EUS-guided pancreatic drainage: A steep learning curve.
EUS-guided pancreatic drainage (EUS-PD) is an efficacious, acceptable risk option for patients with pancreatic duct obstruction who fail conventional ERCP. The aim of this study was to define the learning curve (LC) for EUS-PD. Consecutive patients undergoing EUS-PD by a single operator were included from a dedicated registry. Demographics, procedural info, adverse events, and follow-up data were collected. Nonlinear regression and cumulative sum (CUSUM) analyses were conducted for the LC. Fifty-six patients were included (54% of male, with a mean age of 58 years). Technical success was achieved in 47 patients (84%). Stent placement was antegrade in 36 patients (77%) and retrograde in 11 (23%). Clinical success was achieved in 46/47 (98%) patients who achieved technical success. Adverse events were seen in 13 patients (6 of whom did not achieve technical success) and included bleeding requiring embolization (n = 5), bleeding treated with clips peri-procedurally (n = 1), pancreatitis (n = 5), and a pancreatic fluid collection drained via EUS-drainage (n = 2). The median procedural time was 80 min (range 49-159 min). The CUSUM chart showed that 80-min procedural time was achieved at the 27th procedure. Durations further reduced 40th procedure onward, reaching a plateau indicating proficiency (nonlinear regression P < 0.0001). Endoscopists experienced in EUS-PD are expected to achieve a reduction in procedural time over successive cases, with efficiency reached at 80 min and a learning rate of 27 cases. Continued improvement is demonstrated with additional experience, with plateau indicating mastery suggested at the 40th case. EUS-PD is probably one of the hardest therapeutic endosonographic procedures to learn.


Ophthalmic delivery of Cyclosporine A from Brij-97 microemulsion and surfactant-laden p-HEMA hydrogels.
Cyclosporine A (CyA) is an immunosuppressant drug that is used for treating a variety of ocular diseases and disorders. CyA is commonly delivered via eye drops, which is highly inefficient due to a low bioavailability of less than 5%. The bioavailability of ophthalmic drugs can be substantially improved to about 50% by delivering them via contact lenses. This paper focuses on the development of nanostructured poly (2-hydroxyethyl methacrylate) (p-HEMA) hydrogels containing microemulsions or micelles of Brij 97 (C(18)H(35)(OCH(2)CH(2))(10)) for extended delivery of CyA. Release of CyA from these nanostructured hydrogels was performed in vitro to explore the mechanisms of release and the effects of surfactant concentration, processing conditions and storage on the release kinetics. Results show that the surfactant and microemulsion-laden gels can deliver CyA at therapeutic dosages for a period of about 20 days. Release of the drug is diffusion controlled with effective diffusivities decreasing with increasing surfactant loading. The release kinetics are relatively similar for both surfactant and microemulsion-laden gels with comparable surfactant loading. The results also show that these hydrogels retain their effectiveness even after exposure to all the relevant processing conditions including unreacted monomer extraction, autoclaving and packaging, and so these materials seem to be very promising for ophthalmic delivery of CyA and perhaps other drugs.


Activity of (+)-cyclaradine (Sch 31172) against herpes simplex virus in vitro and in vivo.
(+)-Cyclaradine (Sch 31172) is the carbocyclic derivative of adenosine arabinoside (9-beta-D-arabinofuranosyladenine). Because it is not deaminated by deaminase in serum, as is adenosine arabinoside, (+)-cyclaradine is about 2 to 5 times more active in vitro against herpes simplex virus. (+)-Cyclaradine has in vitro activity nearly equivalent to that of phosphonoformate but is significantly less active than acycloguanosine (acyclovir; ACV), trifluorothymidine, or 9-(1,3-dihydroxy-2-propoxymethyl)guanine. The absolute ratios of in vitro activities are difficult to determine because of variability among virus strains, inoculum size, and dependence on the tissue culture cell line in which the comparative test is carried out. (+)-Cyclaradine is active against TK-, ACV-resistant mutants. In the guinea pig model of vaginal herpes simplex virus infection, (+)-cyclaradine is only slightly less active than ACV when both molecules are nearly equivalently bioavailable; thus, the large difference in activity seen in vitro is not reflected in this in vivo model system.


Korea Community Health Survey Data Profiles.
In 2008, Korea Centers for Disease Control and Prevention initiated the first nationwide survey, Korea Community Health Survey (KCHS), to provide data that could be used to plan, implement, monitor, and evaluate community health promotion and disease prevention programs. This community-based cross-sectional survey has been conducted by 253 community health centers, 35 community universities, and 1500 interviewers. The KCHS standardized questionnaire was developed jointly by the Korea Centers for Disease Control and Prevention staff, a working group of health indicators standardization subcommittee, and 16 metropolitan cities and provinces with 253 regional sites. The questionnaire covers a variety of topics related to health behaviors and prevention, which is used to assess the prevalence of personal health practices and behaviors related to the leading causes of disease, including smoking, alcohol use, drinking and driving, high blood pressure control, physical activity, weight control, quality of life (European Quality of Life-5 Dimensions, European Quality of Life-Visual Analogue Scale, Korean Instrumental Activities of Daily Living ), medical service, accident, injury, etc. The KCHS was administered by trained interviewers, and the quality control of the KCHS was improved by the introduction of a computer-assisted personal interview in 2010. The KCHS data allow a direct comparison of the differences of health issues among provinces. Furthermore, the provinces can use these data for their own cost-effective health interventions to improve health promotion and disease prevention. For users and researchers throughout the world, microdata (in the form of SAS files) and analytic guidelines can be downloaded from the KCHS website (http://KCHS.cdc.go.kr/) in Korean.


[Induction and identification of polyploid of Astragalus membranaceus var. mongholicus].
In this article, improved agar painting method, with semi-solid of 0.2% colchicine and 0.1% agar, was adopted to treat apical buds of Astragalus membranaceus var. mongholicus (Bge.) Hsiao seedlings. Obtained plants were proved to be tetraploids by identification of biological characteristics and chromosome numbers.


Effects of chronic acceleration in animals.
Chronic acceleration describes the exposure of animals to increased acceleration fields of sufficient intensity and duration to induce physiological adaptation. By comparing the degree of changes observed in several fields with the acceleration intensity, it is possible to derive an estimate of the biological effect of gravity. For technical reasons, such studies are limited to artificial fields produced by protracted centrifugation. Observations by various investigators indicate a fairly general response to chronic acceleration. Over the size range presented by these species (0.04-5 kg), there appears to be a direct relationship between body mass and the degree of the acceleration-induced effect (tolerable field intensity, growth repression, inhibition of fat (correction of far) deposition, etc.). However, different response patterns may obtain in homeotherms that differ significantly from this body size range.


Kir2.1 Interaction with Stk38 Promotes Invasion and Metastasis of Human Gastric Cancer by Enhancing MEKK2-MEK1/2-ERK1/2 Signaling.
Potassium ion channels are emerging as promalignant factors involved in cancer progression. In this study, we found that invading human gastric cancer cells express high levels of inwardly rectifying potassium channel 2.1 (Kir2.1). Silencing Kir2.1 markedly reduced the invasive and metastatic capabilities as well as the epithelial-mesenchymal transition (EMT) of gastric cancer cells. The promalignant nature of Kir2.1 in gastric cancer cells was independent of potassium permeation but relied on its interaction with serine/threonine-protein kinase 38 (Stk38) to inhibit ubiquitination and degradation of mitogen-activated protein kinase kinase kinase 2 (MEKK2). Degradation of MEKK2 was mediated by small mothers against decapentaplegic-specific E3 ubiquitin protein ligase 1 (Smurf1), which resulted in activation of the MEK1/2-ERK1/2-Snail pathway in gastric cancer cells. In human gastric cancer tissues, expression was high and positively correlated with invasion depth and metastatic status of the tumors as well as poor overall patient survival. Cox regression analysis identified Kir2.1 as an independent prognostic indicator for patients with gastric cancer. Our results suggest that Kir2.1 is an important regulator of gastric cancer malignancy and acts as a novel prognostic marker and a therapeutic target for gastric cancer.Significance: Kir2.1 contributes to invasion and metastasis by a noncanonical ion permeation-independent signaling pathway and may act as a novel prognostic marker and therapeutic target for gastric cancer. Cancer Res; 78(11); 3041-53. ©2018 AACR.


Differential gene expression of cytochrome P450 11beta-hydroxylase in rat adrenal cortex after in vivo activation.
In situ hybridization histochemistry was used to monitor the expression of 3beta-hydroxysteroid dehydrogenase, delta4-isomerase (3betaHSD) and cytochrome P450 11beta-hydroxylase (P45011beta) messenger RNA (mRNA) in adult rat adrenals after stimulation in vivo. In Exp 1, adrenals were collected from rats injected with saline or ACTH for 1, 2, 3, or 4 days. Adrenal sections from saline-treated rats showed uniform expression of 3betaHSD mRNA that extended from the adrenal capsule to the medullary border. In contrast, P45011beta mRNA showed high levels in the outer fasciculata and low levels in the inner fasciculata/reticularis. In response to ACTH, the integrated density of 3betaHSD hybridization did not increase until 4 days. The integrated density of P45011beta hybridization increased in ACTH-treated rats between 1-4 days due to increased hybridization in the inner fasciculata/reticularis. In Exp 2, rats were treated with ACTH or saline, and adrenals were harvested at 4, 8, or 24 h. The hybridization density of 3betaHSD did not change after ACTH or saline injection. Increased expression of P45011beta mRNA was observed at 4 and 8 h, but not 24 h post-ACTH. In Exp 3, to determine the response to acute stress, adrenals were collected from rats 24 h after surgical laparotomy. The integrated density of 3betaHSD labeling did not change, whereas both hybridization area and mean density of P45011beta increased. Increased expression of P45011beta mRNA was observed in the inner fasciculata similar to that observed after ACTH injection. In addition, adrenal cells were more responsive to ACTH in vitro after surgical stress. These results suggest that the rat adrenal cortex can respond to acute stress by up-regulation of the expression of steroidogenic enzyme genes and that this occurs in part by increasing the number of cells actively expressing P45011beta mRNA. The adrenal response after stress most likely results at least in part from stimulation by ACTH. These findings suggest that changes in adrenal steroidogenesis in response to ACTH may result from recruitment of steroidogenic cells to synthesize and secrete corticosteroids.


