Hierarchical structure in poly(N-vinyl carbazole)/Fe3O4 nanocomposites and the relevant magnetic coercivity.

In this study, we report the dependence of the nanoparticle dispersion on the zero-conversion initiator efficiency in the nanocomposites formed by poly(N-vinyl carbazole) (PNVK) and acrylic acid-modified iron oxide (AA-Fe3O4) nanoparticles via free radical solution polymerization of the precursor solution, that is, a thorough mixture of 28.5 wt% AA-Fe3O4 nanoparticles and the N-vinyl carbazole (NVK) monomer with the solvent dimethylformamide and azobisisobutyronitrile as an initiator. Here three different types of the dispersion state of AA-Fe3O4 nanoparticles in the PNVK matrix have been distinguished by a combined approach of transmission electron microscopy and small-angle X-ray scattering coupled with real-space models of the nanoparticle assemblies. When the polymerization proceeded with a higher zero-conversion initiator efficiency (f°) by pre-polymerization at 115 °C, the generation of a large amount of free radicals could efficiently induce the dominant surface-initiated polymerization of the NVK monomer with the vinyl groups of tethered acrylic acids; in this case, the constitution of "shorter multiple grafted PNVK chains" threaded AA-Fe3O4 nanoparticles to form particle branches and the branches were joined together from branching points along each branch, thereby forming the network structure. However, once the polymerization was conducted at a lower f° by pre-polymerization at 75 °C, a significant reduction in the generation of free radicals likely greatly reduced the efficiency in the occurrence of surface-initiated polymerization at particle surfaces; nevertheless, the self-polymerization of the NVK monomer could still take place to induce a local demixing between the polymerizing longer PNVK chains and AA-Fe3O4 nanoparticles via the attractive depletion mechanism, thus locally leading to the formation of small aggregates. While if the f° was controlled to be intermediate by polymerization at 100 °C, an optimal balance between the rates of the surface-initiated polymerization and the self-polymerization induced a collective construction built from the network and aggregate structures, exhibiting the structural characteristics of large aggregates. Furthermore, the magnetic coercivity of PNVK/AA-Fe3O4 nanocomposites was found to depend on the dispersion state of the AA-Fe3O4 nanoparticles, presenting a tendency towards enhanced coercivity as the dispersion state changed from large aggregates to small aggregates to network structure.

Infective Endocarditis Presented as Acute Pyelonephritis: A Case Report

ABSTRACT Infective endocarditis is less likely to sparkle out preferentially in our minds when evaluating and making differential diagnosis of patients with fever daily in emergency departments. We describe a case of infective endocarditis. He was initially diagnosed with pyelonephritis of the right kidney at a hospital because of the noted right flank knocking pain. His computed tomography showed two wedge-shaped low-density lesions in the spleen and the right kidney separately. It dropped a hint to the emergency department physician of thinking of the feature of infarct. The previously neglected cardiac murmurs were then an important clue. We then performed transthoracic emergent echocardiography and confirmed the diagnosis of infective endocarditis.

Indirect neonatal hyperbilirubinemia in hospitalized neonates on the Thai-Myanmar border: a review of neonatal medical records from 2009 to 2014.

BACKGROUND: Indirect neonatal hyperbilirubinemia (INH) is a common neonatal disorder worldwide which can remain benign if prompt management is available. However there is a higher morbidity and mortality risk in settings with limited access to diagnosis and care. The manuscript describes the characteristics of neonates with INH, the burden of severe INH and identifies factors associated with severity in a resource-constrained setting. METHODS: We conducted a retrospective evaluation of anonymized records of neonates hospitalized on the Thai-Myanmar border. INH was defined according to the National Institute for Health and Care Excellence guidelines as 'moderate' if at least one serum bilirubin (SBR) value exceeded the phototherapy threshold and as 'severe' if above the exchange transfusion threshold. RESULTS: Out of 2980 records reviewed, 1580 (53%) had INH within the first 14 days of life. INH was moderate in 87% (1368/1580) and severe in 13% (212/1580). From 2009 to 2011, the proportion of severe INH decreased from 37 to 15% and the mortality dropped from 10% (8/82) to 2% (7/449) coinciding with the implementation of standardized guidelines and light-emitting diode (LED) phototherapy. Severe INH was associated with: prematurity (< 32 weeks, Adjusted Odds Ratio (AOR) 3.3; 95% CI 1.6-6.6 and 32 to 37 weeks, AOR 2.2; 95% CI 1.6-3.1), Glucose-6-phosphate dehydrogenase deficiency (G6PD) (AOR 2.3; 95% CI 1.6-3.3), potential ABO incompatibility (AOR 1.5; 95% CI 1.0-2.2) and late presentation (AOR 1.8; 95% CI 1.3-2.6). The risk of developing severe INH and INH-related mortality significantly increased with each additional risk factor. CONCLUSION: INH is an important cause of neonatal hospitalization on the Thai-Myanmar border. Risk factors for severity were similar to previous reports from Asia. Implementing standardized guidelines and appropriate treatment was successful in reducing mortality and severity. Accessing to basic neonatal care including SBR testing, LED phototherapy and G6PD screening can contribute to improve neonatal outcomes.

