Myocardial necrosis related to hydrochlorothiazide-induced hypokalemia in cynomolgus monkeys.
Myocardial necrosis is a serious adverse effect that results from the administration of some medications; therefore, when it is observed during preclinical studies it becomes a major drug development concern. Although data from preclinical monkey studies are generally extrapolated to predict effects in humans, few reports have described any mechanism that might explain the occurrence of myocardial necrosis. For this reason, we examined the association between hypokalemia and myocardial necrosis in monkeys. Four female cynomolgus monkeys (Macaca fascicularis) were treated with 50 mg/kg/day hydrochlorothiazide (a thiazide diuretic used for antihypertensive therapy) for 1 or 2 weeks. Clinical, hematological, plasma biochemical, and pathological examinations were conducted. Two animals were kept in a hypokalemic state from day 3 of dosing on, and their mean plasma potassium levels were 2.52 +/- 0.24 and 2.60 +/- 0.24 mmol/l. These animals were necropsied after 1 week of dosing due to an aggravated general condition. A flattened T-wave was noted during electrocardiography. A transient increase in plasma cardiac-specific troponin-I and multifocal myocardial necrosis also occurred. The rest of the animals were occasionally hypokalemic, with mean plasma potassium levels of 3.13 +/- 0.31 or 2.96 +/- 0.30 mmol/l. These animals were necropsied after 2 weeks of dosing. One animal showed evidence of focal myocardial necrosis and a transient increase in plasma cardiac-specific troponin-I. These data suggest that the severe hypokalemia induced by hydrochlorothiazide is likely to be associated with myocardial necrosis in monkeys.


Molsidomine Attenuates Ventricular Electrical Remodeling and Arrhythmogenesis in Rats With Chronic β-Adrenergic Receptor Activation Through the NO/cGMP/PKG Pathway.
This study investigated the effects and associated underlying mechanisms of molsidomine, a nitric oxide (NO) donor, on cardiac electrical remodeling and ventricular tachycardias (VTs) induced by chronic isoprenaline (ISO) stimulation in rats. The rats were randomly divided into groups that were treated with saline (control group), ISO (ISO group), ISO + molsidomine (ISO + M group), and ISO + molsidomine + the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, ISO + M + O group) for 14 days. An electrophysiological study was performed to assess cardiac repolarization, action potential duration restitution, and the induction of action potential duration alternans and VTs in vitro. The properties of the Ca transients, Ca handling-related proteins, and NO/guanosine 3'5'-cyclic monophosphate (cGMP)/protein kinase G (PKG) pathway were examined. Compared with the control group, chronic ISO stimulation prolonged the cardiac repolarization, decreased the Ca transient alternans and action potential duration alternans thresholds, and increased the maximum slope (Smax) of the action potential duration restitution curve and incidence of VTs in vitro. All these effects were attenuated by molsidomine treatment (P < 0.05). Moreover, molsidomine activated cGMP/PKG signaling and stabilized the expression of calcium handling-related proteins compared with the ISO group. However, the protective effects of molsidomine were partially inhibited by ODQ. Our results suggest that molsidomine stabilizes calcium handling and attenuates cardiac electrical remodeling and arrhythmogenesis in rats with chronic β-adrenergic receptor activation. These effects are at least partially mediated by the activation of NO/cGMP/PKG pathway.


Pentaglyme-K salt binary mixtures: phase behavior, solvate structures, and physicochemical properties.
We prepared a series of binary mixtures composed of certain K salts (KX) and pentaglyme (G5) with different salt concentrations and anionic species ([X](-): [(CF3SO2)2N](-) = [TFSA](-), [CF3SO3](-) = [TfO](-), [C4F9SO3](-) = [NfO](-), PF6(-), SCN(-)), and characterized them with respect to their phase diagrams, solvate structures, and physicochemical properties. Their phase diagrams and thermal stability strongly implied the formation of equimolar complexes. Single-crystal X-ray crystallography was performed on certain equimolar complexes, which revealed that G5 molecules coordinate to K(+) cations in a characteristic manner, like 18-crown-6 ether in the crystalline state, irrespective of the paired anions. The solvate structures in the molten state were elucidated by a combination of temperature-dependent Raman spectroscopy and X-ray crystallography. A drastic spectral variation was observed in the [K(G5)1][TfO] Raman spectra, indicating that solvate structures in the crystalline state break apart upon melting. The solvate stability of [K(G5)1]X is closely related to the ion-ion interaction of the parent salts. A stable solvate forms when the ion-dipole interaction between K(+) and G5 overwhelms the ion-ion interaction between K(+) and X(-). Furthermore, the physicochemical properties of certain equimolar mixtures were evaluated. A Walden plot clearly reflects the ionic nature of the molten equimolar complexes. Judging from the structural characteristics and dissociativity, we classified [K(G5)1]X into two groups, good and poor solvate ionic liquids.


Comparing the effect of two methods of using ear protective device on pain intensity in patients undergoing coronary artery bypass grafting: A randomized clinical trial.
Severe pain is the most prevalent complication after Coronary Artery Bypass Grafting (CABG). The aim of this study is to compare the impact of two methods using ear protective devices on pain intensity in patients undergoing CABG. The present randomized clinical trial was conducted between October 2019 and February 2020. The participants included 84 patients undergoing CABG, who were randomly divided into two intervention groups (A, B) and a control group. On the first night after the heart surgery, ear protective devices were used for the patients in group A during the evening and night sleep, while they were used in group B only during the night sleep. A demographic questionnaire and Visual Analog Scale (VAS) were the data collection tools used in this study. Data were analyzed using Chi-square test, paired t-test, and one-way Analysis of Variance (ANOVA) in Statistical Package for the Social Sciences (SPSS) software. Before the intervention, the mean (SD) of pain intensity in the two intervention groups (A, B) and the control group was 6.46 (1.71), 6.32 (1.36), and 6.54 (1.45), respectively, and there was no significant difference between the groups (F2,81 = 0.14; p = 0.86). However, after the intervention, the mean (SD) of pain intensity in the two intervention groups (A, B) and the control group was 3.39 (1.87), 4.46 (1.55), and 6.39 (1.54), respectively, which showed a significant difference (F2,81 = 23.37; p < 0.001). The use of ear protective device is recommended as a non-invasive and accessible way of reducing pain intensity in patients after CABG.


Our Friends Keep Us Together: The Stability of Adolescents' Cross-Race Friendships.
Substantive racial integration depends on both access to cross-race friendship opportunities (demographic integration) and the development of stable and rewarding social relations (social integration). Yet, we know little about the relative stability of cross-race friendship nominations over time. Cross-race friendships are also experienced within social contexts, where other individual, dyadic, and contextual factors may simultaneously affect whether such ties persist. Based on longitudinal network data on over 2,000 students in multiple communities, we test whether cross-race friendships are more or less stable than same-race friendships. We find that cross-race friendships at first glance appear less likely to persist than same-race friendships, but cross-race ties become no less stable than same-race ties after accounting for other social factors, including reciprocity and shared friends. This pattern suggests a threshold process where strong, socially recognized ties embedded among peers face less threat to maintaining friendship stability.


