphate (cyclic AMP) to the initiated skin of the mouse prior to each promotion with 8.5 nmols of 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibited the formation of papillomas and carcinomas. Combined treatments including IBMX and cyclic AMP caused additive reduction of the incidence of skin papillomas and carcinomas promoted by TPA. A good correlation was observed between the reduction of the tumor incidence by IBMX and cyclic AMP and their inhibition of TPA-stimulated polyamine, RNA, protein and DNA synthesis. Since repeated treatments with these agents before or after initiation with a single subcarcinogenic dose of 7,12-dimethylbenz[a]anthracene (DMBA) did not alter significantly the development of skin tumors (Curtis et al.; Perchellet and Boutwell), the present results suggest that, in the two-step initiation-promotion protocol, both IBMX and cyclic AMP treatments may decrease specifically the promoting stimulus of skin carcinogenesis. The same doses of IBMX and cyclic AMP inhibited the accumulation of polyamines and the increase in macromolecular synthesis observed in DMBA-treated skin, but their effect on DMBA-induced skin carcinogenesis was dependent upon the protocol used and the dose of carcinogen applied. IBMX and cyclic AMP treatments failed to inhibit the induction of skin tumors by weekly applications of 0.2 mumol of DMBA. In contrast to the inhibitory effect of cyclic AMP treatment, IBMX enhanced the carcinogenic response to a single topical application of 3.6 mumols of DMBA. The opposite effects of these agents on the carcinogenicity of DMBA correlated well with their different alteration of DMBA-induced unscheduled DNA synthesis in vitro. Cyclic AMP (0.5 mM) enhanced, whereas IBMX (0.5 mM) inhibited, the DMBA-induced incorporation of labeled precursor into DNA of isolated epidermal cells during incubation in the presence of hydroxyurea. Therefore, it is suggested that the different modulation of DMBA carcinogenesis by IBMX and cyclic AMP may result from concomitant effects on both the initiating and promoting components of the carcinogen.


Hypertension and NAFLD risk: Insights from the NHANES 2017-2018 and Mendelian randomization analyses.
Hypertension and non-alcoholic fatty liver disease (NAFLD) share several pathophysiologic risk factors, and the exact relationship between the two remains unclear. Our study aims to provide evidence concerning the relationship between hypertension and NAFLD by analyzing data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 and Mendelian randomization (MR) analyses. Weighted multivariable-adjusted logistic regression was applied to assess the relationship between hypertension and NAFLD risk by using data from the NHANES 2017-2018. Subsequently, a two-sample MR study was performed using the genome-wide association study (GWAS) summary statistics to identify the causal association between hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), and NAFLD. The primary inverse variance weighted (IVW) and other supplementary MR approaches were conducted to verify the causal association between hypertension and NAFLD. Sensitivity analyses were adopted to confirm the robustness of the results. A total of 3144 participants were enrolled for our observational study in NHANES. Weighted multivariable-adjusted logistic regression analysis suggested that hypertension was positively related to NAFLD risk odds ratio (OR) = 1.677; (95% confidence interval [CI], 1.159-2.423). SBP ≥130 mmHg and DBP ≥80 mmHg were also significantly positively correlated with NAFLD. Moreover, hypertension was independently connected with liver steatosis (β = 7.836 [95% CI, 2.334-13.338]). The results of MR analysis also supported a causal association between hypertension (OR = 7.203 [95% CI, 2.297-22.587]) and NAFLD. Similar results were observed for the causal exploration between SBP (OR = 1.024 [95% CI, 1.003-1.046]), DBP (OR = 1.047 [95% CI, 1.005-1.090]), and NAFLD. The sensitive analysis further confirmed the robustness and reliability of these findings (all P >0.05). Hypertension was associated with an increased risk of NAFLD.