Analysis of the modifications of MRI signal of the brachial plexus of rats: Comparative study before and after freezing/thawing.

The aim of this study was to compare the MRI signal of the brachial plexus and surrounding muscles before and after freezing/thawing on a murine model. A first MRI going through the brachial plexuses of 5 healthy Wistar rats was performed immediately post-mortem. A second MRI was performed after freezing at -30°C and then thawing at 20°C for 24hours. All MRI images were segmented to make nerve and muscular structures appear and calculate the average intensity of the MRI signal using the program ImageJ. The average nerve and muscular MRI signals were compared before and after freezing/thawing and rated in grayscale units between 0 and 255. The average intensity of the MRI signal of nerve structures was 40.315 grayscale units before freezing and 31.943 after freezing/thawing. The average intensity of the MRI signal of muscular structures was 25.44 grayscale units before freezing and 35.710 after freezing/thawing. Our results have shown that the intensity of the MRI signal of the brachial plexus was higher before freezing/thawing. The intensity of the MRI signal of muscles was lower than the intensity of the brachial plexus before freezing/thawing and higher after freezing/thawing in muscles than in brachial plexus. The MRI could be used in clinical practice to monitor the reinnervation after frozen nerve allografts.

Design and Use of a Low Cost, Automated Morbidostat for Adaptive Evolution of Bacteria Under Antibiotic Drug Selection.

We describe a low cost, configurable morbidostat for characterizing the evolutionary pathway of antibiotic resistance. The morbidostat is a bacterial culture device that continuously monitors bacterial growth and dynamically adjusts the drug concentration to constantly challenge the bacteria as they evolve to acquire drug resistance. The device features a working volume of ~10 ml and is fully automated and equipped with optical density measurement and micro-pumps for medium and drug delivery. To validate the platform, we measured the stepwise acquisition of trimethoprim resistance in Escherichia coli MG 1655, and integrated the device with a multiplexed microfluidic platform to investigate cell morphology and antibiotic susceptibility. The approach can be up-scaled to laboratory studies of antibiotic drug resistance, and is extendible to adaptive evolution for strain improvements in metabolic engineering and other bacterial culture experiments.

Improvement of the Off-Resonance Saturation, an MRI sequence for positive contrast with SPM particles: Theoretical and experimental study.

The SuperParaMagnetic particles (SPM particles) are used as contrast agents in MRI and produce negative contrast with conventional T2 or T2(∗)-weighted sequences. Unfortunately, the SPM particle detection on images acquired with such sequences is sometimes difficult because negative contrast can be created by artifacts such as air bubbles or calcification. To overcome this problem, new sequences as Off-Resonance Saturation (ORS) were developed to produce positive contrast with SPM particles. This work explores a new way to optimize the contrast generated by the ORS sequence by increasing the number of saturation pulses applied before the imaging sequence. This modified sequence is studied with numerical simulations and experiments on agarose gel phantoms. A theoretical model able to predict the contrast for different values of the sequence parameters is also developed. The results show that the contrast increases with the saturation pulses number with an optimal value of three saturation pulses in order to avoid artifacts and limit the Specific Absorption Rate (SAR) effect. The dependence of the contrast on the SPM particle concentration and sequence parameters is comparable to what was observed for the ORS sequence.

Bottom-up study of the MRI positive contrast created by the Off-Resonance Saturation sequence.

Superparamagnetic iron oxide nanoparticles (SPM particles) are used in MRI to highlight regions such as tumors through negative contrast. Unfortunately, sources as air bubbles or tissues interfaces also lead to negative contrast, which complicates the image interpretation. New MRI sequences creating positive contrast in the particle surrounding, such as the Off-Resonance Saturation sequence (ORS), have thus been developed. However, a theoretical study of the ORS sequence is still lacking, which hampers the optimization of this sequence. For this reason, this work provides a self-consistent analytical expression able to predict the dependence of the contrast on the sequence parameters and the SPM particles properties. This expression was validated by numerical simulations and experiments on agarose gel phantoms on a 11.7 T scanner system. It provides a fundamental understanding of the mechanisms leading to positive contrast, which could allow the improvement of the sequence for future in vivo applications. The influence of the SPM particle relaxivities, the SPM particle concentration, the echo time and the saturation pulse parameters on the contrast were investigated. The best contrast was achieved with SPM particles possessing the smallest transverse relaxivity, an optimal particle concentration and for low echo times.