Feasibility of accelerated partial breast irradiation with volumetric-modulated arc therapy in elderly and frail patients.
Accelerated partial breast irradiation (APBI) is an option for adjuvant radiotherapy according to ASTRO and ESTRO recommendations. Among the available techniques, volumetric-modulated arc therapy (VMAT) is attractive but has not been extensively studied for APBI. This study assessed its feasibility, tolerance and early oncological outcomes. We analysed the data of nine patients (median age 74 years) with ten lesions (one bilateral cancer) treated from May 2011 to July 2012 with APBI using VMAT. The radiation oncologist delineated the surgical tumour bed, and added an 18 mm isotropic margin to obtain the planning target volume (PTV). The dose was 40 Gy prescribed in 4 Gy fractions given twice a day over five days. Patients were regularly followed for toxicities and oncological outcomes. Mean PTV was 100.0 cm(3) and 95 % of the PTV received a mean dose of 99.7 % of the prescribed dose. Hot spots represented 0.3 % of the PTV. 6.2 %, 1.6 % and 0.3 % of the ipsilateral lung volume received 5 Gy (V5Gy), 10 Gy (V10Gy) and 20 Gy (V20Gy), respectively. Regarding the contralateral lung, V5Gy was 0.3 %, and V10Gy and V20Gy were nil. V5Gy accounted for 3.1 % of the heart. An average 580 monitor units were delivered. No acute or late grade ≥ 2 toxicities were observed. With a median follow-up of 26 months, no relapses occurred. In our study, VMAT allowed optimal dosimetry with consequential high therapeutic ratio in elderly and frail patients.


Diabetes insipidus and adrenal insufficiency in a patient with metastatic breast cancer.
A patient previously treated for bilateral breast cancer with mastectomy, radiation therapy and in remission on hormonal therapy for more than five years presented with abdominal symptoms from breast cancer relapse. She developed inappropriate polyuria and hypernatraemia, which responded to desmopressin. In combination with the absence of a high signal from the posterior lobe of the pituitary on MRI , these data indicated the presence of partial central diabetes insipidus. The anterior pituitary showed partial failure (low follicle-stimulating hormone, luteinising hormone and insulin-like growth factor-1 levels). Furthermore, primary adrenal insufficiency had developed, ascribed to bilateral tumour invasion of the adrenals. This rare combination of endocrinological failures in a patient with metastatic breast cancer is discussed.


Polyglycolic Acid Fibrous Scaffold Improving Endothelial Cell Coating and Vascularization of Islet.
Improving islet graft revascularization has become a crucial task for prolonging islet graft survival. Endothelial cells (ECs) are the basis of new microvessels in an isolated islet, and EC coating has been demonstrated to improve the vascularization and survival of an islet. However, the traditional method of EC coating of islets has low efficiency in vitro. This study was conducted to evaluate the effect of a polyglycolic acid (PGA) scaffold on the efficiency of islet coating by ECs and the angiogenesis in the coated islet graft. A PGA fibrous scaffold was used for EC coating of islet culture and was evaluated for its efficiency of EC coating on islets and islet graft angiogenesis. In in vitro experiments, we found that apoptosis index of ECs-coating islet in PGA group (27% ± 8%) was significantly lower than that in control group (83% ± 20%, P < 0.05) after 7 days culture. Stimulation index was significantly greater in the PGA group than in the control group at day 7 after ECs-coating (2.07 ± 0.31 vs. 1.80 ± 0.23, P < 0.05). vascular endothelial growth factor (VEGF) level in the PGA group was significantly higher than the coating in the control group after 7 days culture (52.10 ± 13.50 ng/ml vs. 16.30 ± 8.10 ng/ml, P < 0.05). Because of a tight, circumvallated, adhesive and three-dimensional growth microenvironment, islet cultured in a PGA scaffold had higher coating efficiency showing stronger staining intensity of enzyme than those in the control group after 14 days of culture following ECs-coating. For in vivo study, PGA scaffold significantly prolonged the average survival time of EC-coated islet graft after transplantation compared with control group (15.30 ± 5.60 days vs. 8.30 ± 2.45 days, P < 0.05). The angiogenesis and area of survived grafts were more in the PGA group compared with the control group by measuring the mean microvessel density (8.60 ± 1.21/mm2 vs. 5.20 ± 0.87/mm2, P < 0.05). In addition, expression of VEGF and tyrosin-protein kinase receptor (Tie-2) gene increased in PGA scaffold group than that in control group by real-time reverse transcription-polymerase chain reaction analysis. These results demonstrate that the efficiency of EC coating of islets was successfully increased by culturing ECs on a PGA scaffold. This method enhances the function, survival, and vascularization of isolated islets in vitro and in vivo.


Rapid regression of squamous cell hyperplasia and slow regression of basal cell hyperplasia in the forestomach of F344 rats treated with N-methyl-N'-nitro-N-nitrosoguanidine and/or butylated hydroxyanisole.
Cell kinetics of reversible and persistent forestomach lesions induced by the genotoxic agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and/or the nongenotoxic antioxidant butylated hydroxyanisole (BHA) was investigated. A total of 184 male F344 rats were divided into four groups: Group 1 given an initial single gastric intubation of MNNG received 2% BHA diet from the third wk to the 26th wk and then basal diet; Group 2 receiving 2% BHA without MNNG initiation; Group 3 given MNNG alone; and Group 4 serving as a nontreated control. Rats were sequentially sacrificed at 6, 16, 26, 30, and 46 wk. Bromodeoxyuridine was administered either as a single i.p. injection (100 mg/kg of body weight) 1 h before killing or continuously via an osmotic minipump (120 micrograms/h) for 1, 3, or 7 days prior to sacrifice, in each case labeled cells being detected by immunohistochemistry. Squamous cell hyperplasia (SCH) and basal cell hyperplasia (BCH), each characterized by different phenotypic keratin expression, were induced in Groups 1 to 3. After withdrawal of BHA, rapid regression of SCH and extremely slow regression of BCH were observed. Papillomas and squamous cell carcinomas developed irreversibly in Group 1 and 3, BHA significantly (P less than 0.01) enhancing the incidence of SCC in Group 1. Flash and continuous bromodeoxyuridine labeling revealed SCH to consist of cells of high mitotic activity and short life span, whereas BCH consisted of cells with low mitotic activity and long life span. In addition, highly labeled areas were observed in SCH after cessation of BHA feeding in Group 1 without regression, and similar lesions were also evident in Group 3. The results suggest that rapid regression of SCH and slow regression of BCH reflect different cell kinetic patterns and that highly labeled areas after release from stimulating agents might be preneoplastic changes related to cancer development.