Very severe HLA B27-associated panuveitis mimicking endophthalmitis: a case series.
To report rare but important instances of very severe, hyperacute HLA B27-associated panuveitis, mimicking infective endophthalmitis and providing challenges to both diagnosis and management. Retrospective case review. Four patient records were reviewed. Demographic features, clinical findings, course of uveitis, diagnostic/therapeutic measures, and outcomes are reported. All cases presented with severe panuveitis with visual acuities below 6/60 and poor fundal views. Three patients underwent intraocular fluid sampling for microbiology. All required systemic high-dose corticosteroid treatment, and two also needed oral immunosuppression. All eventually required cataract extraction. Final visual acuity varied from 6/12 to 6/6. HLA B27-associated uveitis may be unusually severe and may cause a panuveitis, mimicking infective endophthalmitis. The course may be prolonged and difficult with frequent complications including cataract.


Unlocking the secrets of peptide transport in wine yeast: insights into oligopeptide transporter functions and nitrogen source preferences.
Limited nitrogen supply can prevent the completion of alcoholic fermentation. Supplementation through peptides as an alternative, natural source of nitrogen for yeast offers an interesting solution for this issue. In this work, the S. cerevisiae peptide transporters of the Opt and Fot families were studied. We demonstrated that Fot and Opt2 have a broader peptide length preference than previously reported, enabling yeasts to acquire sufficient nitrogen from peptides without requiring additional ammonia or amino acids to complete fermentation. On the contrary, Opt1 was unable to consume any peptide in the given conditions, whereas it has been described elsewhere as the main peptide transporter for peptides longer than three amino acid residues in experiments in laboratory conditions. This controversy signifies the need in applied sciences for approaching experimental conditions to those prevalent in the industry for its more accurate characterization. Altogether, this work provides further evidence of the importance of peptides as a nitrogen source for yeast and their consequent positive impact on fermentation kinetics.


Orf with unusual features.
We describe a case of Orf in an immunocompetent man with no history of direct contact with farm animals. The patient presented with numerous large lesions on hands and feet including a lesion in the subungual area. Later on multiple lesions with more bizarre morphology developed on the trunk. The diagnosis was suspected on clinical appearance of the lesion and confirmed later by histopathology. We consider contact with contaminated soil as the possible source of infection as virus can survive in pastures. Awareness of unusual clinical patterns of known entities is important to avoid unnecessary interventions.


Complete Genome Sequence of a Pseudomonas putida Clinical Isolate, Strain H8234.
We report the complete genome sequence of Pseudomonas putida strain H8234, which was isolated from a hospital patient presenting with bacteremia. This strain has a single chromosome (6,870,827 bp) that contains 6,305 open reading frames. The strain is not a pathogen but exhibits multidrug resistance associated with 40 genomic islands.


Endovascular Exclusion of Aortobronchial Fistula and Distal Anastomotic Aneurysm after Extra-Anatomic Bypass for Aortic Coarctation.
The treatment of choice for aortic coarctation in adults remains open surgical repair. Aortobronchial fistula is a rare but potentially fatal late sequela of surgical correction of isthmic aortic coarctation via the interposition of a graft. The endovascular treatment of aortobronchial fistula is still under discussion because of its high risk for infection, especially if the patient has a history of cardiovascular prosthetic implantation. Patients need close monitoring, most notably those with secondary aortobronchial fistula. We discuss the case of a 65-year-old man who presented with the combined conditions, and we briefly review the relevant medical literature.


Children's art as a helpful index of anxiety and self-esteem with plastic surgery.
Children often cannot adequately express their feelings about physical issues that may be affecting them emotionally. Nonverbal communication with art has been a time-tested tool in understanding and interpreting the feelings of children under stress. For 27 years, the author has used art as a helpful index of anxiety and self-esteem in children undergoing plastic surgery for congenital, traumatic, and aesthetic problems. A child psychiatrist and an art therapist evaluated 200 drawings. The evaluations corroborated the need to "listen" to our patients no matter what their size.


Induction of differentiation of avian erythroblastosis virus-transformed erythroblasts by the protein kinase inhibitor H7: analysis of the transcription factor EF1.
The protein kinase inhibitor H7 [1-5(isoquinolinesulfonyl-2-methylpiperazine)] together with a temperature shift to 42 degrees C was found to reproducibly and efficiently induce differentiation of avian erythroblasts transformed with the avian erythroblastosis virus containing v-erbA and a temperature-sensitive v-erbB oncogene. Although a temperature shift to 42 degrees C without H7 results in some elevation of globin transcripts, much higher levels of transcripts accrue when cells are incubated at 42 degrees C with H7; under such conditions, 50-70% of the cells become benzidine positive. In order to investigate the mechanism by which the differentiation occurs, we have characterized and analyzed the levels of the erythroid transcription factor EF1, originally described as a factor binding to the beta H-globin promoter. Protein sequencing of EF1 shows that it is identical to the factor Eryf1. Using a peptide antibody and DNA-binding assays, we demonstrate that EF1 is present at high levels in the nucleus of undifferentiated HD3 cells, and, although there may be a small change when the cells are shifted to 42 degrees C, incubation of the cells with H7 at 42 degrees C does not result in a further elevation commensurate with the high levels of globin transcripts. It is concluded that v-erbA and v-erbB do not repress differentiation by limiting the levels of EF1.


Initial evaluation and management of the patient with suspected pneumonia.
Pneumonia is a common cause of outpatient and emergency department visits. These patients frequently require hospitalization. In spite of improvements in medical care, pneumonia remains a leading cause of death in the United States. Patients must be aggressively evaluated and treated. Familiarity with evolving trends in diagnostic testing, antimicrobial therapy, and regulatory standards will help clinicians provide high quality care.


The separation of racemic crystals into enantiomers by chiral block copolymers.
A series of chiral double hydrophilic block copolymers (DHBCs) was synthesized and employed as additives in the crystallization of calcium tartrate tetrahydrate (CaT). We found that appropriate polymers can slow down the formation of the thermodynamically most stable racemic crystals as well as the formation of one of the pure enantiomeric crystals so that chiral separation by crystallization occurs even when racemic crystals can be formed. In addition, the presence of DHBCs results in major modifications of crystal morphology, creating unusual morphologies of higher complexity. Our study demonstrates the potential application of chiral DHBCs in the control of chirality throughout crystallization, in particular for racemic crystal systems, and also shows that enantiomeric excess of one enantiomer can be maximized by the kinetic control of crystallization.


Cell volume regulation in renal cortical cells.
Both proximal renal tubule cells and cultured Madin-Darby canine kidney (MDCK) cells are capable of regulating their volume in hypotonic media. Regulatory cell volume decrease in proximal straight tubules is impaired by barium, amiloride and acetazolamide and depends on the presence of bicarbonate and of sodium, whereas it is unaffected by complete removal of extracellular chloride. The observations may point to parallel loss of potassium through potassium channels as well as of bicarbonate and sodium via a bicarbonate-sodium cotransport. Alternatively, potassium/hydrogen ion exchange or potassium bicarbonate cotransport could be involved. In MDCK cells, exposure to hypotonic media apparently leads to the activation of an anion channel, while potassium conductance is rather decreased. In both proximal tubules and MDCK cells, volume regulatory decrease is possibly triggered by leucotrienes, which may be released during cell swelling. Cell volume is altered in a variety of conditions even at isotonic extracellular fluid and cell volume-regulatory mechanisms are likely to participate in regulation of renal transepithelial transport.


Percutaneous biopsy for adrenal tumors using ultrasonically guided puncture.
Percutaneous biopsy for adrenal tumors was performed on 12 patients using ultrasonically guided puncture. Of the 12 tumors, 11 were detected incidentally by ultrasonography or computed tomography. In 11 cases, cytological or pathological diagnosis was obtained without any complication. Among these, surgical operation was carried out in 4 cases, in which biopsy findings were confirmed by the examination of the surgical specimens. The other 7 cases were being followed up without surgery. The rate of correct discrimination between benign and malignant adrenal tumors by biopsy was 91% (10/11 cases) in this series. It is accordingly considered that adrenal biopsy is the choice to confirm the diagnosis of nonfunctioning adrenal tumors because of its efficacy and ease of use.


A Green's function method for simulation of time-dependent solute transport and reaction in realistic microvascular geometries.
A novel theoretical method is presented for simulating the spatially resolved convective and diffusive transport of reacting solutes between microvascular networks and the surrounding tissues. The method allows for efficient computational solution of problems involving convection and non-linear binding of solutes in blood flowing through microvascular networks with realistic 3D geometries, coupled with transvascular exchange and diffusion and reaction in the surrounding tissue space. The method is based on a Green's function approach, in which the solute concentration distribution in the tissue is expressed as a sum of fields generated by time-varying distributions of discrete sources and sinks. As an example of the application of the method, the washout of an inert diffusible tracer substance from a tissue region perfused by a network of microvessels is simulated, showing its dependence on the solute's transvascular permeability and tissue diffusivity. Exponential decay of the washout concentration is predicted, with rate constants that are about 10-30% lower than the rate constants for a tissue cylinder model with the same vessel length, vessel surface area and blood flow rate per tissue volume.


Pharmacological characterization of teroxirone, a triepoxide antitumor agent, in rats, rabbits, and humans.
Teroxirone is an experimental triepoxide antitumor agent currently undergoing evaluation in clinical trials. We have developed an assay based on derivatization with diethyldithiocarbamate followed by normal-phase high-performance liquid chromatographic analysis. When 14C-labeled teroxirone is administered to rabbits by rapid i.v. infusion, plasma disappearance of parent drug is very rapid (t1/2 less than 5 min), while plasma 14C-labeled drug equivalents are eliminated at a much slower rate (t1/2 greater than 60 min). Twenty-four-hr urinary recovery of parent drug is less than 1%, while recovery of 14C total radioactivity is 60 to 70%. Rapid plasma elimination (t1/2 less than 5 min) and total body clearance (greater than 5 liters/min) are observed following rapid i.v. administration of teroxirone to humans. When teroxirone is administered to humans at constant rates of infusion, plateau concentrations are rapidly achieved and maintained during infusion. Plasma concentrations rapidly decrease upon cessation of infusion. Less than 1% parent drug is recovered in 24-hr urine. Teroxirone is relatively stable in fresh human plasma and whole blood. Teroxirone is metabolized by rat liver, but not lung, microsomal preparations by an NADPH-independent pathway. Epoxide hydrolysis metabolites are detected in microsomal incubations, and cyclohexene oxide inhibits teroxirone metabolism, suggesting that epoxide hydrase may be responsible for teroxirone biotransformation. Cytotoxicity of teroxirone against continuous human tumor cell lines is abolished in the presence of 9000 X g rat liver supernatant preparations but partially restored when cyclohexene oxide is added to incubation mixtures.


