Acute Rheumatic Fever: Case Report and Literature Review.

A previously healthy 8-year-old Native American female presented with right-sided weakness and joint pain for two weeks. Following an initially unremarkable workup including negative brain and spine MRI she was noticed to have chorea and subsequently diagnosed with acute rheumatic fever (ARF). ARF is a group A streptococcus-related disease that most commonly is a sequelae of pharyngitis. The diagnosis of ARF utilizes the Jones criteria which includes heart disease, arthritis, chorea, the characteristic rash of erythema marginatum, and subcutaneous nodules. The most serious consequences of ARF include rheumatic heart disease and chorea. ARF can be treated with a combination of antibiotics and anti-inflammatories like aspirin.

A Surgical Case of Bronchial Artery Aneurysm Connecting to a Pulmonary Artery and Vein Complicated by Racemose Hemangioma.

We report a surgical case of bronchial artery aneurysm (BAA) that directly connected to a pulmonary artery and a pulmonary vein through an abnormal vessel. It was complicated by racemose hemangioma. This is a rare vascular malformation. An 82-year-old female had a large BAA that was found incidentally. First, we consider treating the BAA with embolization by interventional radiology (IVR). However, because of strong meandering of the bronchial artery, we could not advance a microcatheter into the BAA. Therefore, a surgical operation was performed through a standard posterior lateral thoracotomy. The BAA was located between the upper and lower lobes and directly connected to the pulmonary artery. Some bronchial artery branches that provided inflow to the aneurysm were ligated, and the abnormal vessel that connected the BAA to the upper pulmonary vein was ligated easily. A fistula between the BAA and pulmonary artery was sutured by the cardiovascular surgeon using an artificial cardiopulmonary device, with permissive stenosis of A2b (ascending A2).

TGFß-induced expression of long noncoding lincRNA Platr18 controls breast cancer axonogenesis.

Metastasis is the leading driver of cancer-related death. Tumor cell plasticity associated with the epithelial-mesenchymal transition (EMT), an embryonic program also observed in carcinomas, has been proposed to explain the colonization of distant organs by the primary tumor cells. Many studies have established correlations between EMT marker expression in the primary tumor and metastasis in vivo. However, the longstanding model of EMT-transitioned cells disseminating to secondary sites is still actively debated and hybrid states are presently considered as more relevant during tumor progression and metastasis. Here, we describe an unexplored role of EMT on the tumor microenvironment by controlling tumor innervation. Using in vitro and in vivo breast tumor progression models, we demonstrate that TGFß-mediated tumor cell EMT triggers the expression of the embryonic LincRNA Platr18 those elevated expression controls the expression of the axon guidance protein semaphorin-4F and other neuron-related molecules such as IGSF11/VSIG-3. Platr18/Sema4F axis silencing abrogates axonogenesis and attenuates metastasis. Our observations suggest that EMT-transitioned cells are also locally required in the primary tumor to support distant dissemination by promoting axonogenesis, a biological process known for its role in metastatic progression of breast cancer.

Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia.

Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.

Interleukin-like EMT inducer (ILEI) promotes melanoma invasiveness and is transcriptionally up-regulated by upstream stimulatory factor-1 (USF-1).

Interleukin-like EMT inducer (ILEI, FAM3C) is a secreted factor that contributes to the epithelial-to-mesenchymal transition (EMT), a cell-biological process that confers metastatic properties to a tumor cell. However, very little is known about how ILEI is regulated. Here we demonstrate that ILEI is an in vivo regulator of melanoma invasiveness and is transcriptionally up-regulated by the upstream stimulatory factor-1 (USF-1), an E-box-binding, basic-helix-loop-helix family transcription factor. shRNA-mediated knockdown of ILEI in melanoma cell lines attenuated lung colonization but not primary tumor formation. We also identified the mechanism underlying ILEI transcriptional regulation, which was through a direct interaction of USF-1 with the ILEI promoter. Of note, stimulation of endogenous USF-1 by UV-mediated activation increased ILEI expression, whereas shRNA-mediated USF-1 knockdown decreased ILEI gene transcription. Finally, we report that knocking down USF-1 decreases tumor cell migration. In summary, our work reveals that ILEI contributes to melanoma cell invasiveness in vivo without affecting primary tumor growth and is transcriptionally up-regulated by USF-1.