Performance Enhancement of Polymer Electrode Materials for Lithium-Ion Batteries: From a Rigid Homopolymer to Soft Copolymers.
Synthesizing redox-active units containing polymers is a promising route for improving the cycling stability of organic electrode materials. However, constructing uniform electrode architectures with good polymer dispersion is a big challenge in the case of polymer electrode materials. In this work, we design and synthesize two anthraquinone-containing copolymers and compare their electrochemical performance with that of the corresponding homopolymer. It is uncovered that the copolymers with soft units in the main chain display increased chain flexibility, thus leading to a slightly increased solubility. Because of this, the soft copolymers are less likely to precipitate during solvent volatilization of electrode preparation and thus can form more uniform electrode architectures. The cyclic voltammogram and electrochemical impedance spectroscopy measurements indicate that copolymer electrodes display decreased polarization and improved kinetics compared with the homopolymer electrode. The copolymers exhibit significantly enhanced cycling stability and improved rate performance. After 100 cycles, both copolymers reveal very high capacity retention of above 98%, while the homopolymer retains only 71% of its highest capacity. Moreover, the copolymer can discharge/charge at 1C for over 2000 cycles with almost no capacity fading, indicating excellent long-term cycling performance. This work further demonstrates the importance of molecular structure and electrode architecture in determining the electrochemical performance of polymer electrode materials.


CHARGE association: an update and review for the primary pediatrician.
CHARGE association is a nonrandom pattern of congenital anomalies that occurs together more frequently than one would expect on the basis of chance. This common multiple anomaly condition has an estimated prevalence of 1:10,000. The number of children diagnosed with CHARGE association is increasing, owing presumably to greater awareness of this condition and advances in the care of complex, chronically ill children, resulting in improved survival and outcome. This review of CHARGE association presents diagnostic criteria that may define a concise, recognizable syndrome with a single pathogenetic basis. This review also summarizes our current understanding of the management for this complex and chronic multiple congenital anomaly condition and discusses the pathogenetic basis for this condition.


The LysR-type nitrogen assimilation control protein forms complexes with both long and short DNA binding sites in the absence of coeffectors.
Most LysR-type transcriptional regulators (LTTRs) function as tetramers when regulating gene expression. The nitrogen assimilation control protein (NAC) generally functions as a dimer when binding to DNA and activating transcription. However, at some sites, NAC binds as a tetramer. Like many LTTRs, NAC tetramers can recognize sites with long footprints (74 bp for the site at nac) with a substantial DNA bend or short footprints (56 bp for the site at cod) with less DNA bending. However, unlike other LTTRs, NAC can recognize both types of sites in the absence of physiologically relevant coeffectors, suggesting that the two conformers of the NAC tetramer (extended and compact) are interchangeable without the need for any modification to induce or stabilize the change. In order for NAC to bind as a tetramer, three interactions must exist: an interaction between the two NAC dimers and an interaction between each NAC dimer and its corresponding binding site. The interaction between one dimer and its DNA site can be weak (recognizing a half-site rather than a full dimer-binding site), but the other two interactions must be strong. Since the conformation of the NAC tetramer (extended or compact) is determined by the nature of the DNA site without the intervention of a small molecule, we argue that the coeffector that determines the conformation of the NAC tetramer is the DNA site to which it binds.


Antihypertensive therapy in the presence of proteinuria.
The presence of proteinuria is a well-known risk factor for both the progression of renal disease and cardiovascular morbidity and mortality, and decreases in urine protein excretion level were associated with a slower decrease in renal function and decrease in risk of cardiovascular events. Increased blood pressure has a major role in the development of proteinuria in patients with either diabetic or nondiabetic kidney disease, and all recent guidelines recommend a blood pressure goal less than 130/80 mm Hg in patients with proteinuria to achieve maximal renal and cardiovascular protection. Drugs interfering with the renin-angiotensin system, ie, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, should be used as first-line antihypertensive therapy in patients with proteinuria because they seem to have a blood pressure-independent antiproteinuric effect, and if blood pressure levels are still out of goal, a diuretic should be added to this regimen. A combination of an angiotensin-converting enzyme inhibitor with an angiotensin receptor blocker or other classes of medications shown to decrease protein excretion, such as nondihydropyridine calcium antagonists or aldosterone receptor blockers, should be considered to decrease proteinuria further. This review provides an extended summary of current evidence regarding the associations of blood pressure with proteinuria, the rationale for currently recommended blood pressure goals, and the use of various classes of antihypertensive agents in proteinuric patients.


A new operation for atlanto-axial arthrodesis.
Thirty patients with atlanto-axial subluxation were operated on using the Mitsui Memorial Hospital System. The follow-up averaged one and a half years, and the results were satisfactory in comparison with other operative methods, all patients regaining almost normal function. Stability and safety are the main advantages of this procedure, with almost complete correction of subluxation in most patients.


Anticipating agoraphobic situations: the neural correlates of panic disorder with agoraphobia.
Panic disorder with agoraphobia is characterized by panic attacks and anxiety in situations where escape might be difficult. However, neuroimaging studies specifically focusing on agoraphobia are rare. Here we used functional magnetic resonance imaging (fMRI) with disorder-specific stimuli to investigate the neural substrates of agoraphobia. We compared the neural activations of 72 patients suffering from panic disorder with agoraphobia with 72 matched healthy control subjects in a 3-T fMRI study. To isolate agoraphobia-specific alterations we tested the effects of the anticipation and perception of an agoraphobia-specific stimulus set. During fMRI, 48 agoraphobia-specific and 48 neutral pictures were randomly presented with and without anticipatory stimulus indicating the content of the subsequent pictures (Westphal paradigm). During the anticipation of agoraphobia-specific pictures, stronger activations were found in the bilateral ventral striatum and left insula in patients compared with controls. There were no group differences during the perception phase of agoraphobia-specific pictures. This study revealed stronger region-specific activations in patients suffering from panic disorder with agoraphobia in anticipation of agoraphobia-specific stimuli. Patients seem to process these stimuli more intensively based on individual salience. Hyperactivation of the ventral striatum and insula when anticipating agoraphobia-specific situations might be a central neurofunctional correlate of agoraphobia. Knowledge about the neural correlates of anticipatory and perceptual processes regarding agoraphobic situations will help to optimize and evaluate treatments, such as exposure therapy, in patients with panic disorder and agoraphobia.