Endocrine Long-Term Follow-Up of Children with Neurofibromatosis Type 1 and Optic Pathway Glioma .
Children with optic pathway glioma (OPG) face sequelae related to tumour location and treatment modalities. We aimed to assess the prevalence of hypothalamic-pituitary dysfunctions in children with neurofibromatosis type 1 (NF1) and OPG who did not receive radiotherapy or surgical resection. The causative role of tumour location on endocrinopathy development is investigated. A retrospective follow-up study of 40 children with NF1 and OPG evaluated between August 1996 and May 2015 was undertaken. Patients who underwent radiotherapy or surgical resection were excluded and 36 patients were studied. Tumour location was classified according to the Dodge criteria: stage I, optic nerve alone; stage II, optic chiasm with or without optic nerve involvement; and stage III, involvement of the hypothalamus or other adjacent structures. Endocrinopathies were diagnosed in 20/36 (55.6%) children during a mean follow-up of 9.1 (0.2-13.6) years: 0/4 OPGs were Dodge stage I, 12/21 (57.1%) stage II, and 8/11 (72.7%) stage III. The first endocrinopathy was found at a mean age of 7.4 (5.0-13.2) years, 2.4 (0-6.7) years after tumour diagnosis. We found growth hormone deficiency (GHD; 36.1%), central precocious puberty (33.3%), obesity with insulin resistance/impaired glucose tolerance (11.1%), early puberty (5.5%), GH excess (5.5%), ACTH deficiency (5.5%), hypogonadotropic hypogonadism (2.7%), and thyrotropin deficiency (2.7%). GHD was transient in all of those who were retested. This population is at high risk of endocrinopathies due to tumour location. Lifelong endocrine follow-up is recommended. .


A systematic review of dedicated models of care for emergency urological patients.
To systematically evaluate the spectrum of models providing dedicated resources for emergency urological patients (EUPs). A search of Cochrane, Embase, Medline and grey literature from January 1, 2000 to March 26, 2019 was performed using methods pre-published on PROSPERO. Reporting followed Preferred Reporting Items for Systematic Review and meta-analysis guidelines. Eligible studies were articles or abstracts published in English describing dedicated models of care for EUPs, which reported at least one secondary outcome. Studies were excluded if they examined pathways dedicated only to single presentations, such as torsion, or outpatient solutions, such as rapid access clinics. The primary outcome was the spectrum of models. Secondary outcomes were time-to-theatre, length of stay, complications and cost. Seven studies were identified, totalling 487 patients. Six studies were conference abstracts, while one study was of full-text length but published in grey literature. Four distinct models were described. These included consultant urologists allocated solely to the care of EUPs ("Acute Urological Unit") or dedicated registrars or operating theatres ("Hybrid structures"). In some services, EUPs bypassed emergency department assessment and were referred directly to urology ("Urological Assessment Unit") or were managed by other dedicated means. Allocating services to EUPs was associated with reduced time-to-theatre, length of stay and hospital cost, and improved supervision of junior medical staff. Multiple dedicated models of care exist for EUPs. Low-level evidence suggests these may improve outcomes for patients, staff and hospitals. Higher quality studies are required to explore patient outcomes and minimum requirements to establish these models.


Modulation of DNA polymerases alpha, delta and epsilon by lactate dehydrogenase and 3-phosphoglycerate kinase.
Literature documents that glycolytic enzymes (among them lactate dehydrogenase and 3-phosphoglycerate kinase) can reside in nuclei of mammalian cells and exert functions in DNA replication, transcription and DNA repair, in addition to their role as catalysts in the cytoplasm. Transfer of glycolytic enzymes to cell nuclei requires modification, for example phosphorylation. We studied the effects of phosphorylated lactate dehydrogenase and 3-phosphoglycerate kinase on (i) UV-induced DNA repair, using permeabilized human fibroblasts, and (ii) in vitro DNA synthesis catalyzed by purified DNA polymerases alpha, delta, and epsilon from proliferating rat liver. (i) Phosphorylated lactate dehydrogenase stimulated UV-induced DNA repair synthesis in normal fibroblasts in a dose-dependent manner; the unphosphorylated enzyme slightly inhibited. In repair-deficient xeroderma pigmentosum fibroblasts reparative synthesis was not enhanced whether lactate dehydrogenase was phosphorylated or not, indicating that reparative DNA synthesis must be possible in order to be stimulated. (ii) Activity of purified DNA polymerases alpha, delta, and epsilon was differentially stimulated or inhibited, according to the phosphorylation status of lactate dehydrogenase. DNA polymerases were also modulated by 3-phosphoglycerate kinase, depending on the primer-templates used which were gapped DNA (mimicking a repair mode of DNA synthesis) or single-stranded M13 DNA (representing the replicative mode of DNA synthesis). Since glycolytic enzymes in cell nuclei retain binding ability for their cofactors, cytoplasmic substrates and inhibitors, a regulatory linkage might exist between the energy state of a cell and its replicative and reparative functions.


Non small cell carcinoma metastasis to meningioma.
"Tumor-to-tumor" metastasis is a rare event; meningioma has been reported as the most common primary intracranial tumor to harbor cancer metastases. Several hypotheses have been previously proposed to explain this occurrence, but the exact mechanism by which these metastases develop into meningiomas is not yet understood. Magnetic resonance imaging and spectroscopy have been valuable diagnostic tools, but preoperative diagnosis of metastasis to meningioma remains highly difficult. We present a case report of a metastasis of non-small cell lung cancer into an intracranial meningioma.


Steam-air fluidized bed gasification of distillers grains: Effects of steam to biomass ratio, equivalence ratio and gasification temperature.
In this study, thermochemical biomass gasification was performed on a bench-scale fluidized-bed gasifier with steam and air as fluidizing and oxidizing agents. Distillers grains, a non-fermentable byproduct of ethanol production, were used as the biomass feedstock for the gasification. The goal was to investigate the effects of furnace temperature, steam to biomass ratio and equivalence ratio on gas composition, carbon conversion efficiency and energy conversion efficiency of the product gas. The experiments were conducted using a 3x3x3 full factorial design with temperatures of 650, 750 and 850 degrees C, steam to biomass ratios of 0, 7.30 and 14.29 and equivalence ratios of 0.07, 0.15 and 0.29. Gasification temperature was found to be the most influential factor. Increasing the temperature resulted in increases in hydrogen and methane contents, carbon conversion and energy efficiencies. Increasing equivalence ratio decreased the hydrogen content but increased carbon conversion and energy efficiencies. The steam to biomass ratio was optimal in the intermediate levels for maximal carbon conversion and energy efficiencies.


HTsort: Enabling Fast and Accurate Spike Sorting on Multi-Electrode Arrays.
Spike sorting is used to classify the spikes (action potentials acquired by physiological electrodes), aiming to identify their respective firing units. Now it has been developed to classify the spikes recorded by multi-electrode arrays (MEAs), with the improvement of micro-electrode technology. However, how to improve classification accuracy and maintain low time complexity simultaneously becomes a difficulty. A fast and accurate spike sorting approach named HTsort is proposed for high-density multi-electrode arrays in this paper. Several improvements have been introduced to the traditional pipeline that is composed of threshold detection and clustering method. First, the divide-and-conquer method is employed to utilize electrode spatial information to achieve pre-clustering. Second, the clustering method HDBSCAN (hierarchical density-based spatial clustering of applications with noise) is used to classify spikes and detect overlapping events (multiple spikes firing simultaneously). Third, the template merging method is used to merge redundant exported templates according to the template similarity and the spatial distribution of electrodes. Finally, the template matching method is used to resolve overlapping events. Our approach is validated on simulation data constructed by ourselves and publicly available data and compared to other state-of-the-art spike sorters. We found that the proposed HTsort has a more favorable trade-off between accuracy and time consumption. Compared with MountainSort and SpykingCircus, the time consumption is reduced by at least 40% when the number of electrodes is 64 and below. Compared with HerdingSpikes, the classification accuracy can typically improve by more than 10%. Meanwhile, HTsort exhibits stronger robustness against background noise than other sorters. Our more sophisticated spike sorter would facilitate neurophysiologists to complete spike sorting more quickly and accurately.


[Estimation of vitamin status of moscow student according to data on vitamins intake and their levels in blood].
Supply with vitamins C, A, E and B2 of 61 high school students (38 girls and 23 boys, aged 18–22 years, body mass index – 23.0±0.6 kg/m2) by means of determination of blood plasma concentration of ascorbic acid, retinol and carotenoids, tocopherols and riboflavin has been investigated in the period from May to September. All students were well supplied with vitamin C (only 2 boys had a reduced level of ascorbic acid) and vitamin A. Decreased level of carotenoids was more common in boys (48 versus 24% in girls). 20% of the students were insufficiently supplied with vitamin E, 38% – with vitamin B2. 39% of students (50% girls and 22% boys) were adequately provided with all studied vitamins. 5% of the students had a combined deficiency of 3 vitamins, 20% – 2 vitamins. Student's sufficiency with vitamins B2, C, A, E, carotenoids did not depend on the season. Diet intake of vitamins C, A, carotenoids and vitamin B2 has been calculated basing on the data on the frequency of food consumption during the previous month. Reduced consumption relatively to the Russia RDA of vitamins В2, C and А took place in 63, 54 and 46% of the students respectively. The lack of vitamin B2 in the diet was most pronounced, the value of probabilistic risk corresponded to the average level in 34% of students. Average probabilistic risk of inadequate intake of vitamin A was present in 17% of students, vitamin C – 6%. Coincidence of the results of vitamin C and A status assessment obtained by calculation of vitamin diet intake and by biochemical methods (concentration of vitamins in the blood plasma) was 94 and 83%. These methods are interchangeable if you select the value of the average probability of risk failure intake of these vitamins as a criterion. Proportion of coinciding results of the estimation of vitamin B2 status was 56%. Special well-designed studies on larger sample surveyed are needed for the final output of the interchangeability of methods to assess riboflavin status.


Differentiable SAR Renderer and Image-Based Target Reconstruction.
Forward modeling of wave scattering and radar imaging mechanisms is the key to information extraction from synthetic aperture radar (SAR) images. Like inverse graphics in the optical domain, an inherently-integrated forward-inverse approach would be promising for SAR advanced information retrieval and target reconstruction. This paper presents such an attempt at inverse graphics for SAR imagery. A differentiable SAR renderer (DSR) is developed, which reformulates the mapping and projection algorithm of the SAR imaging mechanism in the differentiable form of probability maps. First-order gradients of the proposed DSR are then analytically derived, which can be back-propagated from rendered image/silhouette to the target geometry and scattering attributes. A 3D inverse target reconstruction algorithm from SAR images is devised. Several simulation and reconstruction experiments are conducted, including targets with and without background, using synthesized data or real measured inverse SAR (ISAR) data by ground radar. Results demonstrate the efficacy of the proposed DSR and its inverse approach.