Cranial MRI in Behçet's disease: 134 examinations of 98 patients.
Two observers, blinded to the patient's neurological status, reviewed 134 MRI studies of 98 consecutive patients with Behçet's disease (BD), to define imaging patterns and to look for any relationship between the MRI findings and the timing of the examination in patients with differing courses of disease. There were 43 patients with overt parenchymal central nervous system (CNS) involvement, 22 with attacks and remissions, 15 with secondary progressive and six with primary progressive disease; 14 had raised intracranial pressure (RICP). Of the remaining 41 patients without specific neurological complaints, 16 had abnormalities on examination (silent CNS involvement) and 25 did not. During an acute CNS attack, the most common finding was a large lesion in the brain-stem or basal ganglia, extending to the diencephalon. On MRI performed after remission of an acute attack or during secondary progression, the same sites were affected, but the lesions were smaller or scattered, with less clearly defined margins. In primary progressive disease or silent CNS involvement, the cerebral white matter was most commonly involved, but almost half the MRI studies were normal. The brain parenchyma was abnormal in only one of the patients with RICP. MRI was normal in all but three patients without clinical CNS involvement, in whom it showed a few millimetric white-matter lesions. Brain-stem atrophy was seen in 15 patients examined >1 year after an initial parenchymal CNS episode, with secondary progressive cases predominating.


Photodegradation kinetics of p-tert-octylphenol, 4-tert-octylphenoxy-acetic acid and ibuprofen under simulated solar conditions in surface water.
Direct and indirect (sensitized) photolysis of p-tert-octylphenol (OP), 4-octylphenoxy-acetic acid (OP1EC), and ibuprofen (IBU) were investigated in laboratory water and surface water under simulated and natural sunlight conditions. Photodegradation obeyed apparent-first order kinetics with rates increasing in the presence of NO₂⁻, NO₃⁻, and humic acid (HAC). The bimolecular rate constants, k″, were determined for the reactions of OP and OP1EC with hydroxyl radical (·OH) using photolyzed hydrogen peroxide (H₂O₂) as the hydroxyl radical (·OH) and IBU as the reference compound. The k″ values for OP and OP1EC were (average and standard deviation) (10.9 ± 0.5) × 10⁹ M⁻¹ s⁻¹ and (8.6 ± 0.5) × 10⁹ M⁻¹ s⁻¹, respectively. Direct photolysis of OP is small with a quantum yield of 0.015 in the range of 285-295 nm. Based on laboratory and average solar intensity data, the estimated half-life of OP in different Singapore surface waters was estimated to range from 0.6 to 2.5d. The steady state hydroxyl radical concentration ([·OH](ss)) was estimated using a kinetic model that considered dissolved organic carbon compounds (DOC), nitrate, and nitrite as ·OH sources, and DOC, CO₃²⁻ and HCO₃⁻ as scavengers. In surface waters containing DOC 2.3-6.5 mg L⁻¹, nitrate 0-3.2 mg L⁻¹, and nitrite 0-2.5 mg L⁻¹, the calculated [·OH](ss) ranged from 5.2 × 10⁻¹⁵ to 9.6 × 10⁻¹⁵ M. Half-lives calculations based on this model underestimated the measured half-life by a factor of approximately 4.2 to 1.1. DOC was predicted to be the most important sensitizer except in a sample that contained relatively high nitrate and nitrite. In the presence of NO₃⁻, photoreactions produced nitrated OP and IBU. A mechanism for OP photolysis in the presence of nitrate is proposed.