C-peptide, testosterone, estrogen, cortisol and zinc in patients with benign hyperplasia of the prostate.
Patients with benign hyperplasia of the prostate (BHP) were studied in relation to aberrant serum c-peptide, testosterone, estrone, cortisol and morning fasting glucose, to analyze the syntropy of diabetes and BHP. The results were compared to patients with bladder cancer without BHP and, after correction of the patients' weights and ages, the control failed to prove any significance. This is consistent with the incidence rate of maturity onset diabetes in prostate adenomas (n = 527, 7.3%) and of a control group (8.5%) of patients, 60--70 years of age. Zinc, another parameter associated with insulin function, is frequently observed to change in BHP and is significantly increased in prostatic tissue which possibly acts as a zinc pool. In this study, however, no effect of prostatectomy on serum zinc was demonstrable even in a long-term control of 9 months, suggesting a sensitive and rapid regulation of this metal independent from the prostate.


[Sport-related concussion].
Sport-related concussion is a frequent and complex pathology whose physiopathological mechanisms are not completely understood yet. A recent consensus statement has been published with the objective to provide practicioners with an overview of literature and give some guidelines based on the current state of knowledge. An 11R approach (Recognise, Remove, Re-evaluate, Rest, Rehabilitation, Refer, Recover, Return to sport, Reconsider, Residual effects and sequelae, Risk reduction) is proposed to evaluate and manage sport-related concussion. There is currently no available test predicting recovery, but the risk factors for a slow recovery are now known. Return to daily activities (as school) and to full sport participation should follow the graduated return-to-school or - sport strategy, and the ultimate decision is clinically based, and made by the physician.


Rapid and Efficient Collection of Platinum from Karstedt's Catalyst Solution via Ligands-Exchange-Induced Assembly.
Reported herein is a novel strategy for the rapid and efficient collection of platinum from Karstedt's catalyst solution. By taking advantage of a ligand-exchange reaction between alkynols and the 1,3-divinyltetramethyldisiloxane ligand (MViMVi) that coordinated with platinum (Pt(0)), the Karstedt's catalyst particles with a size of approximately 2.5 ± 0.7 nm could be reconstructed and assembled into larger particles with a size of 150 ± 35 nm due to the hydrogen bonding between the hydroxyl groups of the alkynol. In addition, because the silicone-soluble MViMVi ligand of the Karstedt's catalyst was replaced by water-soluble alkynol ligands, the resultant large particles were readily dispersed in water, resulting in rapid, efficient, and complete collection of platinum from the Karstedt's catalyst solutions with platinum concentrations in the range from ∼20 000 to 0.05 ppm. Our current strategy not only was used for the rapid and efficient collection of platinum from the Karstedt's catalyst solutions, but it also enabled the precise evaluation of the platinum content in the Karstedt's catalysts, even if this platinum content was extremely low (i.e., 0.05 ppm). Moreover, these platinum specimens that were efficiently collected from the Karstedt's catalyst solutions could be directly used for the evaluation of platinum without the need for pretreatment processes, such as calcination and digestion with hydrofluoric acid, that were traditionally used prior to testing via inductively coupled plasma mass spectrometry in conventional methods.


[Chorionic gonadotropin (beta-HCG) in the amniotic fluid in normal pregnant women].
Human chorionic gonadotropin beta subunit (beta-HCG) was measured in amniotic fluid and radioimmunoassay levels compared with those obtained in plasma from normal pregnant women. Amniotic beta-HCG exhibited a secretory pattern similar to that seen in the plasma compartment. Nonetheless amniotic beta-HCG had an elevation peak later than its plasma counterpart, with a progressive decrease that persisted throughout gestation without reaching a nadir as it occurred in plasma. Such a pattern of HCG production contained in the amnion is compatible with an HCG conformation released by the syncytiotrophoblast.


Preparation of oligonucleotides and their use in molecular weight estimations.
Yeast RNA was used to prepare oligonucleotides employed to calibrate a G-50 Sephadex column. The oligonucleotides' preparation, isolation, desalting and characterization is described. Data obtained by chromatography of the oligonucleotides demonstrate that the molecular weights of oligonoucleotides can be easily determined by interpolation using plots of elution volumes (Ve) versus molecular weights (M). Errors greater than 20% are obtained if the conventional plot of Ve-Vo/Vs versus log M is used (where Vo is the void volume of the column and Vs is the volume of the column occupied by the inert phase, the G-50 Sephadex).


Biosensors Incorporating Bimetallic Nanoparticles.
This article presents a review of electrochemical bio-sensing for target analytes based on the use of electrocatalytic bimetallic nanoparticles (NPs), which can improve both the sensitivity and selectivity of biosensors. The review moves quickly from an introduction to the field of bio-sensing, to the importance of biosensors in today's society, the nature of the electrochemical methods employed and the attendant problems encountered. The role of electrocatalysts is introduced with reference to the three generations of biosensors. The contributions made by previous workers using bimetallic constructs, grouped by target analyte, are then examined in detail; following which, the synthesis and characterization of the catalytic particles is examined prior to a summary of the current state of endeavor. Finally, some perspectives for the future of bimetallic NPs in biosensors are given.


GeneChip resequencing of the smallpox virus genome can identify novel strains: a biodefense application.
We developed a set of seven resequencing GeneChips, based on the complete genome sequences of 24 strains of smallpox virus (variola virus), for rapid characterization of this human-pathogenic virus. Each GeneChip was designed to analyze a divergent segment of approximately 30,000 bases of the smallpox virus genome. This study includes the hybridization results of 14 smallpox virus strains. Of the 14 smallpox virus strains hybridized, only 7 had sequence information included in the design of the smallpox virus resequencing GeneChips; similar information for the remaining strains was not tiled as a reference in these GeneChips. By use of variola virus-specific primers and long-range PCR, 22 overlapping amplicons were amplified to cover nearly the complete genome and hybridized with the smallpox virus resequencing GeneChip set. These GeneChips were successful in generating nucleotide sequences for all 14 of the smallpox virus strains hybridized. Analysis of the data indicated that the GeneChip resequencing by hybridization was fast and reproducible and that the smallpox virus resequencing GeneChips could differentiate the 14 smallpox virus strains characterized. This study also suggests that high-density resequencing GeneChips have potential biodefense applications and may be used as an alternate tool for rapid identification of smallpox virus in the future.