Intracranial hemorrhage in a term newborn with severe von Willebrand disease type 3 associated with sinus venous thrombosis.
Intracranial hemorrhage of term neonates with severe von Willebrand disease type 3 and near normal delivery have not been published to date. We report on a term newborn with severe type 3 VWD who suffered a large intracranial bleeding presumably subsequent to sinus venous thrombosis. This case is remarkable in two aspects: i) with respect to the low risk of perinatal intracranial hemorrhage even in neonates with VWD type 3 and ii) since VWD type 3 with factor VIII:C levels < 5 IU/dl does not seem to protect from thromboembolism. Guidelines for the management of hemophilia advise atraumatic delivery of neonates with known or suspected bleeding disorders, however primary caesarean section in the absence of complications is not obligatory. To answer the question whether the presented case could have an impact on the recommended management we carried out a worldwide survey including 24 participating specialized centers. Except a single case from Sweden of a female neonate with VWD type 3 who also had an inhibitor against VWF no further cases were reported to us. We conclude that CNS bleeding in term neonates with severe VWD type 3 is a rare event that requires additional risk factors for manifestation. Therefore, the amendment of current guidelines does not seem to be mandatory.


[Possibility of detecting visual functional disturbance in rats by the open-field test].
In order to determine whether visual disturbance in small rodents is detectable by means of the open-field test, the ambulation scores of enucleated and intact rats in an open-field were measured. In a 30-min test of Slc:Wistar/ST rats, there were significant differences in ambulation scores between enucleated and intact rats in the first 10-min. In addition, the effects of observation times (09:00-11:00, 13:00-15:00 and 17:00-19:00 hr) and strains on the open-field test were studied using a 10-min test. Regardless of observation times, ambulation scores of enucleated rats of the Slc:Wistar/ST and F344/N Slc strains were significantly elevated as compared with those of intact rats from both strains. When tested during the 13:00-15:00 hr period, there were significant differences in the Slc:SD rats. These findings indicate that the changes in ambulation are due to visual disturbance. However, significant ambulatory changes in F344/N Slc rats were documented at the three different observation times. Based on these results, Slc:Wistar/ST rats appear to be suitable for detecting visual disturbance by the open-field test.


The modular organization of the cerebral cortex: Evolutionary significance and possible links to neurodevelopmental conditions.
The recognition of discernible anatomical regularities that appear to self-organize during development makes apparent the modular organization of the cerebral cortex. The metabolic cost engendered in sustaining interneuronal communications has emphasized the viability of short connections among neighboring neurons. This pattern of connectivity establishes a microcircuit which is repeated in parallel throughout the cerebral cortex. This canonical circuit is contained within the smallest module of information processing of the cerebral cortex; one which Vernon Mountcastle called the minicolumn. Plasticity within the brain is accounted, in part, by the presence of weak linkages that allow minicolumns to process information from a variety of sources and to quickly adapt to environmental exigencies without a need for genetic change. Recent research suggests that interlaminar correlated firing between minicolumns during the decision phase of target selection provides for the emergence of some executive functions. Bottlenecks of information processing within this modular minicolumnar organization may account for a variety of mental disorders observed in neurodevelopmental conditions.


[Global strategies in prevention of infectious diseases on the turn of the second and third millennium: expectation versus reality].
Prevention has been the greatest success in the field of infectious diseases. Control of infectious diseases is being challenged by many factors, like standards of living, human behaviour, mass population movements, emergence of infectious like HIV/AIDS and SARS, the re-emergence of infections such as tuberculosis, development of resistance in bacteria, viruses and parasites, modern rate of global travel, etc. Although great advances have been made, a considerable burden of morbidity and mortality from infectious diseases remains globally. The aim of any control program can be defined by three levels--containment, elimination and eradication. Prevention methods are many aspects, including introduction of prevention guidelines, low cost interventions, vector control, surveillance, and vaccination, etc.


Detecting and classifying lesions in mammograms with Deep Learning.
In the last two decades, Computer Aided Detection (CAD) systems were developed to help radiologists analyse screening mammograms, however benefits of current CAD technologies appear to be contradictory, therefore they should be improved to be ultimately considered useful. Since 2012, deep convolutional neural networks (CNN) have been a tremendous success in image recognition, reaching human performance. These methods have greatly surpassed the traditional approaches, which are similar to currently used CAD solutions. Deep CNN-s have the potential to revolutionize medical image analysis. We propose a CAD system based on one of the most successful object detection frameworks, Faster R-CNN. The system detects and classifies malignant or benign lesions on a mammogram without any human intervention. The proposed method sets the state of the art classification performance on the public INbreast database, AUC = 0.95. The approach described here has achieved 2nd place in the Digital Mammography DREAM Challenge with AUC = 0.85. When used as a detector, the system reaches high sensitivity with very few false positive marks per image on the INbreast dataset. Source code, the trained model and an OsiriX plugin are published online at https://github.com/riblidezso/frcnn_cad .


A regulatory role for TRAF1 in antigen-induced apoptosis of T cells.
Tumor necrosis factor receptor (TNFR)-associated factor 2 (TRAF2) and TRAF1 were found as components of the TNFR2 signaling complex, which exerts multiple biological effects on cells such as cell proliferation, cytokine production, and cell death. In the TNFR2-mediated signaling pathways, TRAF2 works as a mediator for activation signals such as NF-kappaB, but the role of TRAF1 has not been previously determined. Here we show in transgenic mice that TRAF1 overexpression inhibits antigen-induced apoptosis of CD8(+) T lymphocytes. Our results demonstrate a biological role for TRAF1 as a regulator of apoptotic signals and also support the hypothesis that the combination of TRAF proteins in a given cell type determines distinct biological effects triggered by members of the TNF receptor superfamily.


Metabolic response of Clostridium ljungdahlii to oxygen exposure.
Clostridium ljungdahlii is an important synthesis gas-fermenting bacterium used in the biofuels industry, and a preliminary investigation showed that it has some tolerance to oxygen when cultured in rich mixotrophic medium. Batch cultures not only continue to grow and consume H2, CO, and fructose after 8% O2 exposure, but fermentation product analysis revealed an increase in ethanol concentration and decreased acetate concentration compared to non-oxygen-exposed cultures. In this study, the mechanisms for higher ethanol production and oxygen/reactive oxygen species (ROS) detoxification were identified using a combination of fermentation, transcriptome sequencing (RNA-seq) differential expression, and enzyme activity analyses. The results indicate that the higher ethanol and lower acetate concentrations were due to the carboxylic acid reductase activity of a more highly expressed predicted aldehyde oxidoreductase (CLJU_c24130) and that C. ljungdahlii's primary defense upon oxygen exposure is a predicted rubrerythrin (CLJU_c39340). The metabolic responses of higher ethanol production and oxygen/ROS detoxification were found to be linked by cofactor management and substrate and energy metabolism. This study contributes new insights into the physiology and metabolism of C. ljungdahlii and provides new genetic targets to generate C. ljungdahlii strains that produce more ethanol and are more tolerant to syngas contaminants.


[Empirical research of the relationship between related knowledge, attitude and behavior of hypertension patients based on the structural equation model].
To analyze the relationship among hypertension-relevant knowledge, attitude and behavior and to provide evidence for prevention of hypertension. Methods: A total of 5 861 employees with hypertension from 10 provinces were selected, and their data were collected by uniform questionnaires. The structural equation model was established by using LISREL version 8.7. Knowledge, attitude and behavior was set as latent variables, and the observed variables corresponding to latent variables served as explicit variables. The parametric estimation of the structural equation model is based on polyserial correlation coefficients and asymptotical covariance matrix. Results: Knowledge directly affected attitude, and the impact coefficient was 0.84; attitude directly affect behavior, and the impact coefficient was 0.38; knowledge showed indirect effect on behavior; the structural equation model fitted the data well. Conclusion: Hypertension-related knowledge significantly affect attitude, while knowledge and attitude showed slight effect on behavior. There were other factors that affected the patient's behavior. It was suggested that we should fully consider the factors for behavior in health education, and adopt more appropriate measures in hypertension control.


[Relationship between obesity and death by multi-morbidity status in older adults in China].
Objective: To explore the relationship between obesity status and death stratified by different multi-morbidity status in older adults in China. Methods: Data for older Chinese adults aged ≥65 years were from Chinese Longitudinal Healthy Longevity Survey (CLHLS). Multi-morbidity patterns based on 13 chronic conditions were explored using exploratory factor analysis. Cox models were used to examine relationships between obesity status and death stratified by disease count and multi-morbidity patterns at baseline, respectively. Besides, obesity status was defined by baseline body mass index and waist circumference. Results: A total of 6 272 participants were included in the analyses. Multi-morbidity including cardio-metabolic, sensory perception and other patterns were identified. For those without any chronic condition, compared with those without central obesity, central obesity was associated with a higher risk for death (HR=1.66, 95%CI:1.04-2.66). For those only with one chronic condition, compared with normal weight, underweight was associated with a higher risk for death (HR=1.41, 95%CI: 1.10-1.80). For those with multi-morbidity, compared with normal weight, underweight increased the risk for death (HR=1.19, 95%CI:1.05-1.34). Compared with those without central obesity, central obesity decreased the risk for death (HR=0.88, 95%CI:0.78-0.99). Conclusions: Relationships between obesity status and death varied by multi-morbidity status in older adults in China. Underweight and non-central obesity were associated with increased risks for death in older adults with only one chronic disease or multi-morbidity. Therefore, it is necessary to pay attention to multi-morbidity status in the management of obesity in older adults and provide effective targeted body weight management plan.


Baseline Indicators and Implementation Strategies in a Statewide Correctional Nurse Competencies Program: Mid-Year Report.
This 3-year, public-academic workforce development project aimed to establish indicators for quality correctional nursing care to empirically test the translation of correctional nursing standards into practical and applied competencies. Approaches to document indicators and achieve implementation of a correctional nurse competency system include (a) knowledge transfer and exchange, (b) system mapping, (c) adherence to implementation plan and strategy, and (d) practice-based action research. Indicators were established. Twenty-five percent (n = 111) of nurses maintained clinical credentials beyond the basic requirements; 86% (n = 381) of nurses received continuing nursing education certificates, 98% (n = 434) of nurses were satisfied with the program, and 43% (n = 9,052) of inmate/patients were satisfied with clinical care. Quality ratings of program educators averaged 4.79 on a 5-point scale. Innovation is supported by adding continuous improvement components to the implementation of a correctional nurse competency system effort. Team members' consensus decision making enabled them to apply their domain-specific knowledge to assess the success of the implementation strategy.