Hematologic effects of recombinant murine granulocyte-macrophage colony-stimulating factor on the peripheral blood and bone marrow.
Recombinant murine granulocyte-macrophage colony-stimulating factor (GM-CSF) was noted to support rat bone marrow colony formation in vitro. The in vivo hematologic effects of a single intravenous injection of murine GM-CSF were therefore investigated. Doses of murine GM-CSF between 0.1 and 5 micrograms/rat caused an increasing leukocytosis that did not further increase with a dose of 25 micrograms/rat. In contrast, human GM-CSF at 25 micrograms/rat did not induce any significant peripheral hematologic effects. Murine GM-CSF induced peripheral neutrophilia and monocytosis, peaking between 4 and 8 hours and subsiding to baseline by 12 hours. Neutropenia and monocytopenia, which reached a nadir at 15 minutes, preceded the leukocytosis, suggesting that GM-CSF activates these leukocytes and causes transient intravascular margination. A mild lymphopenia occurred between 2 to 8 hours. The bone marrow at 6 hours after injection of GM-CSF demonstrated a variable and slight left-shifted myeloid hyperplasia most noticeable at the level of promyelocytes and myelocytes, suggesting a myeloproliferative effect. The marrow at 6 hours also demonstrated a decrease in mature neutrophils, documenting that the marrow contributes to the increased number of circulating neutrophils. Once-daily injection of GM-CSF for 7 days induced a repetitive daily neutrophilia of the same magnitude. The marrow after 1 week of injections did not show a generalized myeloid hyperplasia, but did show an increase in eosinophils and a decrease in lymphocytes. Granulocyte-macrophage colony-stimulating factor plus granulocyte colony-stimulating factor (G-CSF) have been reported to synergize in vitro in both mouse and human bone marrow colony assays. However GM-CSF plus G-CSF in vivo, administered as either a single injection or as daily injections for 1 week, were found in the present study to induce, at most, an additive effect on circulating numbers of neutrophils. It is concluded that murine GM-CSF will be useful in the rat model to study the in vivo hematoreconstitutive effects of GM-CSF alone and in combination with other hematologic growth factors. The relatively rapid kinetics and lesser magnitude of GM-CSF-induced neutrophilia and monocytosis, as compared to G-CSF and M-CSF, respectively, and the lesser myeloproliferative effect of GM-CSF in bone marrow smears, as compared to G-CSF, might be taken to suggest that GM-CSF's natural activity is predominantly as an inflammatory rather than a myeloproliferative factor.


The RXR agonist bexarotene improves cholesterol homeostasis and inhibits atherosclerosis progression in a mouse model of mixed dyslipidemia.
The activity of the antitumoral agent bexarotene (Targretin, Bexarotene) depends on its binding to the nuclear retinoid-X receptor (RXR) and subsequent transcriptional regulation of target genes. Through RXR activation, bexarotene may modulate numerous metabolic pathways involved in atherosclerosis. Here, we investigated the effect of bexarotene on atherosclerosis progression in a dyslipidemic murine model, the human apolipoprotein E2 knockin mouse, that develops essentially macrophage-laden lesions. Atherosclerotic lesions together with different metabolic pathways involved in atherosclerosis were investigated in mice treated or not with bexarotene. Bexarotene protects from atherosclerosis development in mice, at least in part by improving the circulating cholesterol distribution profile likely via a marked decrease of dietary cholesterol absorption caused by modulation of intestinal expression of genes recently identified as major players in this process, Niemann-Pick-C1-Like1 (NPC1L1) and CD13. This atheroprotection appears despite a strong hypertriglyceridemia. Moreover, bexarotene treatment only modestly modulates inflammatory gene expression in the vascular wall, but markedly enhanced the capacity of macrophages to efflux cellular lipids. These data provide evidence of a favorable pharmacological effect of bexarotene on atherosclerosis despite the induction of hypertriglyceridemia, likely via a beneficial action on intestinal absorption and macrophage efflux.