Effects of weaning on total and free iodothyronines in lambs.
Weaning is a crucial period in the management of lambs, resulting in physiological and mental challenges, that may have prolonged effects on lamb's health and welfare. To evaluate the effect of weaning on total and free triiodothyronine (T3, fT3) and thyroxine (T4, fT4) concentrations in serum of lambs by enzyme immunoassay. Animal and methods: The study was performed on two groups of 17 clinically healthy Comisana cross-bred lambs (7 males and 10 females) with or without weaning at 10 weeks of age. Serum samples were collected at the age of 8 weeks, 24 h and 2 weeks after weaning in the experimental group and at similar times in the non-weaned control group. Enzyme immunoassay was performed. Statistical analysis was done by one-way analysis of variance. Compared to control animals, weaned animals showed significantly decreased T3 and elevated T4 concentrations two weeks after weaning with higher concentrations in both males and females in contrast to 24 h after weaning. Body weight (BW) was significantly restored in both females (11% increase) and males (6%) two weeks after weaning as compared to 24 h after weaning. No gender effects were shown for total and free iodothyronine changes. Significant positive correlations were observed between BW and T4 concentrations in both females (r = 0.692) and males (r = 0.856), fT3 concentrations in males (r = 0.968) and fT4 concentrations in females (r = 0.862). Total iodothyronines could represent an indicator of their different metabolic activity with their magnitude altered two weeks following weaning.


Intravascular Images of Coronary Stenosis with Multiple Channels in a Patient with Antiphospholipid Syndrome: The Optical Coherence Tomography Findings.
Intravascular images of coronary stenosis by antiphospholipid syndrome (APS) would be beneficial to understand the mechanism of this disease. A 59-year-old woman with APS/systemic lupus erythematosis (SLE) underwent emergent coronary angiography which revealed stenosis with micro channels in the proximal left anterior descending artery. According to optical coherence tomography (OCT), the central lumen was surrounded by a thick septum with a homogenous and high intensity. Multiple small channels existed near the vessel wall with diffuse intimal hyperplasia. White thrombi were floating distal to the stenosis. Intravascular images obtained by optical coherence tomography (OCT) revealed the microstructure of complex coronary stenosis, which had ambiguous findings on angiography and intravascular ultrasound (IVUS) in an acute coronary syndrome (ACS) patient with APS/SLE.


On the nature of serological tissue polypeptide antigen (TPA); monoclonal keratin 8, 18, and 19 antibodies react differently with TPA prepared from human cultured carcinoma cells and TPA in human serum.
A panel of monoclonal antibodies which recognize the rod domains of human keratin 8, 18, or 19 was tested for its capacity to replace TPA antiserum as anchoring antibody in a two-site TPA immuno-radiometric assay kit. All six antibodies could anchor a TPA preparation, with varying efficiencies, when iodinated TPA antiserum monitored antigen binding. Conversely, the soluble keratin 8, 18, and 19 rod complex could efficiently replace the TPA preparation as antigen when TPA antiserum anchored and detected antigen binding. Moreover, in immunoblots the TPA antiserum recognized the rod domains of human keratins 8, 18, and 19. In contrast to the general reaction of the keratin antibodies with a TPA preparation, the reactions with TPA in human serum were antibody and sample dependent. A keratin 19- and a keratin 8-specific antibody anchored TPA in all sera consistently and efficiently, while the other 4 antibodies anchored serological TPA inefficiently. TPA in human serum was found in immunoblots to be somewhat more heterogeneous in size than the standard TPA preparation. The data presented here indicate that TPA in patients' sera is a degradation product of keratins 8, 18, and 19. The significance of these findings is discussed.


Human serum albumin-flavonoid interactions monitored by means of tryptophan kinetics.
A nonextensive model of decay kinetics has been used to describe fluorescence behavior of tryptophan in human serum albumin on binding two flavonoids, quercetin and morin. We demonstrate that this approach, alternative to multiexponential representation of usually complex decays of tryptophan, is more adequate and can be beneficial in noninvasive lifetime sensing based on intrinsic fluorescence.


The influence of potassium clavulanate on the rate of amoxicillin sodium degradation in phosphate and acetate buffers in the liquid state.
The stability of aqueous admixtures of amoxicillin sodium and potassium clavulanate was studied in the liquid state at selected pH values. Potassium clavulanate was found to catalyze the rate of degradation of amoxicillin sodium under the conditions of this study. In phosphate buffer (at pH 7.0) both amoxicillin sodium and potassium clavulanate showed first-order degradation when stored separately. However, when combined the rate of amoxicillin degradation increased and t(90) values for amoxicillin decreased from 69.6 min for amoxicillin alone to 10.8 min for amoxicillin in the combination at 55 degrees C. A kinetic model was developed that explained the catalytic behavior of potassium clavulanate and phosphate buffer. In acetate buffer the rate of degradation of amoxicillin sodium followed first-order kinetics, but the catalytic effect of clavulanate caused curvature in the rate plots at higher temperatures and clavulanate concentrations. This catalytic effect was less than that occurred in phosphate buffer (where the t(90) value of amoxicillin decreased from 137.3 min for amoxicillin alone to 52.5 min for amoxicillin in combination at 55 degrees C). First-order bi-exponential decay occurred with amoxicillin degradation, which explained this change in rate.


Evaluating the effectiveness of innovative design for a community mental health center.
The effectiveness of the design of the inpatient and day patient areas of a community mental health center was evaluated in 1969, soon after the center was opened, and again in 1974. The focal area is a large, irregularly shaped communal space; it opens onto a wide, encircling corridor ringed with bedrooms, multiuse rooms, and offices. The center was designed to encourage different behaviors and varied uses of space, to promote interaction, and to stimulate and challenge patients. In 1974 the evaluators found the design still worked well for the unit that still operated the same kind of program the center was designed for, a therapeutic community, even though the unit admitted sicker patients than planned. The design did not work as well for the second unit, which had become a crisis intervention program for patients who were often highly agitated, suicidal, or determined to escape; security and surveillance were major problems.


Rectus sheath catheters reduce opiate use in pancreaticoduodenectomy: a pre- and postintervention cohort study.
Pancreaticoduodenectomy is the only curative option for patients with pancreatic cancer; however, pain remains a considerable problem postoperatively. With many centres moving away from using epidural analgesia, there is the need to evaluate alternative opiate sparing techniques for postoperative analgesia. We sought to determine if rectus sheath catheters (RSCs) had an opiate sparing and analgesic effect compared with standard care alone (opiate analgesia). We conducted a retrospective pre- and postintervention cohort study of patients undergoing pancreaticoduodenectomy at a single tertiary academic hospital in Toronto, Canada, between April 2018 and December 2019. All patients undergoing a pancreaticoduodenectomy were eligible for inclusion. Among the 101 patients identified, 84 (61 control, 23 RSCs) were analyzed after exclusion criteria were applied (epidural analgesia, admission to intensive care intubated or reintubated within the first 96 hours). The pre-intervention group received a semi-standardized course of analgesics, including intravenous hydromorphone, acetaminophen, ketamine, with or without nonsteroidal anti-inflammatory, and with or without intravenous lidocaine; the latter 2 drugs were at the individual anesthesiologist and surgeon's preference. For the postintervention group, the same course of analgesics were used, with the addition of RSCs. These were inserted at the end of the operation, with a loading dose of ropivacaine administered and followed by a programmed intermittent bolus regime for 72-96 hours. The primary outcome measure was total postoperative opiate consumption (oral morphine equivalents). Secondary outcomes included pain scores (numeric rating scale) and treatment-related adverse effects. Opiate consumption (oral morphine equivalents) at 96 hours was significantly lower (median 188 mg, interquartile range [IQR] 112-228 v. 242.4 mg, IQR 166.8-352) with and without RSC, respectively (p = 0.01). The RSC group used significantly less opiates at each time point from 24 hours postoperatively, with no significant difference in pain scores between the groups and no significant catheter-related complications. The use of RSCs was associated with significant reductions in postoperative opiate consumption. Given the ease of placement and management, with minimal complications, RSCs should be incorporated into a course of postoperative multimodal analgesia. A large scale randomized controlled trial should be conducted to further investigate these findings.