Interleukin-like EMT inducer regulates partial phenotype switching in MITF-low melanoma cell lines.

ILEI (FAM3C) is a secreted factor that contributes to the epithelial-to-mesenchymal transition (EMT), a cell biological process that confers metastatic properties to a tumor cell. Initially, we found that ILEI mRNA is highly expressed in melanoma metastases but not in primary tumors, suggesting that ILEI contributes to the malignant properties of melanoma. While melanoma is not an epithelial cell-derived tumor and does not undergo a traditional EMT, melanoma undergoes a similar process known as phenotype switching in which high (micropthalmia-related transcription factor) MITF expressing (MITF-high) proliferative cells switch to a low expressing (MITF-low) invasive state. We observed that MITF-high proliferative cells express low levels of ILEI (ILEI-low) and MITF-low invasive cells express high levels of ILEI (ILEI-high). We found that inducing phenotype switching towards the MITF-low invasive state increases ILEI mRNA expression, whereas phenotype switching towards the MITF-high proliferative state decreases ILEI mRNA expression. Next, we used in vitro assays to show that knockdown of ILEI attenuates invasive potential but not MITF expression or chemoresistance. Finally, we used gene expression analysis to show that ILEI regulates several genes involved in the MITF-low invasive phenotype including JARID1B, HIF-2α, and BDNF. Gene set enrichment analysis suggested that ILEI-regulated genes are enriched for JUN signaling, a known regulator of the MITF-low invasive phenotype. In conclusion, we demonstrate that phenotype switching regulates ILEI expression, and that ILEI regulates partial phenotype switching in MITF-low melanoma cell lines.

Hydrogenase-3 contributes to anaerobic acid resistance of Escherichia coli.

BACKGROUND: Hydrogen production by fermenting bacteria such as Escherichia coli offers a potential source of hydrogen biofuel. Because H(2) production involves consumption of 2H(+), hydrogenase expression is likely to involve pH response and regulation. Hydrogenase consumption of protons in E. coli has been implicated in acid resistance, the ability to survive exposure to acid levels (pH 2-2.5) that are three pH units lower than the pH limit of growth (pH 5-6). Enhanced survival in acid enables a larger infective inoculum to pass through the stomach and colonize the intestine. Most acid resistance mechanisms have been defined using aerobic cultures, but the use of anaerobic cultures will reveal novel acid resistance mechanisms. METHODS AND PRINCIPAL FINDINGS: We analyzed the pH regulation of bacterial hydrogenases in live cultures of E. coli K-12 W3110. During anaerobic growth in the range of pH 5 to 6.5, E. coli expresses three hydrogenase isoenzymes that reversibly oxidize H(2) to 2H(+). Anoxic conditions were used to determine which of the hydrogenase complexes contribute to acid resistance, measured as the survival of cultures grown at pH 5.5 without aeration and exposed for 2 hours at pH 2 or at pH 2.5. Survival of all strains in extreme acid was significantly lower in low oxygen than for aerated cultures. Deletion of hyc (Hyd-3) decreased anoxic acid survival 3-fold at pH 2.5, and 20-fold at pH 2, but had no effect on acid survival with aeration. Deletion of hyb (Hyd-2) did not significantly affect acid survival. The pH-dependence of H(2) production and consumption was tested using a H(2)-specific Clark-type electrode. Hyd-3-dependent H(2) production was increased 70-fold from pH 6.5 to 5.5, whereas Hyd-2-dependent H(2) consumption was maximal at alkaline pH. H(2) production, was unaffected by a shift in external or internal pH. H(2) production was associated with hycE expression levels as a function of external pH. CONCLUSIONS: Anaerobic growing cultures of E. coli generate H(2) via Hyd-3 at low external pH, and consume H(2) via Hyd-2 at high external pH. Hyd-3 proton conversion to H(2) is required for acid resistance in anaerobic cultures of E. coli.

A new chondrogenic differentiation initiator with the ability to up-regulate SOX trio expression.