Immunoinformatics approach for multi-epitope vaccine design against structural proteins and ORF1a polyprotein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
The lack of effective treatment against the highly infectious SARS-CoV-2 has aggravated the already catastrophic global health issue. Here, in an attempt to design an efficient vaccine, a thorough immunoinformatics approach was followed to predict the most suitable viral proteins epitopes for building that vaccine. The amino acid sequences of four structural proteins (S, M, N, E) along with one potentially antigenic accessory protein (ORF1a) of SARS-CoV-2 were inspected for the most appropriate epitopes to be used for building the vaccine construct. Several immunoinformatics tools were used to assess the antigenicity (VaxiJen server), immunogenicity (IEDB immunogenicity tool), allergenicity (AlgPred), toxigenicity (ToxinPred server), interferon-gamma inducing capacity (IFNepitope server), and the physicochemical properties of the construct (ProtParam tool). The final candidate vaccine construct consisted of 468 amino acids, encompassing 29 epitopes. The CTL epitopes that passed the antigenicity, allergenicity, toxigenicity and immunogenicity assessment were four epitopes from S protein, one from M protein, two from N protein, 12 from the ORF1a polyprotein and none from E protein. While the HTL epitopes that passed the antigenicity, allergenicity, toxigenicity and INF-[Formula: see text] were one from S protein, three from M protein, six from the ORF1a polyprotein and none from N and E proteins. All the vaccine properties and its ability to trigger the humoral and cell-mediated immune response were validated computationally. Molecular modeling, docking to TLR3, simulation, and molecular dynamics were also carried out. Finally, a molecular clone using pET28::mAID expression plasmid vector was prepared. The overall results of the study suggest that the final multi-epitope chimeric construct is a potential candidate for an efficient protective vaccine against SARS-CoV-2.


Antileishmanial activity of polycyclic derivatives.
33 polycyclic derivatives have been studied and tested on Leishmania donovani and L. major promastigotes. Their antileishmanial activity was assessed in vitro and an assay of their cytotoxicity was realized on human myelomonocytic cell line. The reference molecules used in the assays were amphotericin B and pentamidine. Among the compounds tested, 29 possess an antileishmanial activity; 25 of those were more active against L. donovani than amphotericin B, and nine were as effective as amphotericin B against L. major. Many synthesized derivatives were more active against L. donovani than against L. major. The cytotoxicity studies have shown that among the thirty-three derivatives tested, 12 molecules have an IC50 towards THP-1 cells about equal than that reference drugs, the 21 other derivatives are much less toxic. A 3D QSAR study was undertaken and has permitted to predict activity against L. donovani and L. major and to highlight critical area to optimize activity against the two species.


New human breast cancer cells to study progesterone receptor isoform ratio effects and ligand-independent gene regulation.
All known progesterone target cells coexpress two functionally different progesterone receptor (PR) isoforms: 120-kDa B-receptors (PR-B) and N-terminally truncated, 94-kDa A-receptors (PR-A). Their ratio varies in normal and malignant tissues. In human breast cancer cells, homodimers of progesterone-occupied PR-A or PR-B regulate different gene subsets. To study PR homo- and heterodimers, we constructed breast cancer cell lines in which isoform expression is controlled by an inducible system. PR-negative cells or cells that stably express one or the other isoform were used to construct five sets of cells: (i) PR-negative control cells (Y iNull), (ii) inducible PR-A cells (Y iA), (iii) inducible PR-B cells (Y iB), (iv) stable PR-B plus inducible PR-A cells (B iA), and (v) stable PR-A plus inducible PR-B cells (A iB). Expression levels of each isoform and/or the PR-A/PR-B ratios could be tightly controlled by the dose of inducer as demonstrated by immunoblotting and transcription studies. Induced PRs underwent normal progestin-dependent phosphorylation and down-regulation and regulated exogenous promoters as well as endogenous gene expression. Transcription of exogenous promoters was dependent on the PR-A/PR-B ratio, whereas transcription of endogenous genes was more complex. Finally, we have described several genes that are regulated by induced PR-A even in the absence of ligand.