Sleep-disordered breathing, type 2 diabetes and the metabolic syndrome.
Sleep-disordered breathing (SDB) encompasses a spectrum of conditions that can lead to altered sleep homeostasis. In particular, obstructive sleep apnoea (OSA) is the most common form of SDB and is associated with adverse cardiometabolic manifestations including hypertension, metabolic syndrome and type 2 diabetes, ultimately increasing the risk of cardiovascular disease. The pathophysiological basis of these associations may relate to repeated intermittent hypoxia and fragmented sleep episodes that characterize OSA which drive further mechanisms with adverse metabolic and cardiovascular consequences. The associations of OSA with type 2 diabetes and the metabolic syndrome have been described in studies ranging from epidemiological and observational studies to controlled trials investigating the effects of OSA therapy with continuous positive airway pressure (CPAP). In recent years, there have been rising prevalence rates of diabetes and obesity worldwide. Given the established links between SDB (in particular OSA) with both conditions, understanding the potential influence of OSA on the components of the metabolic syndrome and diabetes and the underlying mechanisms by which such interactions may contribute to metabolic dysregulation are important in order to effectively and holistically manage patients with SDB, type 2 diabetes or the metabolic syndrome. In this article, we review the literature describing the associations, the possible underlying pathophysiological mechanisms linking these conditions and the effects of interventions including CPAP treatment and weight loss.


Evaluation of the influence of blood glucose level on oral candidal colonization in complete denture wearers with Type-II Diabetes Mellitus: An in vivo Study.
Candidal colonization in complete denture wearers is a commonly encountered condition that worsens in the presence of untreated Diabetes Mellitus. The aim of this study was to evaluate the correlation between oral candidiasis in denture-bearing mucosa and elevated blood glucose levels in complete denture wearers and to evaluate the effect of oral hypoglycemic drug therapy in controlling oral candidal colonization in denture-bearing mucosa of complete denture wearers with Type II Diabetes Mellitus. This prospective observational study involved the participation of 15 complete denture wearers with Type II Diabetes Mellitus. The sample collection was made prior and after oral hypoglycaemic drug intervention, by swabbing the rugal surfaces of palatal mucosa, cultured and the density of the candidal colony formed was analyzed and interpreted as colony forming units (CFU) per mL. The candidal samples CFU and corresponding pre- and post-prandial blood glucose levels were estimated, analyzed and compared using Karl Pearson correlation analysis and paired t-test (α = 0.05). The Karl Pearson correlation analysis showed that there was a positive correlation between the blood glucose levels (PPS and FBS) and the candidal colonization (CFU) (P < 0.05). The mean values of all the variables were analyzed using the paired t-test. There was significant reduction in the mean values of blood glucose levels (P < 0.001) and the mean values of the CFU (P < 0.001) following oral hypoglycemic drug therapy. Positive correlation was observed between oral candidiasis in complete denture-bearing mucosa and elevated blood glucose levels and oral hypoglycemic drug therapy has a positive effect in controlling oral candidal colonization in complete denture wearers with Type II Diabetes Mellitus.


Management of early pregnancy bleeding in the accident and emergency department.
Over a period of 6 months, from February to July 1987, 26,837 patients attended St Mary's A&E Department. Of these, 179 (0.7%) were complaining of bleeding in pregnancy of less than 20 weeks gestation. In May 1987 new management guidelines were introduced. These emphasised the importance of vaginal examination and the use of ultrasound to determine the viability of the pregnancy. As a result, the incidence of admission fell from 15 of 53 (28%) to 7 of 58 (12%), referral to the on-call gynaecologist from 23 of 53 (44%) to 13 of 58 (22%) and reattendance rates from 11 of 53 (15%) to 4 of 58 (4%) (all changes P less than 0.05).


Common variable immunodeficiency--a case report and review.
Common Variable Immunodeficiency is a rare primary immunodeficiency presenting usually in young adults with repeated sinopulmonary infections as a result of profound hypogammaglobulinemia. A clinical report of the first documented patient in this region is presented along with a brief review of the recent advances made especially in understanding pathogenesis and management of patients with this disorder.


Evaluation of the antibacterial activity of new root canal sealers.
The purpose of this study was to compare the antimicrobial effect of AH-26, RealSeal (RS), and GuttaFlow after 24 hours and after one week. All sealers were prepared according to the manufacturers' directions immediately before testing. The microorganisms used in this assay included Staphylococcus aureus and Streptococcus mutans, which were prepared from isolated species in the microbiology laboratory. The antimicrobial effects of each sealer were determined by measuring the diameter of the zone of inhibition in millimeters after incubation at 37 degrees C for 24 hours and for seven days in a humid atmosphere. Each test was repeated three times. In the 24-hour samples, as well as in seven-day samples, the antibacterial activity of AH-26 was significantly greater than two other materials tested against both bacteria (p < 0.05). The antibacterial activities of RS and GuttaFlow against Staphylococcus aureus were not significantly different from each other (p > 0.05) in 24-hour as well as seven-day samples, but RS had significantly greater effect against Streptococcus mutans than GuttaFlow (p < 0.05). The products studied exhibited some variable antibacterial properties. In 24 hours, as well as in seven days, the AH-26 exerted the greatest activity against both organisms tested.