Theoretical and experimental study of ON-Resonance Saturation, an MRI sequence for positive contrast with superparamagnetic nanoparticles.

Superparamagnetic iron oxide nanoparticles (SPM particles) are widely used in MRI as negative contrast agents. Their detection is sometimes difficult because negative contrast can be caused by different artifacts. To overcome this problem, MRI protocols achieving positive contrast specific to SPM particles were developed such as the ON-Resonance Saturation (ONRS) sequence. The aim of the present work is to achieve a bottom-up study of the ONRS sequence by an understanding of the physical mechanisms leading to positive contrast. A complete theoretical modeling, a novel numerical simulation approach and experiments on agarose gel phantoms on a 11.7 T MRI system were carried out for this purpose. The influence of the particle properties and concentration - as well as the effect of the sequence parameters on the contrast - were investigated. It was observed that theory and experiments were in strong agreement. The tools developed in this work allowed to predict the parameters leading to the maximum contrast. For example, particles presenting a low transverse relaxivity can provide an interesting positive contrast after optimization of their concentration in the sample.

Toxicity and carcinogenicity studies of Ginkgo biloba extract in rat and mouse: liver, thyroid, and nose are targets.

Ginkgo biloba extract (GBE) is a popular herbal supplement that is used to improve circulation and brain function. In spite of widespread human exposure to relatively high doses over potentially long periods of time, there is a paucity of data from animal studies regarding the toxicity and carcinogenicity associated with GBE. In order to fill this knowledge gap, 3-month and 2-year toxicity and carcinogenicity studies with GBE administered by oral gavage to B6C3F1/N mice and F344/N rats were performed as part of the National Toxicology Program's Dietary Supplements and Herbal Medicines Initiative. The targets of GBE treatment were the liver, thyroid, and nose. These targets were consistent across exposure period, sex, and species, albeit with varying degrees of effect observed among studies. Key findings included a notably high incidence of hepatoblastomas in male and female mice and evidence of carcinogenic potential in the thyroid gland of both mice and rats. Various nonneoplastic lesions were observed beyond control levels in the liver, thyroid gland, and nose of rats and mice administered GBE. Although these results cannot be directly extrapolated to humans, the findings fill an important data gap in assessing risk associated with GBE use.

Spatial and temporal MRI profile of ischemic tissue after the acute stages of a permanent mouse model of stroke.

OBJECT: To characterize the progression of injured tissue resulting from a permanent focal cerebral ischemia after the acute phase, Magnetic Resonance Imaging (MRI) monitoring was performed on adult male C57BL/6J mice in the subacute stages, and correlated to histological analyses. MATERIAL AND METHODS: Lesions were induced by electrocoagulation of the middle cerebral artery. Serial MRI measurements and weighted-images (T2, T1, T2* and Diffusion Tensor Imaging) were performed on a 9.4T scanner. Histological data (Cresyl-Violet staining and laminin-, Iba1- and GFAP-immunostainings) were obtained 1 and 2 weeks after the stroke. RESULTS: Two days after stroke, tissues assumed to correspond to the infarct core, were detected as a hyperintensity signal area in T2-weighted images. One week later, low-intensity signal areas appeared. Longitudinal MRI study showed that these areas remained present over the following week, and was mainly linked to a drop of the T2 relaxation time value in the corresponding tissues. Correlation with histological data and immuno-histochemistry showed that these areas corresponded to microglial cells. CONCLUSION: The present data provide, for the first time detailed MRI parameters of microglial cells dynamics, allowing its non-invasive monitoring during the chronic stages of a stroke. This could be particularly interesting in regards to emerging anti-inflammatory stroke therapies.

Complex histopathologic response in rat kidney to oral ß-myrcene: an unusual dose-related nephrosis and low-dose alpha2u-globulin nephropathy.