Experimental Enhancement of Feelings of Transcendence, Tenderness, and Expressiveness by Music in Christian Liturgical Spaces.
In western cultures, when it comes to places of worship and liturgies, music, acoustics and architecture go hand in hand. In the present study, we aimed to investigate whether the emotions evoked by music are enhanced by the acoustics of the space where the music was composed to be played on. We explored whether the emotional responses of western naïve listeners to two vocal pieces from the Renaissance, one liturgical and one secular, convolved with the impulse responses of four Christian temples from the United Kingdom, were modulated by the appropriate piece/space matching. In an alternative forced choice task where participants had to indicate their preference for the original recording of the piece (not convolved with any temple-like acoustics) vs. the convolved one, no significant differences were found. However, in the tasks where participants rated their emotional in response to each piece and acoustic condition, the factorial ANCOVA analyses performed on the results revealed significant effects. We observed that, across pieces and spaces, participants found the temple-like acoustics as more transcendent, compared to the acoustics of the original version of the pieces. In addition, they rated the secular piece as more tender and the liturgical piece as more expressive in its original versions, compared to the convolved ones. We conclude that the acoustic signature of the four Christian temples causes an exaltation of certain emotions on listeners, although this effect is not associated to one or another musical piece.


Simultaneous determination of atorvastatin calcium and ramipril in capsule dosage forms by high-performance liquid chromatography and high-performance thin layer chromatography.
Two simple and accurate methods to determine atorvastatin calcium and ramipril in capsule dosage forms were developed and validated using HPLC and HPTLC. The HPLC separation was achieved on a Phenomenex Luna C18 column (250 x 4.6 mm id, 5 microm) in the isocratic mode using 0.1% phosphoric acid-acetonitrile (38 + 62, v/v), pH 3.5 +/- 0.05, mobile phase at a flow rate of 1 ml/min. The retention times were 6.42 and 2.86 min for atorvastatin calcium and ramipril, respectively. Quantification was achieved with a photodiode array detector set at 210 nm over the concentration range of 0.5-5 microg/mL for each, with mean recoveries (at three concentration levels) of 100.06 +/- 0.49% and 99.95 +/- 0.63% RSD for atorvastatin calcium and ramipril, respectively. The HPTLC separation was achieved on silica gel 60 F254 HPTLC plates using methanol-benzene-glacial acetic acid (19.6 + 80.0 + 0.4, v/v/v) as the mobile phase. The Rf values were 0.40 and 0.20 for atorvastatin calcium and ramipril, respectively. Quantification was achieved with UV densitometry at 210 nm over the concentration range of 50-500 ng/spot for each, with mean recoveries (at three concentration levels) of 99.98 +/- 0.75% and 99.87 +/- 0.83% RSD for atorvastatin calcium and ramipril, respectively. Both methods were validated according to International Conference on Harmonization guidelines and found to be simple, specific, accurate, precise, and robust. The mean assay percentages for atorvastatin calcium and ramipril were 99.90 and 99.55% for HPLC and 99.91 and 99.47% for HPTLC, respectively. The methods were successfully applied for the determination of atorvastatin calcium and ramipril in capsule dosage forms without any interference from common excipients.


Major shifts at the range edge of marine forests: the combined effects of climate changes and limited dispersal.
Global climate change is likely to constrain low latitude range edges across many taxa and habitats. Such is the case for NE Atlantic marine macroalgal forests, important ecosystems whose main structuring species is the annual kelp Saccorhiza polyschides. We coupled ecological niche modelling with simulations of potential dispersal and delayed development stages to infer the major forces shaping range edges and to predict their dynamics. Models indicated that the southern limit is set by high winter temperatures above the physiological tolerance of overwintering microscopic stages and reduced upwelling during recruitment. The best range predictions were achieved assuming low spatial dispersal (5 km) and delayed stages up to two years (temporal dispersal). Reconstructing distributions through time indicated losses of ~30% from 1986 to 2014, restricting S. polyschides to upwelling regions at the southern edge. Future predictions further restrict populations to a unique refugium in northwestern Iberia. Losses were dependent on the emissions scenario, with the most drastic one shifting ~38% of the current distribution by 2100. Such distributional changes might not be rescued by dispersal in space or time (as shown for the recent past) and are expected to drive major biodiversity loss and changes in ecosystem functioning.