Effects of laryngeal manual therapy (LMT) and transcutaneous electrical nerve stimulation (TENS) in vocal folds diadochokinesis of dysphonic women: a randomized clinical trial.
To verify and compare the effect of transcutaneous electrical nerve stimulation (TENS) and laryngeal manual therapy (LMT) on laryngeal diadochokinesis (DDK) of dysphonic women. Twenty women with bilateral vocal nodules participated and were equally divided into: LMT Group - LMT application; TENS Group - TENS application; both groups received 12 sessions of treatment, twice a week, with a duration of 20 minutes each, applied by the same therapist. The women were evaluated as to laryngeal DDK at three moments: diagnostic, pre-treatment, and post-treatment, which produced three groups of measurements. The DDK recording was performed with intersected repetition of vowels /a/ and / i/. The analysis of vowels was performed by the program Motor Speech Profile Advanced (MSP)-KayPentax. The DDK parameters of the three evaluations were compared by means of the paired t-test (p≤0.05). The measurements of laryngeal DDK parameters were similar in the phase without treatment, indicating no individual variability over time. There was no change with respect to the speed of DDK after intervention, but after LMT, DDK of the vowel /i/ was more stable in terms of the duration of the emissions and intensity of emissions repeated. These results show improved coordination of vocal folds movement during phonation. There were no changes in the DDK parameters following TENS. LMT provides greater regularity of movement during laryngeal diadochokinesis in dysphonic women, which extends knowledge on the effect of rebalancing the larynx muscles during phonation, although TENS does not impact laryngeal diadochokinesis.


The neurobiological basis of human aggression: A review on genetic and epigenetic mechanisms.
Aggression is an evolutionary conserved behavior present in most species including humans. Inadequate aggression can lead to long-term detrimental personal and societal effects. Here, we differentiate between proactive and reactive forms of aggression and review the genetic determinants of it. Heritability estimates of aggression in general vary between studies due to differing assessment instruments for aggressive behavior (AB) as well as age and gender of study participants. In addition, especially non-shared environmental factors shape AB. Current hypotheses suggest that environmental effects such as early life stress or chronic psychosocial risk factors (e.g., maltreatment) and variation in genes related to neuroendocrine, dopaminergic as well as serotonergic systems increase the risk to develop AB. In this review, we summarize the current knowledge of the genetics of human aggression based on twin studies, genetic association studies, animal models, and epigenetic analyses with the aim to differentiate between mechanisms associated with proactive or reactive aggression. We hypothesize that from a genetic perspective, the aminergic systems are likely to regulate both reactive and proactive aggression, whereas the endocrine pathways seem to be more involved in regulation of reactive aggression through modulation of impulsivity. Epigenetic studies on aggression have associated non-genetic risk factors with modifications of the stress response and the immune system. Finally, we point to the urgent need for further genome-wide analyses and the integration of genetic and epigenetic information to understand individual differences in reactive and proactive AB. © 2015 Wiley Periodicals, Inc.


Increased activity of in situ catalysts for alkyne metathesis.
[reaction: see text] Reaction of an enyne (1,1-diphenyl-pent-1-ene-3-yne) with a preheated mixture of Mo(CO)6/4-chlorophenol/3-hexyne at 130 degrees C furnished 1,1,6,6-tetraphenylhex-1,5-diene-3-yne in an 80% yield. If the starting material was heated with a mixture of Mo(CO)6 and 4-chlorophenol under identical conditions, no reaction was observed.


Empirical mode decomposition using deep learning model for financial market forecasting.
Financial market forecasting is an essential component of financial systems; however, predicting financial market trends is a challenging job due to noisy and non-stationary information. Deep learning is renowned for bringing out excellent abstract features from the huge volume of raw data without depending on prior knowledge, which is potentially fascinating in forecasting financial transactions. This article aims to propose a deep learning model that autonomously mines the statistical rules of data and guides the financial market transactions based on empirical mode decomposition (EMD) with back-propagation neural networks (BPNN). Through the characteristic time scale of data, the intrinsic wave pattern was obtained and then decomposed. Financial market transaction data were analyzed, optimized using PSO, and predicted. Combining the nonlinear and non-stationary financial time series can improve prediction accuracy. The predictive model of deep learning, based on the analysis of the massive financial trading data, can forecast the future trend of financial market price, forming a trading signal when particular confidence is satisfied. The empirical results show that the EMD-based deep learning model has an excellent predicting performance.


Bioinspired, Size-Tunable Self-Assembly of Polymer-Lipid Bilayer Nanodiscs.
Polymer-based nanodiscs are valuable tools in biomedical research that can offer a detergent-free solubilization of membrane proteins maintaining their native lipid environment. Herein, we introduce a novel ca. 1.6 kDa SMA-based polymer with styrene:maleic acid moieties that can form nanodiscs containing a planar lipid bilayer which are useful to reconstitute membrane proteins for structural and functional studies. The physicochemical properties and the mechanism of formation of polymer-based nanodiscs are characterized by light scattering, NMR, FT-IR, and TEM. A remarkable feature is that nanodiscs of different sizes, from nanometer to sub-micrometer diameter, can be produced by varying the lipid-to-polymer ratio. The small-size nanodiscs (up to ca. 30 nm diameter) can be used for solution NMR spectroscopy studies whereas the magnetic-alignment of macro-nanodiscs (diameter of > ca. 40 nm) can be exploited for solid-state NMR studies on membrane proteins.


Neural ECM in addiction, schizophrenia, and mood disorder.
The extracellular matrix (ECM) has a prominent role in brain development, maturation of neural circuits, and adult neuroplasticity. This multifactorial role of the ECM suggests that processes that affect composition or turnover of ECM in the brain could lead to altered brain function, possibly underlying conditions of impaired mental health, such as neuropsychiatric or neurodegenerative disease. In support of this, in the last two decades, clinical and preclinical research provided evidence of correlations and to some degree causal links, between aberrant ECM function and neuropsychiatric disorders, the most prominent being addiction and schizophrenia. Based on these initial observations of involvement of different classes of ECM molecules (laminin, reelin, and their integrin receptors, as well as tenascins and chondroitin sulfate proteoglycans), ECM targets have been suggested as a novel entry point in the treatment of neuropsychiatric disorders. Hence, understanding how ECM molecules contribute to proper neuronal functioning and how this is dysregulated in conditions of mental illness is of pivotal importance. In this chapter, we will review available literature that implicates the different classes of brain ECM molecules in psychiatric disorders, with a primary focus on addiction (opiates, psychostimulants, and alcohol), and we will compare these ECM adaptations with those implicated in schizophrenia and mood disorders.


New Delhi metallo-β-lactamase-1: structure, inhibitors and detection of producers.
Since its discovery in 2008, New Delhi metallo-β-lactamase-1 (NDM-1)-producing Enterobacteriaceae have disseminated globally, facilitated predominantly by gut colonization and the spread of plasmids carrying the bla NDM-1 gene. With few effective antibiotics against NDM-1 producers, and resistance developing to those which remain, there is an urgent need to develop new treatments. To date, most drug design in this area has been focused on developing an NDM-1 inhibitor and has been aided by the wealth of structural and mechanistic information available from high resolution x-ray crystallography and molecular modeling. This review aims to summarize current knowledge regarding the detection of NDM-1 producers, the mechanism of action of NDM-1 and to highlight recent attempts toward the development of clinically useful inhibitors.