During random screening for chondrogenic differentiation inducers, we found that Compound-1, 4-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-1H-pyrazol-3-yl]benzene-1,3-diol, initiated chondrogenic differentiation of the chondroprogenitor cell line ATDC5. Compound-1 initiated chondrogenic differentiation of the mesenchymal stem cell line C3H10T1/2 in regions where cell aggregates formed and simultaneously inhibited adipogenic differentiation. In C3H10T1/2 cells, Compound-1 increased the expression of Sry-related high-mobility-group box transcription factors L-SOX5, SOX6, and SOX9 (SOX trio) more strongly than bone morphogenic protein (BMP)-2. cAMP-dependent protein kinase (PKA) inhibitors suppressed Compound-1-dependent L-SOX5 and SOX6 up-regulation. PKA inhibitors also suppressed the up-regulation of aggrecan mRNA induced by Compound-1, indicating that increases in L-SOX5 and SOX6 mRNA, in which the PKA pathway participates, are involved in the mechanisms behind the action of Compound-1. On the other hand, the SOX6 and aggrecan gene expression, which were up-regulated by BMP-2, were not affected by the PKA inhibitor. Compound-1 induced chondrogenic differentiation of bone marrow stromal cells and recovered cartilage matrix production by primary chondrocytes, which had been decreased by interleukin-1beta. These results show the potential of Compound-1 to be a new cartilage repair agent for inducing chondrogenic differentiation via SOX trio up-regulation.

Cytoplasmic acidification and the benzoate transcriptome in Bacillus subtilis.

BACKGROUND: Bacillus subtilis encounters a wide range of environmental pH. The bacteria maintain cytoplasmic pH within a narrow range. Response to acid stress is a poorly understood function of external pH and of permeant acids that conduct protons into the cytoplasm. METHODS AND PRINCIPAL FINDINGS: Cytoplasmic acidification and the benzoate transcriptome were observed in Bacillus subtilis. Cytoplasmic pH was measured with 4-s time resolution using GFPmut3b fluorimetry. Rapid external acidification (pH 7.5 to 6.0) acidified the B. subtilis cytoplasm, followed by partial recovery. Benzoate addition up to 60 mM at external pH 7 depressed cytoplasmic pH but left a transmembrane Delta pH permitting growth; this robust adaptation to benzoate exceeds that seen in E. coli. Cytoplasmic pH was depressed by 0.3 units during growth with 30 mM benzoate. The transcriptome of benzoate-adapted cells was determined by comparing 4,095 gene expression indices following growth at pH 7, +/- 30 mM benzoate. 164 ORFs showed > or = 2-fold up-regulation by benzoate (30 mM benzoate/0 mM), and 102 ORFs showed > or = 2-fold down-regulation. 42% of benzoate-dependent genes are regulated up or down, respectively, at pH 6 versus pH 7; they are candidates for cytoplasmic pH response. Acid-stress genes up-regulated by benzoate included drug resistance genes (yhbI, yhcA, yuxJ, ywoGH); an oligopeptide transporter (opp); glycine catabolism (gcvPA-PB); acetate degradation (acsA); dehydrogenases (ald, fdhD, serA, yrhEFG, yjgCD); the TCA cycle (citZ, icd, mdh, sucD); and oxidative stress (OYE-family yqjM, ohrB). Base-stress genes down-regulated by benzoate included malate metabolism (maeN), sporulation control (spo0M, spo0E), and the SigW alkali shock regulon. Cytoplasmic pH could mediate alkali-shock induction of SigW. CONCLUSIONS: B. subtilis maintains partial pH homeostasis during growth, and withstands high concentrations of permeant acid stress, higher than for gram-negative neutralophile E. coli. The benzoate adaptation transcriptome substantially overlaps that of external acid, contributing to a cytoplasmic pH transcriptome.

In vivo serial evaluation of superparamagnetic iron-oxide labeled stem cells by off-resonance positive contrast.

MRI is emerging as a diagnostic modality to track iron-oxide-labeled stem cells. This study investigates whether an off-resonance (OR) pulse sequence designed to generate positive contrast at 1.5T can assess the location, quantity, and viability of delivered stem cells in vivo. Using mouse embryonic stem cell transfected with luciferase reporter gene (luc-mESC), multimodality validation of OR signal was conducted to determine whether engraftment parameters of superparamagnetic iron-oxide labeled luc-mESC (SPIO-luc-mESC) could be determined after cell transplantation into the mouse hindlimb. A significant increase in signal- and contrast-to-noise of the SPIO-luc-mESC was achieved with the OR technique when compared to a gradient recalled echo (GRE) sequence. A significant correlation between the quantity of SPIO-luc-mESC and OR signal was observed immediately after transplantation (R(2) = 0.74, P < 0.05). The assessment of transplanted cell viability by bioluminescence imaging (BLI) showed a significant increase of luciferase activities by day 16, while the MRI signal showed no difference. No significant correlation between BLI and MRI signals of cell viability was observed. In conclusion, using an OR sequence the precise localization and quantitation of SPIO-labeled stem cells in both space and time were possible. However, the OR sequence did not allow evaluation of cell viability.