Effect of volume of oocyte cytoplasm on embryo development after parthenogenetic activation, intracytoplasmic sperm injection, or somatic cell nuclear transfer.
Animal cloning methods are now well described and are becoming routine. Yet, the frequency at which live cloned offspring are produced remains below 5%, irrespective of the nuclear donor species or cell type. One possible explanation is that the reprogramming factor(s) of each oocyte is insufficient or not properly adapted for the receipt of a somatic cell nucleus, because it is naturally prepared only for the receipt of a gamete. Here, we have increased the oocyte volume by oocyte fusion and examined its subsequent development. We constructed oocytes with volumes two to nine times greater than the normal volume by the electrofusion or mechanical fusion of intact and enucleated oocytes. We examined their in vitro and in vivo developmental potential after parthenogenetic activation, intracytoplasmic sperm injection (ICSI) and somatic cell nuclear transfer (SCNT). When the fused oocytes were activated parthenogenetically, most developed to morulae or blastocysts, regardless of their original size. Diploid fused oocytes were fertilized by ICSI and developed normally and after embryo transfer, we obtained 12 (4-15%) healthy and fertile offspring. However, enucleated fused oocytes could not support the development of mice cloned by SCNT. These results suggest that double fused oocytes have normal potential for development after fertilization, but oocytes with extra cytoplasm do not have enhanced reprogramming potential.


[Ambulance in emergency medicine].
The ambulance service is very important in emergency medicine. The aim of this study was to investigate the new governing statuate of private ambulance service and to propose some new ideas. We examinated the new governing statuate of private ambulance service, rules of patient transporte between the hospitals and reports written by SSK Goztepe Educational Hospital ambulance drivers. We concluded that SSK Goztepe Educational Hospital ambulance drivers have a iot of problems especially at the rules of patient transport between the hospitals and there are some defiencies at the new governing statuate of private ambulance service. We concluded that it is necesssary to manage all the ambulance services in one center; all the private ambulance services have to have a specialist and all these must be determinated by the special rules. Key words: Regulation ofprivate ambulance, emergency head maintanence, ambulance services


Research Beyond the Ivory Tower: Partnering with Safety-Net Health Systems for Equity.
Safety-net health systems serve primarily low-income, racially/ethnically diverse patients who bear a disproportionate burden of disease and high social needs. Many safety-net institutions are publicly funded and are under-resourced to deliver high-quality and timely care. Further, little clinical and translational research includes safety-net populations due to lack of funding, structure to support research, and low prioritization. However, we argue that US health care as a whole will lose key insights across all levels of translational medicine-T1-T4 research, if safety-net health systems do not participate in research. Solutions such as targeted funds for safety-net research, consortium arrangements for research infrastructure, and increasing ways for clinician-researchers to have their primary home in safety-net settings are suggested to fill this gap. Achieving health equity in the U.S. is contingent upon safety-net inclusion in research to advance knowledge and develop, test, and evaluate innovations applicable across all patient populations.


Climbing the entropy barrier: driving the single- towards the multichannel Kondo effect by a weak coulomb blockade of the leads.
We study a model proposed recently in which a small quantum dot is coupled symmetrically to several large quantum dots characterized by a charging energy E(c). Even if E(c) is much smaller than the Kondo temperature T(K), the long-ranged interactions destabilize the single-channel Kondo effect and induce a flow towards a multichannel Kondo fixed point associated with a rise of the impurity entropy with decreasing temperature. Such an "uphill flow" implies a negative impurity specific heat, in contrast with all systems with local interactions. An exact solution found for a large number of channels allows us to capture this physics and to predict transport properties.