Distinct roles of the cytochrome pathway and alternative oxidase in leaf photosynthesis.
In illuminated leaves, mitochondria are thought to play roles in optimizing photosynthesis. However, the roles of the cytochrome pathway (CP) and alternative oxidase (AOX) in photosynthesis, in particular in the redox state of the photosynthetic electron transport chain, are not separately characterized. We examined the effects of specific inhibition of two respiratory pathways, CP and AOX, on photosynthetic oxygen evolution and the redox state of the photosynthetic electron transport chain in broad bean (Vicia faba L.) leaves under various light intensities. Under saturating photosynthetic photon flux density (PPFD; 700 micromol photon m(-2) s(-1)), inhibition of either pathway caused a decrease in the steady-state levels of the photosynthetic O(2) evolution rate and the PSII operating efficiency, Phi(II). Because these inhibitors, at the concentrations applied to the leaves, had little effect on photosynthesis in the intact chloroplasts, two respiratory pathways are essential for maintenance of high photosynthetic rates at saturating PPFD. CP or AOX inhibition affected to Chl fluorescence parameters (e.g. photochemical quenching and non-photochemical quenching) differently, suggesting that CP and AOX contribute to photosynthesis in different ways. At low PPFD (100 micromol photon m(-2) s(-1)), only the inhibition of AOX, not CP, lowered the photosynthetic rate and Phi(II). AOX inhibition also decreased the Phi(II)/Phi(I) ratio even at low PPFD levels. These data suggest that AOX inhibition caused the over-reduction of the photosynthetic electron transport chain and induced the cyclic electron flow around PSI (CEF-PSI) even at the low PPFD. Based on these results, we discuss possible roles for CP and AOX in the light.


Femtosecond-laser-patterned origami Janus membrane toward enhanced water fog harvesting.
Fog harvesting is an effective way to relieve water shortages in arid regions; thus, improving the efficiency of fog harvesting is urgently needed for both academic research and practical applications. Here, we report an origami patterned Janus (O-P-Janus) membrane using laser-ablated copper foams inspired by origami handcraft and traditional Chinese architecture. Compared to the planar fully ablated Janus membrane, our O-P-Janus membrane, with selectively ablated rectangular areas, exhibits an exceptional water collection rate (WCR) of approximately 267%. The underlying physical mechanism of WCR enhancement is revealed and attributed to the enhanced fog adsorbing capacity on the upper superhydrophobic origami structures and the accelerated removal of accumulated droplets beneath the lower superhydrophilic V-shaped tips. This O-P-Janus membrane with excellent fog collection performance should open up a new avenue for both device designs and potential applications toward structuring-enhanced fog collection and microfluidic control platforms.


Gene knockdown by morpholino-modified oligonucleotides in the zebrafish (Danio rerio) model: applications for developmental toxicology.
The zebrafish (Danio rerio) has long been used as a model for developmental biology, making it an excellent model to use also in developmental toxicology. The many advantages of zebrafish include their small size, prolific spawning, rapid development, and transparent embryos. They can be easily manipulated genetically through the use of transgenic technology and gene knockdown via morpholino-modified antisense oligonucleotides (MOs). Knocking down specific genes to assess their role in the response to toxicant exposure provides a way to further our knowledge of how developmental toxicants work on a molecular and mechanistic level while establishing a relationship between these molecular events and morphological, behavioral, and/or physiological effects (i.e., phenotypic anchoring). In this chapter, we address important considerations for using MOs to study developmental toxicology in zebrafish embryos and provide a protocol for their use.


Marine-Based Nutraceuticals: An Innovative Trend in the Food and Supplement Industries.
Recent trends in functional foods and supplements have demonstrated that bioactive molecules play a major therapeutic role in human disease. Nutritionists and biomedical and food scientists are working together to discover new bioactive molecules that have increased potency and therapeutic benefits. Marine life constitutes almost 80% of the world biota with thousands of bioactive compounds and secondary metabolites derived from marine invertebrates such as tunicates, sponges, molluscs, bryozoans, sea slugs and many other marine organisms. These bioactive molecules and secondary metabolites possess antibiotic, antiparasitic, antiviral, anti-inflammatory, antifibrotic and anticancer activities. They are also inhibitors or activators of critical enzymes and transcription factors, competitors of transporters and sequestrants that modulate various physiological pathways. The current review summaries the widely available marine-based nutraceuticals and recent research carried out for the purposes of isolation, identification and characterization of marine-derived bioactive compounds with various therapeutic potentials.


Peptide models for beta-turns. A circular dichroism study.
The circular dichroism spectra of four beta-turn model peptides, Z-Aib-Pro-Aib-Pro-OMe (1), Piv-Pro-Aib- NHMe (2), Piv-Pro-D-Ala- NHMe (3) and Piv-Pro-Val- NHMe (4) have been examined under a wide range of solvent conditions, using methanol, hexafluoroisopropanol and cyclohexane. Type I and Type II beta-turns have been observed for peptides 1 and 2 respectively, in the solid state, while the Pro-D-Ala sequence adopts a Type II beta-turn in a related peptide crystal structure. A class C spectrum is observed for 1 in various solvents suggesting a variant of a Type I (III) structure. The Type II beta-turn is characterized by a CD spectrum having two positive CD bands at approximately 230 nm and approximately 202 nm, a feature observed in Piv-Pro-D-Ala- NHMe in cyclohexane and methanol and for Piv-Pro-Aib- NHMe in methanol. Peptide 2 exhibits solvent dependent CD spectra, which may be rationalized by considering Type II, III and V reverse turn structures. Piv-Pro-Val- NHMe adopts non-beta-turn structures in polar solvents, but exhibits a class B spectrum in cyclohexane suggesting a population of Type I beta-turns.


The diaphysial axis-metacarpal head angle in the management of fractures of the base of the proximal phalanx in children.
The diaphysial axis-metacarpal head angle (DHA) is the angle formed between the longitudinal axis of the diaphysis of the proximal phalanx and central point of the metacarpal head. The normal DHA ranges from 177.1° and 180.0°. There were no significant differences between DHA measurements when taken by the same observer at two separate occasions (P = 0.986) or when taken by two different observers (P = 0.948). We have put an algorithm of management of paediatric phalangeal base fractures incorporating the DHA in the decision making. A prospective study of 92 children (5-14 years) with phalangeal base fractures was conducted. Closed reduction was possible in all but one case in which open reduction and K-wire fixation was required. Closed reduction of the remaining 91 fractures yielded a 'good' reduction in 80 cases (no finger deformity on clinical examination with a post-reduction DHA greater than 177°). After a mean follow-up of 4.2 months, all these 80 cases qualified for an excellent outcome as per Al-Qattan's criteria. The remaining 11 children were considered to have an 'acceptable' reduction (no scissoring, but there was a mild residual lateral deviation of the finger with a DHA angle of 169.4° to 176.2°). At a mean follow-up of 28 months, all these 11 mal-united fractures remodelled with normalization of the DHA; and all 11 children qualified for an excellent outcome as per Al-Qattan's criteria. The current series stresses on the advantages of using DHA in the objective assessment of paediatric phalangeal base fractures and demonstrates the remodelling of fractures with about 10° of lateral deviation.


Tetraruthenium Polyoxometalate as an Atom-Efficient Bifunctional Oxygen Evolution Reaction/Oxygen Reduction Reaction Catalyst and Its Application in Seawater Batteries.
Although development and utilization of efficient catalysts with earth-abundant and cheap elements are desired, precious noble metal-based catalysts are still widely used and studied due to the urgent need to address energy and environmental issues. Polyoxometalates (POMs) can be excellent candidates in this context. In this study, we found that oxo-bridged tetraruthenium polyoxometalate (RuPOM) exhibits excellent electrocatalytic activity for both oxygen evolution and reduction reactions (OER and ORR) with minimal use of noble metal elements and can be used for the development of efficient seawater batteries (SWBs). The deposition of RuPOM on a desired electrode with conducting carbon Ketjen black (KB) by the simple slurry coating method imparted bifunctional OER/ORR activity to the underlying electrode. Although the mass activity was similar, RuPOM/KB mixtures exhibited superior activity even compared to commercially available Pt/C when comparing the activity per noble metal element. Based on these findings, we employed RuPOM to develop efficient SWBs. RuPOM significantly lowered the charging potential and increased the discharging potential of SWBs, which are related to OER and ORR, respectively. This study can provide insights into the development of POM-based electrocatalysts and their application in energy storage and conversion devices.


Incidence, knowledge and health seeking behaviour for perceived allergies at household level: a case study in Ilala district Dar es Salaam Tanzania.
To determine incidence of perceived allergies, causes and management, of disorders associated with allergies at household level in Ilala district. A cross sectional study was conducted in Ilala district involving a total of 400 households randomly selected 8 wards out of 22 wards in the district and head of the household interviewed using a structured questionnaire. Of the household members interviewed, 66.8% being females, about 60.0% reported to be allergic to different substances. Food 16.7%, animal dander and fur 15.4%, pollen 13.3%, house dust 11.7%, medicines 8.3%, cosmetics 5.8, and plants 6.3% were the most common causes of allergy within the households. Most individuals were not aware of the source of allergy. Only few (40.4%) respondents had some knowledge about allergy, and they acquired the information through different sources such as mass media, school, friends, other families etc. In terms of prevention, 39.2% knew how the allergies could be prevented, and 41.2% had knowledge on appropriate medicines for the control and treatment of different allergic symptoms. Skin allergies 35.9%, respiratory allergies 13.3%, and allergies of the eye 10.8% were observed to be the most common complains. The study shows high prevalence of perceived allergy disorders in the community associated with poor understanding on the possible causes and preventive measures. This highlights the need conduct public education to raise awareness on allergy with a focus on causes and avoidance of exposure to allergens to mitigate effects of allergy in the society.