Oral gavage studies with ß-myrcene in male F344 rats showed a complex renal pathology comprising both alpha2u-globulin (α2u-g) nephropathy, an unusual nephrosis involving the outer stripe of outer medulla (OSOM), and an increased incidence of renal tubule tumors by 2 years. In the 90-day and 2-year studies, respectively, α2u-g nephropathy and linear papillary mineralization were observed in males at the two lower doses but were absent from the high dose. Nephrosis was characterized by dilation of the S3 tubules, nuclear enlargement (including karyomegaly), and luminal pyknotic cells, all in the outermost OSOM. Nephrosis was minimal at the higher doses in the 90-day study, but progressed to a severe grade in males dosed with 1,000 mg/kg for 2 years. Renal tubule tumors developed in treated groups with incidences up to 30% in the 250 and 500 mg/kg male dose groups. Tumors at the lower doses in males may have been associated with α2u-g nephropathy, while those at higher doses in both sexes may have been due to the nephrosis. Because ß-myrcene induced a complex spectrum of renal pathology, the α2u-g nephropathy mechanism cannot be the sole mechanism of carcinogenesis in these rats.

Do early MRI signals predict lesion size in a neonatal stroke rat model?

SUMMARY: In this study, we compared lesion size by using VADC and VT2 at 0, 2, 5, 24, and 48 hours and histologic lesions at 48 hours in a P7 rat stroke model. The best correlation between VHISTO and VADC was at H0, and between VHISTO and VT2, at H2-H5. Early MR imaging signals allowed excluding "no-lesion" and "no-reflow" animals to help standardize this neonatal stroke model and predict lesion size.

Identification of a Maleimide-Based Glycogen Synthase Kinase-3 (GSK-3) Inhibitor, BIP-135, that Prolongs the Median Survival Time of Δ7 SMA KO Mouse Model of Spinal Muscular Atrophy.

The discovery of upregulated glycogen synthase kinase-3 (GSK-3) in various pathological conditions has led to the development of a host of chemically diverse small molecule GSK-3 inhibitors, such as BIP-135. GSK-3 inhibition emerged as an alternative therapeutic target for treating spinal muscular atrophy (SMA) when a number of GSK-3 inhibitors were shown to elevate survival motor neuron (SMN) levels in vitro and to rescue motor neurons when their intrinsic SMN level was diminished by SMN-specific short hairpin RNA (shRNA). Despite their cellular potency, the in vivo efficacy of GSK-3 inhibitors has yet to be evaluated in an animal model of SMA. Herein, we disclose that a potent and reasonably selective GSK-3 inhibitor, namely BIP-135, was tested in a transgenic Δ7 SMA KO mouse model of SMA, and found to prolong the median survival of these animals. In addition, this compound was shown to elevate the SMN protein level in SMA patient-derived fibroblast cells as determined by western blot, and was neuroprotective in a cell-based, SMA-related model of oxidative stress-induced neurodegeneration.

Dynamic structure factor for large aggregate clusters with internal motions: a self-consistent light-scattering study on conjugated polymer solutions.

The aggregation properties of a standard conjugated polymer, poly(2-methoxy-5-(2'-ethylhexyloxy)-1,4-phenylenevinylene) (MEH-PPV), in two distinct solvents (chloroform and toluene) and a range of polymer concentrations (c = 0.1-3 mg/mL) have been unequivocally resolved using combined dynamic and static light scatterings (DLS/SLS). The prime challenges for analyzing this peculiar, practically important, solution system arise from the wide size distribution and unknown aggregate morphology, as well as pronounced interferences between translational and internal motions of aggregate clusters of considerably varying size. To cope with these central difficulties, we propose a self-consistent formulation for analyzing the dynamic structure factor in DLS experiment by extending an existing theory on free-draining bead-spring chains that explicitly accounts for internal fluctuations, along with two candidate form factors on Gaussian coil and rigid sphere, respectively, serving as two limiting cases to be discriminated in combined DLS and SLS measurements. Given that no accessibility to ultrasmall angular resolutions is a prerequisite, the suggested protocol can readily be carried out in conventional light-scattering apparatus. The present analyses unanimously support the rigid-sphere form factor in describing the entire set of light-scattering data on MEH-PPV solutions, differing from early small-angle neutron/X-ray scattering interpretations suggesting certain 2D fractal structures for the aggregation network. Scrutiny into the interior dynamics of aggregate clusters further disclosed that the segmental motions are noticeably more suppressed than for usual, nonaggregated polymer solutions, and no existing theories based on the bead-spring picture can yet capture the observed scaling behavior as manifested by the present data. Accordingly, we report several first-revealed properties of MEH-PPV solutions on the aggregate morphology, the size distribution (and mean size), mean aggregation number, and interior segmental dynamics, which serve as valuable information for linking solution properties with those for dried thin films in contemporary applications with conducting conjugated polymers.

Liver toxicity and carcinogenicity in F344/N rats and B6C3F1 mice exposed to Kava Kava.