Characterization of strong promoters from an environmental Flavobacterium hibernum strain by using a green fluorescent protein-based reporter system.
We developed techniques for the genetic manipulation of Flavobacterium species and used it to characterize several promoters found in these bacteria. Our studies utilized Flavobacterium hibernum strain W22, an environmental strain we isolated from tree hole habitats of mosquito larvae. Plasmids from F. hibernum strain W22 were more efficiently (approximately 1,250-fold) transferred by electroporation into F. hibernum strain W22 than those isolated from Escherichia coli, thus indicating that an efficient restriction barrier exists between these species. The strong promoter, tac, functional in proteobacteria, did not function in Flavobacterium strains. Therefore, a promoter-trap plasmid, pSCH03, containing a promoterless gfpmut3 gene was constructed. A library of 9,000 clones containing chromosomal fragments of F. hibernum strain W22 in pSCH03 was screened for their ability to drive expression of the promoterless gfpmut3 gene. Twenty strong promoters were used for further study. The transcription start points were determined from seven promoter clones by the 5' rapid amplification of cDNA ends technique. Promoter consensus sequences from Flavobacterium were identified as TAnnTTTG and TTG, where n is any nucleotide, centered approximately 7 and 33 bp upstream of the transcription start site, respectively. A putative novel ribosome binding site consensus sequence is proposed as TAAAA by aligning the 20-bp regions upstream of the translational start site in 25 genes. Our primary results demonstrate that at least some promoter and ribosome binding site motifs of Flavobacterium strains are unusual within the bacterial domain and suggest an early evolutionary divergence of this bacterial group. The techniques presented here allow for more detailed genetics-based studies and analyses of Flavobacterium species in the environment.


Biological control of Eotetranychus lewisi and Tetranychus urticae (Acari: Tetranychidae) on strawberry by four phytoseiids (Acari: Phytoseiidae).
The spider mite, Eotetranychus lewisi (McGregor) (Acari: Tetranychidae), is a new emerging pest in California commercial strawberries. The predatory mite Phytoseiulus persimilis (Athias-Henriot) (Acari: Phytoseiidae), typically used for biocontrol of Tetranychus urticae (Koch) (Acari: Tetranychidae), provided growers little to no control of E. lewisi. Four commonly used phytoseiid predatory mites: P. persimilis, Neoseiulus californicus (McGregor), N. fallacis (Garman), and Amblyseius andersoni (Chant), were used in lab studies to investigate which is best at managing E. lewisi populations. We als o investigated t he interactions between T. urticae and E. lewisi and in relation to phytoseiid efficiency given the potential for indirect effects of biocontrol. When E. lewisi and T. urticae are present on the same leaf, T. urticae populations increase and begin displacing E. lewisi. P. persimilis did not feed on E. lewisi, but the other three predatory mites consumed the spider mites and lowered their populations. When both E. lewisi and T. urticae are present on the same leaf, N. fallacis and A. andersoni fed on both types of mites equally and were capable of decreasing both populations. N. californicus fed on E. lewisi first and decreased its population, but allowed T. urticae populations to increase. P. persimilis may be insufficient at controlling E. lewisi and its use may instead enhance E. lewisi populations.


Analyses of the ratio of ganglion cell-inner plexiform layer thickness to vessel density according to age in healthy eyes.
To identify how the inner retinal layer and microvasculature change with age by analyzing the relationships of ganglion cell-inner plexiform layer (GC-IPL) thickness, vessel density (VD), and the ratio of these measurements with age in healthy eyes. Participants were divided into five groups according to age. The GC-IPL thickness, VD, and GC-IPL/VD ratio were compared among the groups. Linear regression analyses were performed to identify relationships of GC-IPL/VD ratio with age. The average GC-IPL thicknesses were 84.84 ± 5.28, 84.22 ± 5.30, 85.20 ± 6.29, 83.29 ± 7.06, and 82.26 ± 5.62 μm in the 20s, 30s, 40s, 50s, and 60s age groups, respectively. The VDs were 20.94 ± 1.50, 21.06 ± 1.50, 20.99 ± 1.03, 20.71 ± 0.93, and 19.74 ± 1.73 mm-1 in the 20s, 30s, 40s, 50s, and 60s age groups, respectively. The GC-IPL/VD ratio was 4.05, 4.00, 4.06, 4.02, and 4.17 in each group, respectively, and the ratio of the 60s age group was significantly higher than that of other groups. In linear regression analyses, the GC-IPL/VD ratio was significantly associated with age in the participants aged ≥ 50 years (B = 0.014, P = 0.013), whereas it was not in the participants aged < 50 years (B = 0.003, P = 0.434). GC-IPL thickness and macular VD showed a tendency to decrease beginning in the 50s age group and the GC-IPL/VD ratio was significantly increased in the 60s age group. Additionally, the GC-IPL/VD ratio was positively associated with age in subjects aged ≥ 50 years, which implies a more pronounced decline over time in VD rather than GC-IPL thickness.