Automated analysis of fluvoxamine in rat plasma using a column-switching system and ion-pair high-performance liquid chromatography.

We have established a robust, fully automated analytical method for the analysis of fluvoxamine in rat plasma using a column-switching ion-pair high-performance chromatography system. The plasma sample was injected onto a precolumn packed with Shim-pack MAYI-ODS (50 microm), where the drug was automatically purified and enriched by on-line solid-phase extraction. After elution of the plasma proteins, the analyte was back-flushed from the precolumn and then separated isocratically on a reversed-phase C18 column (L-column ODS) with a mobile phase (acetonitrile-0.1% phosphoric acid, 36:64, v/v) containing 2 mM sodium 1-octanesulfonate. The analyte was monitored by a UV detector at a wavelength of 254 nm. The calibration line for fluvoxamine showed good linearity in the range of 5-5000 ng/mL (r > 0.999) with the limit of quantification of 5 ng/mL (RSD = 6.51%). Accuracy ranged from -2.94 to 4.82%, and the within- and between-day precision of the assay was better than 8% across the calibration range. The analytical sensitivity and accuracy of this assay is suitable for characterization of the pharmacokinetics of orally-administered fluvoxamine in rats.

[Effect of lamivudine for hepatitis B virus reactivation in blood cancer patients undergoing immunosuppressive chemotherapy].

Immunosuppressants are often used in the treatment of cancer. Several recent studies have shown hepatitis B virus (HBV) reactivation after immunosuppressive chemotherapy in HB surface antigen (HBsAg)-negative patients who were positive for antibody to HB core antigen (anti-HBc) and/or antibody to HBsAg (anti-HBs). This study reports the medical course of 11 patients with blood cancer who underwent chemotherapy. All patients had at least one positive HBV marker (HBsAg, anti-HBs, anti-HBc). Before immunosuppressive chemotherapy, 5 patients were treated with lamivudine and 6 had no antiviral drug treatment. None of the lamivudine treated patients had HBV reactivation, but HBV was reactivated in all of the patients not treated with this antiviral drug, one of whom had severe exacerbation of liver function and died due to hepatic failure. Because lamivudine treatment was effective in preventing HBV reactivation in patients receiving immunosuppressive chemotherapy, HBsAg-negative patients with anti-HBs and/or anti-HBc need the antiviral medicines before immunosuppressive therapy.

Clinical significance of serum RCAS1 levels detected by monoclonal antibody 22-1-1 in patients with cholangiocellular carcinoma.

BACKGROUND/AIMS: The tumor-associated antigen, RCAS1, has been reported to be expressed in various types of cancer, including cholangiocarcinoma. We measured serum RCAS1 levels in patients with intrahepatic cholangiocellular carcinoma (CCC) and other hepatobiliary diseases, and examined the clinical significance of serum RCAS1 as a tumor marker. METHODS: Sera collected from the patients and healthy volunteers were used for ELISA for RCAS1. The values of RCAS1 for CCC patients were compared to those of other tumor marker proteins. RESULTS: Serum RCAS1 levels exceeded the normal limit in a high percentage (73.9%) of CCC patients. The positivity rate was higher than those of CA19-9 and CEA. No correlation was found between the RCAS1 and CA19-9 concentrations. Serum RCAS1 was positive in many cases that were negative for CA19-9. Surgical resection of CCC reduced the RCAS1 level to within the normal range. On the other hand, serum RCAS1 levels were elevated in very few cases of benign hepatobiliary disease. CONCLUSIONS: As a tumor marker in CCC, RCAS1 is, at least, of complementary value to CA19-9 and CEA. Measuring serum RCAS1 contributes to the diagnostic accuracy, and is useful for estimating tumor progression or therapeutic effect.