Kava Kava is an herbal supplement used as an alternative to antianxiety drugs. Although some reports suggest an association of Kava Kava with hepatotoxicity , it continues to be used in the United States due to lack of toxicity characterization. In these studies F344/N rats and B6C3F1 mice were administered Kava Kava extract orally by gavage in corn oil for two weeks, thirteen weeks or two years. Results from prechronic studies administered Kava Kava at 0.125 to 2g/kg body weight revealed dose-related increases in liver weights and incidences of hepatocellular hypertrophy. In the chronic studies, there were dose-related increases in the incidences of hepatocellular hypertrophy in rats and mice administered Kava Kava for up to 1g/kg body weight. This was accompanied by significant increases in incidences of centrilobular fatty change. There was no treatment- related increase in carcinogenic activity in the livers of male or female rats in the chronic studies. Male mice showed a significant dose-related increase in the incidence of hepatoblastomas. In female mice, there was a significant increase in the combined incidence of hepatocellular adenoma and carcinoma in the low and mid dose groups but not in the high dose group. These findings were accompanied by several nonneoplastic hepatic lesions.

Comparative study of photothermolysis of cancer cells with nuclear-targeted or cytoplasm-targeted gold nanospheres: continuous wave or pulsed lasers.

We conduct a comparative study on the efficiency and cell death pathways of continuous wave (cw) and nanosecond pulsed laser photothermal cancer therapy using gold nanospheres delivered to either the cytoplasm or nucleus of cancer cells. Cytoplasm localization is achieved using arginine-glycine-aspartate peptide modified gold nanospheres, which target integrin receptors on the cell surface and are subsequently internalized by the cells. Nuclear delivery is achieved by conjugating the gold nanospheres with nuclear localization sequence peptides originating from the simian virus. Photothermal experiments show that cell death can be induced with a single pulse of a nanosecond laser more efficiently than with a cw laser. When the cw laser is applied, gold nanospheres localized in the cytoplasm are more effective in inducing cell destruction than gold nanospheres localized at the nucleus. The opposite effect is observed when the nanosecond pulsed laser is used, suggesting that plasmonic field enhancement of the nonlinear absorption processes occurs at high localization of gold nanospheres at the nucleus. Cell death pathways are further investigated via a standard apoptosis kit to show that the cell death mechanisms depend on the type of laser used. While the cw laser induces cell death via apoptosis, the nanosecond pulsed laser leads to cell necrosis. These studies add mechanistic insight to gold nanoparticle-based photothermal therapy of cancer.

Fourteen-week toxicity study of green tea extract in rats and mice.

The toxicity of green tea extract (GTE) was evaluated in 14-week gavage studies in male and female F344/NTac rats and B6C3F1 mice at doses up to 1,000 mg/kg. In the rats, no treatment-related mortality was noted. In the mice, treatment-related mortality occurred in male and female mice in the 1,000 mg/kg dose groups. The cause of early deaths was likely related to liver necrosis. Treatment-related histopathological changes were seen in both species in the liver, nose, mesenteric lymph nodes, and thymus. In addition, in mice, changes were seen in the Peyer's patches, spleen, and mandibular lymph nodes. The no adverse effect level (NOAEL) for the liver in both species was 500 mg/kg. In the nose of rats, the NOAEL in males was 62.5 mg/kg, and in females no NOAEL was found. No NOAEL was found in the nose of female or male mice. The changes in the liver and nose were considered primary toxic effects of GTE, while the changes in other organs were considered to be secondary effects. The nose and liver are organs with high metabolic enzyme activity. The increased susceptibility of the nose and liver suggests a role for GTE metabolites in toxicity induction.

Antimalarial and antileishmanial activities of histone deacetylase inhibitors with triazole-linked cap group.

Histone deacetylase inhibitors (HDACi) are endowed with plethora of biological functions including anti-proliferative, anti-inflammatory, anti-parasitic, and cognition-enhancing activities. Parsing the structure-activity relationship (SAR) for each disease condition is vital for long-term therapeutic applications of HDACi. We report in the present study specific cap group substitution patterns and spacer-group chain lengths that enhance the antimalarial and antileishmanial activity of aryltriazolylhydroxamates-based HDACi. We identified many compounds that are several folds selectively cytotoxic to the plasmodium parasites compared to standard HDACi. Also, a few of these compounds have antileishmanial activity that rivals that of miltefosine, the only currently available oral agent against visceral leishmaniasis. The anti-parasite properties of several of these compounds tracked well with their anti-HDAC activities. The results presented here provide further evidence on the suitability of HDAC inhibition as a viable therapeutic option to curb infections caused by apicomplexan protozoans and trypanosomatids.