Prostate stem cell antigen as therapy target: tissue expression and in vivo efficacy of an immunoconjugate.
We conducted an expression analysis of prostate stem cell antigen (PSCA)in normal urogenital tissues, benign prostatic hyperplasia (n = 21), prostatic intraepithelial neoplasia (n = 33), and primary (n = 137) and metastatic (n = 42) prostate adenocarcinoma, using isotopic in situ hybridization on tissue microarrays. In normal prostate, we observe PSCA expression in the terminally differentiated, secretory epithelium; strong expression was also seen in normal urothelium. Forty-eight percent of primary and 64% of metastatic prostatic adenocarcinomas expressed PSCA RNA. Our studies did not confirm a positive correlation between level of PSCA RNA expression and high Gleason grade. We characterized monoclonal anti-PSCA antibodies that recognize PSCA expressed on the surface of live cells, are efficiently internalized after antigen recognition, and kill tumor cells in vitro in an antigen-specific fashion upon conjugation with maytansinoid. Unconjugated anti-PSCA antibodies demonstrated efficacy against PSCA-positive tumors by delaying progressive tumor growth in vivo. Maytansinoid-conjugated antibodies caused complete regression of established tumors in a large proportion of animals. Our results strongly suggest that maytansinoid-conjugated anti-PSCA monoclonal antibodies should be evaluated as a therapeutic modality for patients with advanced prostate cancer.


Activity-Dependent Nr4a2 Induction Modulates Synaptic Expression of AMPA Receptors and Plasticity via a Ca2+/CRTC1/CREB Pathway.
Transcription factors have a pivotal role in synaptic plasticity and the associated modification of neuronal networks required for memory formation and consolidation. The nuclear receptors subfamily 4 group A (Nr4a) have emerged as possible modulators of hippocampal synaptic plasticity and cognitive functions. However, the molecular and cellular mechanisms underlying Nr4a2-mediated hippocampal synaptic plasticity are not completely known. Here, we report that neuronal activity enhances Nr4a2 expression and function in cultured mouse hippocampal neurons (both sexes) by an ionotropic glutamate receptor/Ca2+/cAMP response element-binding protein/CREB-regulated transcription factor 1 (iGluR/Ca2+/CREB/CRTC1) pathway. Nr4a2 activation mediates BDNF production and increases expression of iGluRs, thereby affecting LTD at CA3-CA1 synapses in acute mouse hippocampal slices (both sexes). Together, our results indicate that the iGluR/Ca2+/CREB/CRTC1 pathway mediates activity-dependent expression of Nr4a2, which is involved in glutamatergic synaptic plasticity by increasing BDNF and synaptic GluA1-AMPARs. Therefore, Nr4a2 activation could be a therapeutic approach for brain disorders associated with dysregulated synaptic plasticity.SIGNIFICANCE STATEMENT A major factor that regulates fast excitatory synaptic transmission and plasticity is the modulation of synaptic AMPARs. However, despite decades of research, the underlying mechanisms of this modulation remain poorly understood. Our study identified a molecular pathway that links neuronal activity with AMPAR modulation and hippocampal synaptic plasticity through the activation of Nr4a2, a member of the nuclear receptor subfamily 4. Since several compounds have been described to activate Nr4a2, our study not only provides mechanistic insights into the molecular pathways related to hippocampal synaptic plasticity and learning, but also identifies Nr4a2 as a potential therapeutic target for pathologic conditions associated with dysregulation of glutamatergic synaptic function.