Challenges in educating patients and parents about differences in sex development.
This article reviews practical approaches to talking with parents and youth about Differences in Sex Development (DSD) which are conditions that affect chromosomal, gonadal, or anatomic sexual development, one of the most personal, and in our society, private areas of life. Talking with parents and patients about these conditions can be challenging given the complexity of sexual development and the sensitive nature of the information being shared. Changing approaches to disclosing or communicating information about conditions, such as DSD are reviewed as well as factors leading to revision in the diagnostic nomenclature. Building on these developments, strategies used by an established DSD team to enhance shared decision making and partnership with families and patients are presented followed by examples of how some particularly challenging, but not uncommon clinical situations were approached. The paper concludes by endorsing the importance of understanding the social and cultural needs and beliefs of the parents and patients with DSD to set the stage for effective disclosure of medical facts. To be most useful to parents and youth, medical disclosure needs to include discussion of practical implications and strategies to help families and patients digest, understand, and work with the information provided.


Antibiotic-disrupted ribosome biogenesis facilitates tumor chemokine superinduction.
Upon exposure to internal or external stressors, ribosomes stand sentinel via modulation of ribosome assembly and protein translation. Ribosome-dependent cellular dysfunctions have been associated with pathophysiological processes during inflammation and tumorigenesis. In the present study, ribosome biogenesis was assessed to determine its effects on tumor chemokines, potentially contributing to cancer cell malignant features. In particular, ribosome biogenesis inhibition by antibiotic actinomycin D (ActD) enhanced the expression of chemokines in intestinal cancer cells under endoplasmic reticulum stress that governs multiple pro-tumoral reprogramming. Mechanistically, ribosome biogenesis inhibition superinduced proinflammatory chemokines via transcriptional and post-transcriptional regulation. Moreover, ribosomal stress-responsive p53 and its target macrophage inhibitory cytokine 1 (MIC-1) mediated chemokine superinduction by activating TGF-β-activated kinase 1 (TAK-1) and nuclear factor-kappa B (NF-κB) in intestinal cancer cells. Cancer cell-based regulation of chemokine induction via MIC-1 signaling was verified using clinical transcriptome datasets. Clinical tumor tissue-derived MIC-1 was a positive regulator of chemokines and genes involved in the ribosome biogenesis pathway, supporting the in vitro assessments. Moreover, MIC-1-correlated chemokine expressions predicted poor prognoses in patients with colorectal cancer. Ribosome-based chemokine regulation via MIC-1 signaling would provide novel insights into translational interventions against malignant inflammatory insults.


Psychological Distance Impacts Subgroup Reciprocity in Technological Innovation Networks: The Mediating Role of Divisive Faultlines.
As information flows at ever-increasing speeds across technological innovation networks, it is crucial to optimize reciprocity among partnering enterprises. However, the impact of psychological distance on subgroup reciprocity in such networks has not yet been investigated. To address this gap, the current study drew on theories of faultlines and cohesive subgroups to model the relationship between psychological distance and subgroup reciprocity within technological innovation networks. Our hypotheses were tested using data from 174 respondents working in Yunnan Province, China. The results were as follows: first, psychological distance had negative effects on subgroup reciprocity in technological innovation networks; second, relationship-divisive and innovation-divisive faultlines negatively impacted reciprocity within and between subgroups; third, the faultlines partially mediated the negative relationship between psychological distance and intra-subgroup reciprocity; and fourth, the negative relationship between psychological distance and subgroup reciprocity was not mediated by the faultlines. The findings uncover the psychological mechanism of subgroup reciprocity within technological innovation networks. They will inform the decision-making process of enterprises when selecting partners within their technological innovation networks and support the development of effective reciprocal relationships with other innovators.


A Study of Continuous Renal Replacement Therapy and Acute Peritoneal Dialysis in Hemodynamic Unstable Patients.
The objective of the following study was to assess the outcome of continuous renal replacement therapy (CRRT) and acute peritoneal dialysis (PD) in dialysis-requiring renal failure in patients with hemodynamic instability. A retrospective analysis of all the patients who received CRRT and acute PD over a period of 1 year at our institute, a tertiary care center, was done for diagnosis, type of renal replacement therapy (RRT), and survival outcome. The indications for administering either of the therapy were usual indications of doing hemodialysis with the presence of hemodynamic instability (systolic blood pressure <90 mm of Hg even with inotropes). Forty patients, 22 in CRRT and 18 in acute PD group were studied. All these patients required inotropes to maintain desired blood pressure. Twenty-five (62.5%) patients had acute kidney injury (AKI), and 15 (37.5%) had chronic kidney disease (CKD) superimposed over other primary diagnosis. A total of 8 (20%) patients (4 in CRRT, 4 in acute PD) survived at the time of discharge from hospital. The mean age of survivors was approximately a decade less than nonsurvivors (P = 0.15). Overall, there were no survivors in CKD group and all the patients who survived at the time of discharge from hospital had underlying AKI (P = 0.016). This study showing comparable survival outcome in acute PD and CRRT gives evidence that either of the modalities can be adopted in hemodynamically unstable patients requiring RRT depending on the resources available.


Doping: a challenge to the endocrinologist. A reappraisal in view of the Olympic Games of 2004.
The aim of this review is to provide an update on drug abuse by athletes, their mode of action and the technical difficulties of detection. The most common doping agents are the anabolic steroids (AS), testosterone derivatives modified to take advantage of the anabolic rather than the androgenic properties of the hormone. However, there are numerous side-effects that discourage their use. Several other substances and hormones, GH and rhEPO are currently used alone or combined to enhance performance. The diversity in nature of the substances used requires a constant alertness of physicians to detect drug abuse in sports. Doping is not limited to the professional athletes. It seems to be a generalized phenomenon that reflects modern society's concept of success. Therefore, the campaign to eradicate doping must also focus on individual responsibility. Since modern-day doping is strongly related to hormonal preparations, endocrinologists may play a pivotal role in providing information, protecting athletes' health and, moreover, retaining the ethical value of sport.


Gelling properties of heat-denatured beta-lactoglobulin aggregates in a high-salt buffer.
Thermal denaturation, rheological, and microstructural properties of gels prepared from native beta-lactoglobulin (beta-LG) and preheated or heat-denatured beta-LG (HDLG) aggregates were compared. The HDLG was prepared by heating solutions of 4% beta-LG in deionized water, pH 7.0, at 80 degrees C for 30 min and then diluted to the desired concentration in 0.6 M NaCl and 0.05 M phosphate buffer at pH 6.0, 6.5, and 7.0. When reheated to 71 degrees C, HDLG formed a gel at a concentration of 2% protein. At pH 7.0, 3% HDLG gelled at 52.5 degrees C and had a storage modulus (G') of 2200 Pa after cooling. beta-LG (3%) in 0.6 M NaCl and 0.05 M phosphate buffer, pH 7.0, did not gel when heated to 71 degrees C. The gel point of 3% HDLG decreased by 10.5 degrees C and the G' did not change when the pH was decreased to 6.0. The HDLG gel microstructure was composed of strands and clumps of small globular aggregates in contrast to beta-LG gels, which contained a particulate network of compacted globules. The HDLG formed a gel at a lower concentration and lower temperature than beta-LG in the high-salt buffer, suggesting an application in meat systems or other food products prepared with salt and processed at temperatures of < or =71 degrees C.


Immunization with truncated sequence of Telomerase Reverse Transcriptase induces a specific antitumor response in vivo.
To select the MHC-I-binding epitope-rich sequence of mice telomerase reverse transcriptase (mTERT) and study the antitumor immune response induced by truncated TERT through mRNA-transfected dendritic cells (DCs) immunization in mice. The MHC-I-binding epitopes of TERT were predicted using bioinformatics software. The selected sequence of TERT (Truncated mTERT, TERT(t), mTERT cDNA 1776 bp-2942 bp encoding 584 aa-969 aa) was cloned from B16 mouse melanoma cells and inserted into pBluescriptIIKS(+) plasmid downstream of the T7 promoter. TERT(t) RNA was prepared through in vitro transcription. Bone marrow-derived DCs were electroporated with TERT(t) RNA and used to immunize syngeneic naïve mice. The quantity and cytotoxic activity of TERT-specific cytotoxic T lymphocytes (CTLs) in mice spleen were evaluated using IFN-gamma enzyme-linked immunospot (ELISPOT) and Lactate dehydrogenase release assay. The immunoprophylactic effects against TERT positive tumor induced by TERT(t) RNA transfected DC in vivo were evaluated through an immunized-challenged mouse model. TERT(t) was cloned and in vitro transcribed into TERT(t) mRNA. As shown in FCM analysis, the efficiency of DC electroporation is 35.1% (29.7-41.2%). After electroporation, a subtle increase of costimulator and MHC-II molecules were expressed on the cell surface. Immunization of TERT(t) mRNA transfected DCs induced IFN-gamma-secreting CTLs which manifested specific cytotoxic activity against TERT-positive target cells. In a cancer mouse model, vaccination of TERT(t) mRNA-transfected DCs suppressed the growth of TERT positive tumors (p=0.001) and prolong the survival time of tumor-bearing animals (p=0.029). TERT(t) evokes an antitumor immune response in vivo which is targeted to TERT. TERT(t) can be used as an antigeneic sequence to produce anti-TERT tumor vaccine.


Polymorphisms of α1-antitrypsin and Interleukin-6 genes and the progression of hepatic cirrhosis in patients with a hepatitis C virus infection.
Hepatitis C virus (HCV) infection represents a serious health problem. The -174 G/C mutation in the pro inflammatory cytokine interleukin-6 (IL-6) is associated with developing liver diseases. Likewise, the S and Z mutations in the serine protease inhibitor α1-antitrypsin (A1AT) are associated with pulmonary emphysema and/or liver cirrhosis. We explored the distribution of the single nucleotide polymorphisms (SNPs) of IL-6 and A1AT genes in chronic HCV-infected patients and evaluated their impact on the progression of liver cirrhosis. One hundred and fifty Egyptian HCV-infected patients together with 100 healthy controls were enrolled in this study. The patient groups were subdivided into chronic hepatitis patients (n = 85) and cirrhotic patients (n = 65). The SNP of IL-6 (-174 G/C, rs1800795), A1AT Z mutation (342 Glu/Lys, rs28929474) and A1AT S mutation (264 Glu/Val, rs17580) were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Cirrhotic patients exhibited significantly increased frequency of the A1AT S allele compared with the controls (34.6 vs. 5.0%), while the chronic hepatitis patients showed a higher frequency of the A1AT Z allele compared with the controls (14.7 vs. 2.5%). Remarkably, IL-6 (CC genotype) was detected only in the chronic hepatitis patients. Multivariate regression analysis showed that aspartate transaminase (AST) and the S alleles of A1AT, represented as SS+MS genotypes, were significantly independent predictors for development of liver cirrhosis. We concluded that inheritance of deficient S and Z alleles of the A1AT gene but not IL-6 (-174 G/C), were associated with progressive liver diseases.


Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016.
The discovery of the endogenous melanocortin agonists in the 1950s have resulted in sixty years of melanocortin ligand research. Early efforts involved truncations or select modifications of the naturally occurring agonists leading to the development of many potent and selective ligands. With the identification and cloning of the five known melanocortin receptors, many ligands were improved upon through bench-top in vitro assays. Optimization of select properties resulted in ligands adopted as clinical candidates. A summary of every melanocortin ligand is outside the scope of this review. Instead, this review will focus on the following topics: classic melanocortin ligands, selective ligands, small molecule (non-peptide) ligands, ligands with sex-specific effects, bivalent and multivalent ligands, and ligands advanced to clinical trials. Each topic area will be summarized with current references to update the melanocortin field on recent progress. This article is part of a Special Issue entitled: Melanocortin Receptors - edited by Ya-Xiong Tao.


Reversible Folding of a β-Hairpin Peptide by a Metal-Chelating Amino Acid.
5-(1-Hydroxy-pyridin-2(1H)-onyl)-l-alanine (Hop) is a N-hydroxy-1,2-pyridone functionalized α-amino acid with the desired metal-chelating properties of DOPA (3,4-dihydroxy phenylalanine) but without its unwanted redox activity. The Fmoc-protected amino acid Fmoc-l-Hop(tBu)-OH (11) was synthesized from glycine phosphonate followed by enzymatic hydrolysis of the methyl ester yielding the Hop l-isomer in 96 % ee. The amino acid 11 is used in automated peptide synthesis for the assembly of a 14mer β-hairpin peptide with the sequence [dsb1, 14 ]H-CHXETGKHGHKLVC-OH (X=W, l-Hop). While the 10 π electron containing indole side chain of l-Trp in peptide 14 completes the formation of a hydrophobic cluster and results in 90 % folding, the folded fraction is significantly decreased to approximately 30 % for the 6 π electron l-Hop side chain in peptide 16. Metal chelation of Ga3+ reconstitutes the folding of 16 to above 60 % due to the formation of the Ga(16)3 trimer. The chelation process of 16 is monitored by NMR spectroscopy and the subsequent release of Ga3+ by a competitive metal chelator exemplifies the reversible oligomerization of peptide epitopes by metal chelation, bearing the opportunity to synthesize protein-sized aggregates on the basis of reversible chemistry in water.


Multitargeted Imidazoles: Potential Therapeutic Leads for Alzheimer's and Other Neurodegenerative Diseases.
Alzheimer's disease (AD) is a complex, multifactorial disease in which different neuropathological mechanisms are likely involved, including those associated with pathological tau and Aβ species as well as neuroinflammation. In this context, the development of single multitargeted therapeutics directed against two or more disease mechanisms could be advantageous. Starting from a series of 1,5-diarylimidazoles with microtubule (MT)-stabilizing activity and structural similarities with known NSAIDs, we conducted structure-activity relationship studies that led to the identification of multitargeted prototypes with activities as MT-stabilizing agents and/or inhibitors of the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways. Several examples are brain-penetrant and exhibit balanced multitargeted in vitro activity in the low μM range. As brain-penetrant MT-stabilizing agents have proven effective against tau-mediated neurodegeneration in animal models, and because COX- and 5-LOX-derived eicosanoids are thought to contribute to Aβ plaque deposition, these 1,5-diarylimidazoles provide tools to explore novel multitargeted strategies for AD and other neurodegenerative diseases.


Chronic bronchitis in the iron and steel industry: prevalence study.
The paper reports the results of a prevalence study on functional impairment and chronic bronchitis in 733 foundry workers and in a control group of 1041 workers not exposed to the specific risks of the iron and steel industry. This study is the first part of a longitudinal study lasting 5 years within the framework of the Fourth Research Programme of the European Coal and Steel Community. Data on microclimate and particulate pollution for the various departments showed uniformly cold and damp conditions. Concentrations of pollutants were generally below the current T.L.V.'s. The subjects were subdivided into groups according to age, smoking and length of exposure. All the subjects were administered the "E.C.S.C. Questionnaire for the study of chronic bronchitis and pulmonary emphysema" and underwent a chest X-ray and spirometry to measure FVC, FEV1 and Vmax 50. The prevalence of functional impairment and chronic bronchitis was higher in the foundry workers than in the group of non-exposed workers. A statistical standardization was made of the effect of age and smoking thus accentuating the effect of exposure. The results are compared with the data obtained by other epidemiologic studies on working populations exposed to a similar risk.


Disease progression in Hutchinson-Gilford progeria syndrome: impact on growth and development.
Hutchinson-Gilford progeria syndrome is a rare and uniformly fatal segmental "premature aging" disease that affects a variety of organ systems. We sought to more clearly define the bone and weight abnormalities in patients with progeria as potential outcome parameters for prospective clinical trials. We collected and analyzed longitudinal medical information, both retrospectively and prospectively, from a total of 41 children with Hutchinson-Gilford progeria syndrome spanning 14 countries, from the Progeria Research Foundation Medical and Research Database at the Brown University Center for Gerontology. In addition to a number of previously well-defined phenotypic findings in children with progeria, this study identified abnormalities in the eruption of secondary incisors lingually and palatally in the mandible and maxilla, respectively. Although bony structures appeared normal in early infancy, clavicular resorption, coxa valga, avascular necrosis of the femoral head, modeling abnormalities of long bones with slender diaphyses, flared metaphyses, and overgrown epiphyses developed. Long bones showed normal cortical thickness centrally and progressive focal demineralization peripherally. The most striking finding identified in the retrospective data set of 35 children was an average weight increase of only 0.44 kg/year, beginning at approximately 24 months of age and persisting through life, with remarkable intrapatient linearity. This rate is >2 SD below normal weight gain for any corresponding age and sharply contrasts with the parabolic growth pattern for normal age- and gender-matched children. This finding was also confirmed prospectively. Our analysis shows evidence of a newly identified abnormal growth pattern for children with Hutchinson-Gilford progeria syndrome. The skeletal and dental findings are suggestive of a developmental dysplasia rather than a classical aging process. The presence of decreased and linear weight gain, maintained in all of the patients after the age of 2 years, provides the ideal parameter on which altered disease status can be assessed in clinical trials.


Renal calcium stones: insights from the control of bone mineralization.
Extracellular pyrophosphate (PPi) plays a central role in the control of normal bone mineralization since it antagonizes inorganic phosphate in the promotion of hydroxyapatite deposition. Studies using knock-out mice have established the functional importance of PPi generation via nucleotide pyrophosphatase phosphodiesterases (NPP) and of PPi transmembrane transport by the progressive ankylosis (ANK) protein. Tissue non-specific alkaline phosphatase activity counteracts this by hydrolysis of PPi to inorganic phosphate. The molecular nature and transport function of ANK are reviewed. A close parallel is drawn between the controlled mineralization of bone and the prevention of abnormal calcium crystal deposition within the kidney, especially when concentrated urine is produced. Pyrophosphate is present in urine, and ANK is expressed in the cortical collecting duct where PPi transport to both the tubular lumen and the renal interstitium may occur. Pyrophosphate may also be generated here by nucleoside triphosphate diphosphohydrolases (NTPD2 and 3) together with NPP1. Alkaline phosphatase activity is restricted to the proximal nephron, remote from these sites of PPi generation, transport and function. The physiological importance of PPi generation and transport in preventing idiopathic calcium renal stone disease and nephrocalcinosis now needs to be established.


The influence of 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene promoter on the incidence, growth and operative risk of abdominal aortic aneurysm.
a single base pair deletion/insertion (4G/5G) polymorphism in the plasminogen activator inhibitor (PAI-1) promoter appears to influence PAI-1 synthesis (increased PAI-1 and inhibition of fibrinolysis with the 4G allele) and survival after severe trauma. to identify whether the 4G/5G polymorphism influences the natural history of abdominal aortic aneurysm (AAA). Four hundred and sixty patients with small AAA were genotyped for the 4G/5G polymorphism. AAA growth was assessed from serial ultrasonographic measurements, subject to linear regression analysis. Mortality following eventual elective surgery was recorded. the frequency of the 3 genotypes (4G4G, 4G5G and 5G5G) was in Hardy-Weinberg equilibrium and similar to that in a healthy population. The mean aneurysm growth rate was 0.37, 0.35 and 0.44 cm/year respectively for patients of 4G4G, 4G5G and 5G5G genotype respectively, p = 0.07. The 30d mortality following open elective aneurysm repair was 8% (7/87), 8% (11/145) and 0% (0/56) for patients of 4G4G, 4G5G and 5G5G genotype respectively, giving a higher mortality for those carrying a 4G allele p = 0.03. polymorphism of the PAI-1 gene promoter does not influence the development of AAA, although AAA growth is faster for patients of 5G5G genotype. However, this genotype (5G5G), which is associated with enhanced fibrinolysis, appears protective following open aneurysm repair. This effect of PAI-1 genotype on survival following surgery is likely to have widespread significance in vascular and general surgery.


MicroRNA 199a-5p Attenuates Retrograde Transport and Protects against Toxin-Induced Inhibition of Protein Biosynthesis.
Retrograde transport (RT) allows cells to retrieve receptors and other cellular cargoes for delivery to the Golgi apparatus, contributing to the maintenance of cellular homeostasis. This transport route is also commonly used by several bacterial toxins to exert their deleterious actions on eukaryotic cells. While the retrograde transport process has been well characterized, the contribution of microRNAs (miRNAs) in regulating this cellular transport mechanism remains unknown. Here, we determined that mir-199a and mir-199b, members of the intronic miRNA family, coordinate genes regulating RT and endosome trafficking. We demonstrate that miR-199a-5p attenuates the expression of Vps26A, Rab9B, and M6PR, thereby controlling RT from endosomes to the trans-Golgi network (TGN). Importantly, we found that overexpression of a Vps26A construct resistant to the inhibitory action of miR-199a-5p abrogates the effect of miR-199a-5p on RT. Finally, we demonstrate that miR-199-5p overexpression attenuates Shiga toxin type 1 (Stx1)-mediated inhibition of protein biosynthesis. In summary, our work identifies the first noncoding RNA that influences RT and reduces the inhibition of protein biosynthesis caused by bacterial toxins.


Premature escape beats induced by overdrive pacing in canine Purkinje fibers. Evidence for the role of normal automaticity as an underlying cellular mechanism.
Premature escape beats induced in conscious dogs with chronic complete atrioventricular block have been defined as escape beats occurring on cessation of overdrive pacing and having a coupling interval to the last paced beat shorter than the coupling interval between the premature escape beat and the second postpacing beat. Triggered activity has been proposed as the primary underlying mechanism. We used standard microelectrode techniques to study the effects of overdrive pacing on normal automatic canine Purkinje fibers to determine if premature escape beats could be induced and if so, to define the underlying cellular mechanism(s). For this purpose, we overdrive-paced Purkinje fibers for 10 and 50 seconds and for 10 and 50 beats at a pacing cycle length (PCL) of 1,000-200 msec. In addition, to help distinguish among major arrhythmogenic mechanisms, we used a matrix of drugs consisting of propranolol, nadolol, lidocaine, ethmozin, and doxorubicin. Fifty-second stimulation trains induced "classic" overdrive suppression of the first three postpacing impulses, whereas 10-second overdrive pacing induced significant overdrive suppression only at a PCL of 200 msec. With 50-beat overdrive pacing and a PCL of 1,000-600 msec, there was overdrive suppression of postpacing impulses, whereas reduced overdrive suppression was observed at a PCL of 400-200 msec. Ten-beat stimulation trains induced a "flat response" of postpacing impulses. Ten- and 50-beat overdrive pacing provoked premature escape beats in 66% of the fibers, with the higher incidence at a PCL of 200 msec for 50-beat stimulation trains. No shortening of the coupling interval of premature escape beats was observed at faster pacing rates. Only lidocaine (which suppresses normal automaticity) abolished premature escape beats. We conclude that normal automaticity is the most likely mechanism underlying premature escape beats in Purkinje fibers with high levels of membrane potential.


Acetate-nonutilizing mutants of Neurospora rassa. II. Biochemical deficiencies and the roles of certain enzymes.
The levels of Krebs cycle, glyoxylate cycle, and certain other enzymes were measured in a wild-type strain and in seven groups of acetate-nonutilizing (acu) mutants of Neurospora crassa, both after growth on a medium containing sucrose and after a subsequent 6-hr incubation in a similar medium, containing acetate as the sole source of carbon. In the wild strain, incubation in acetate medium caused a rise in the levels of isocitrate lyase, malate synthase, phosphoenolpyruvate carboxykinase, acetyl-coenzyme A synthetase, nicotinamide adenine dinucleotide phosphate-linked isocitrate dehydrogenase, citrate synthase, and fumarate hydratase. Isocitrate lyase activity was absent in acu-3 mutants; acu-5 mutants lacked acetyl-coenzyme A synthetase activity; and no oxoglutarate dehydrogenase activity (or only low levels) could be detected in acu-2 and acu-7 mutants. In acu-6 mutants, phosphoenolpyruvate carboxykinase activity was either very low or absent. No specific biochemical deficiencies could be attributed to the acu-1 and acu-4 mutations. The role of several of these enzymes during growth on acetate is discussed.


Gastrointestinal stromal tumor (GIST) pathogenesis, familial GIST, and animal models.
Once a poorly understood pathologic entity, gastrointestinal stromal tumor (GIST) has emerged in recent years as a distinct oncologic-molecular paradigm that is now a leading model for kinase-targeted therapies in Oncology. Most GISTs are KIT-expressing and KIT-signaling driven mesenchymal tumors, many of which have KIT-activating mutations. A small subset of GIST show activating mutations in PDGFRA, encoding for a related member of the type III receptor tyrosine kinase family. The revelation of KIT expression as a diagnostic signature of GIST has not only revolutionized the pathologic criteria in classifying GIST, but also shed light onto the histogenesis of these tumors. The similarities in KIT immunoreactivity and ultrastructural appearance between GISTs and the intestinal pacemaker, the interstitial cells of Cajal (ICC), suggested that GISTs derive from or differentiate toward the ICC lineage. KIT plays a significant role in proliferation, survival, and differentiation of hematopoietic stem cells, mast cells, melanocytes, and interstitial cells of Cajal; and activating KIT mutations have been identified in tumors affecting most of these cell lineages. The observation that KIT mutations may be inherited, as seen in familial GIST syndrome, was used to develop murine models harboring a germline gain-of-function mutation, as a model for studying of KIT oncogenic mechanisms. These murine models of human GIST promise to become powerful preclinical tools in elucidating oncogenic signaling mechanisms by using genetic approaches and targeted pharmacological intervention. As true animal models of human cancer, they provide superior information compared with the more commonly used xenografts and transgenic mouse models. This review summarizes the recent knowledge on the central role of KIT oncogenic activation and subsequent signal transduction in the pathogenesis of GIST. In addition, we provide an updated discussion on familial GIST syndrome in relationship to genotype-phenotype characteristics. A succinct description of the available murine models of human GIST is presented and their applicability in further understanding of the KIT oncogenic signaling, drug screening, and mechanisms of drug resistance is discussed. This is a US government work. There are no restrictions on its use.


Beneficial effect of long-acting injectable risperidone on the neurocognitive deficit of a schizophrenic patient: A case report.
We report the case of a 37-year-old female patient suffering from schizophrenia, disorganized type. Adherence to treatment was always a major problem. During the last 2 years the patient was disorganized and was refusing treatment. Since the patient was already receiving a very high (double) dose per os, it was decided to administer two 50 ml ampoules of long-acting, injectable risperidone plus 5 mg of haloperidol per os daily. After 80 days of treatment, all positive, negative and even neurocognitive symptoms improved markedly. Extrapyramidal side effects did not appear at any stage of treatment. The most impressive neurocognitive improvement concerned the clock drawing test, which was in parallel with her improvement in both the positive and negative symptoms of the PANSS.


The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism: novel insights into drug mechanisms of action.
The differential transcriptional response of Mycobacterium tuberculosis to drugs and growth-inhibitory conditions was monitored to generate a data set of 430 microarray profiles. Unbiased grouping of these profiles independently clustered agents of known mechanism of action accurately and was successful at predicting the mechanism of action of several unknown agents. These predictions were validated biochemically for two agents of previously uncategorized mechanism, pyridoacridones and phenothiazines. Analysis of this data set further revealed 150 underlying clusters of coordinately regulated genes offering the first glimpse at the full metabolic potential of this organism. A signature subset of these gene clusters was sufficient to classify all known agents as to mechanism of action. Transcriptional profiling of both crude and purified natural products can provide critical information on both mechanism and detoxification prior to purification that can be used to guide the drug discovery process. Thus, the transcriptional profile generated by a crude marine natural product recapitulated the mechanistic prediction from the pure active component. The underlying gene clusters further provide fundamental insights into the metabolic response of bacteria to drug-induced stress and provide a rational basis for the selection of critical metabolic targets for screening for new agents with improved activity against this important human pathogen.


Reversible flow of cholesteryl ester between high-density lipoproteins and triacylglycerol-rich particles is modulated by the fatty acid composition and concentration of triacylglycerols.
We determined the influence of fasting (FAST) and feeding (FED) on cholesteryl ester (CE) flow between high-density lipoproteins (HDL) and plasma apoB-lipoprotein and triacylglycerol (TG)-rich emulsions (EM) prepared with TG-fatty acids (FAs). TG-FAs of varying chain lengths and degrees of unsaturation were tested in the presence of a plasma fraction at d > 1.21 g/mL as the source of CE transfer protein. The transfer of CE from HDL to FED was greater than to FAST TG-rich acceptor lipoproteins, 18% and 14%, respectively. However, percent CE transfer from HDL to apoB-containing lipoproteins was similar for FED and FAST HDL. The CE transfer from HDL to EM depended on the EM TG-FA chain length. Furthermore, the chain length of the monounsaturated TG-containing EM showed a significant positive correlation of the CE transfer from HDL to EM (r = 0.81, P < 0.0001) and a negative correlation from EM to HDL (r = -041, P = 0.0088). Regarding the degree of EM TG-FAs unsaturation, among EMs containing C18, the CE transfer was lower from HDL to C18:2 compared to C18:1 and C18:3, 17.7%, 20.7%, and 20%, respectively. However, the CE transfer from EMs to HDL was higher to C18:2 than to C18:1 and C18:3, 83.7%, 51.2%, and 46.3%, respectively. Thus, the EM FA composition was found to be the rate-limiting factor regulating the transfer of CE from HDL. Consequently, the net transfer of CE between HDL and TG-rich particles depends on the specific arrangement of the TG acyl chains in the lipoprotein particle core.


A mobilizable pool of d-amphetamine in adipose after daily administration to rats.
Six daily injections (subacute) of 2.5 mg d-amphetamine/kg resulted in a 60% higher concentration of unchanged drug in adipose compared with adipose from rats injected once. Subacute treatment also resulted in 30% less amphetamine in brain one hour after injection, when the animals were killed for tissue analysis. Moderate stress, in the form of foot shock for fifteen minutes, terminating fifteen minutes prior to sacrifice, mobilized the drug from adipose and doubled brain levels of amphetamine in the subacute group. Brain levels in the group given a single dose of drug were unaltered by shock, but heart content of amphetamine was increased 30% as a result of shock. It is concluded that enhanced reactivity to some of the behavioral effects of amphetamine, upon repeated administration, may be due to cumulation of the drug in mobilizable pools.


High-voltage electroencephalogram spindles in rats, aging and 5-HT2 antagonism.
We examined the effects of serotonin-2 (5-hydroxytryptamine-2, 5-HT2) receptor antagonists on the so-called high-voltage spindles (HVS, electroencephalographic patterns, characterized by large amplitude rhythmic waves mainly in the alpha band), recorded from the frontal cortex of young, middle-aged and old freely-moving rats during waking immobility. The study was based on the assumption that the effects of 5-HT2 receptor antagonists on the HVS activity depend on the age of rats, because there is evidence for an age-related decrease in the 5-HT2 binding sites density. Four parameters of the electroencephalogram (EEG) were used to characterize the HVS activity: the square root-transformed EEG peak power in the alpha band, the frequency corresponding to this peak (both measured from the EEG power spectra using the fast Fourier transform), the HVS mean duration, and the HVS incidence (both measured from the EEG records). The EEG parameters were analyzed after i.p. administration of three 5-HT2 receptor antagonists: ketanserin, ritanserin and cyproheptadine. In young rats, the three drugs increased the alpha power, but did not change the alpha peak-corresponding frequency. Ketanserin and ritanserin did not change the HVS mean duration and HVS incidence, while cyproheptadine increased both these parameters in young rats. In middle-aged and old untreated rats, the HVS activity was significantly increased. The three 5-HT2 antagonists did not change the HVS activity in aged rats, which could be due to age-related suppression of the 5-HT2 receptor functions.