Cephalometric Analysis of the Facial Skeletal Morphology of Female Patients Exhibiting Skeletal Class II Deformity with and without Temporomandibular Joint Osteoarthrosis.
This study evaluated the differences in the facial morphological characteristics of female patients exhibiting skeletal class II deformity with and without temporomandibular joint osteoarthrosis. Eighty-three female patients with skeletal class II deformity were included in this study; these patients were classified into three groups on the basis of the condylar features shown in cone-beam computed tomography scans: normal group, indeterminate for osteoarthrosis group, and osteoarthrosis group. The cephalometric differences among the three groups were evaluated through one-way ANOVA. Of the 83 patients, 52.4% were diagnosed with osteoarthrosis, as indicated by the changes in the condylar osseous component. The cephalometric measurements that represented skeletal characteristics, including mandibular position relative to the cranial base, mandibular plane angle (MP-SN), posterior facial height (S-Go), and facial height ratio, were significantly different among the three groups (p < 0.05). The patients in the osteoarthrosis group yielded the smallest S-Go, the highest MP-SN, and the most retruded mandible. Temporomandibular joint osteoarthrosis is commonly observed in female patients with skeletal class II deformity. The morphological characteristics of the facial skeleton in patients with bilateral condylar osteoarthrosis may be altered.


Thyroid dysfunction and pregnancy outcomes.
Pregnancy has a huge impact on the thyroid function in both healthy women and those that have thyroid dysfunction. The prevalence of thyroid dysfunction in pregnant women is relatively high. The objective of this review was to increase awareness and to provide a review on adverse effect of thyroid dysfunction including hyperthyroidism, hypothyroidism and thyroid autoimmune positivity on pregnancy outcomes. In this review, Medline, Embase and the Cochrane Library were searched with appropriate keywords for relevant English manuscript. We used a variety of studies, including randomized clinical trials, cohort (prospective and retrospective), case-control and case reports. Those studies on thyroid disorders among non-pregnant women and articles without adequate quality were excluded. Overt hyperthyroidism and hypothyroidism has several adverse effects on pregnancy outcomes. Overt hyperthyroidism was associated with miscarriage, stillbirth, preterm delivery, intrauterine growth retardation, low birth weight, preeclampsia and fetal thyroid dysfunction. Overt hypothyroidism was associated with abortion, anemia, pregnancy-induced hypertension, preeclampsia, placental abruption, postpartum hemorrhage, premature birth, low birth weight, intrauterine fetal death, increased neonatal respiratory distress and infant neuro developmental dysfunction. However the adverse effect of subclinical hypothyroidism, and thyroid antibody positivity on pregnancy outcomes was not clear. While some studies demonstrated higher chance of placental abruption, preterm birth, miscarriage, gestational hypertension, fetal distress, severe preeclampsia and neonatal distress and diabetes in pregnant women with subclinical hypothyroidism or thyroid autoimmunity; the other ones have not reported these adverse effects. While the impacts of overt thyroid dysfunction on feto-maternal morbidities have been clearly identified and its long term impact on childhood development is well known, data on the early and late complications of subclinical thyroid dysfunction during pregnancy or thyroid autoimmunity are controversial. Further studies on maternal and neonatal outcomes of subclinical thyroid dysfunction maternal are needed.


Gluconeogenesis from amino acids in neonatal rat liver.
1. The utilization of amino acids for gluconeogenesis by rat liver develops in postnatal life, reaching maximum activity at the fifth day. 2. The activity of aspartate transaminase shows a similar trend in postnatal development and the increased activity appears to be due to the soluble enzyme. 3. The activity of alanine transaminase is low in foetal and postnatal rat liver and increases in activity at about the twentieth day. 4. Aspartate, glutamate and alanine make a major contribution to gluconeogenesis in the postnatal rat liver.


Moderate low birth weight and infectious disease mortality during infancy and childhood.
The purpose of this study was to determine whether moderately low birth weight, singleton babies without congenital anomalies are at increased risk for postperinatal infectious disease mortality. The study cohort consisted of 54,795 live births assembled at 12 medical school-affiliated hospitals in different regions of the United States between 1959 and 1966 and followed prospectively. After exclusions of multiple gestation births, very low birth weight (less than 1,500 g) births, births with major congenital anomalies, and first-week deaths, 51,931 children remained for analysis. Postperinatal infectious disease mortality was assessed through age 7 years. Causes of death were classified independently by two pediatricians, blinded to birth weight status, according to an algorithm developed for the study. Moderately low birth weight infants and children were at increased risk of infectious disease mortality (relative risk (RR) = 2.49, 95% confidence interval (CI) 1.74-3.55). The risk persisted among those whose deaths met our strictest criteria for infectious etiology and was sustained beyond infancy throughout the age interval under analysis. Among those with moderate low birth weight, there was an increased risk among those with preterm birth (RR = 2.77, 95% CI 1.19-6.46) but not among those who were born small-for-gestational age (RR = 1.19, 95% CI 0.37-3.83). The data suggest that moderate low birth weight renders individuals vulnerable to infectious disease mortality during both infancy and childhood. Among moderately low birth weight infants and children, this vulnerability appeared to be attributable primarily to preterm birth rather than to intrauterine growth retardation.


[Molecular Mechanism and Progression of Primary Resistance to EGFR-TKI - Analysis of 2 Cases].
Tyrosine kinase inhibitor (TKI) have been proved to be effective in the treatment of advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) sensitive mutation, which is superior to chemotherapy. However, there are still some patients with sensitive mutations have primary drug resistance. It may be related to the coexistence of susceptible and resistant mutations of EGFR gene, downstream mutations of EGFR pathway, MET amplification and BIM deletion polymorphism. We present 2 cases of primary drug resistance and analyze the reasons. .


Phase II trial of 96-hour paclitaxel in previously treated patients with advanced esophageal cancer.
A 96-hour infusion schedule of paclitaxel demonstrates tolerability and antitumor activity in lung cancer and breast cancer refractory to short-duration infusion paclitaxel. Given the activity of paclitaxel in esophageal cancer, a phase II trial of 96-hour infusion paclitaxel in esophageal cancer was undertaken. Both adenocarcinoma and squamous cell histology were included. Paclitaxel was administered at 140 mg/m2 over 96 hours every 21 days. Patients who had metastatic disease to the liver and transaminases greater than two times normal value received 120 mg/m2. Response to treatment was evaluated after the first two cycles and subsequently every third cycle. Ten men and four women were entered. All were eligible for response and had stage IV disease. Thirteen patients were previously treated. All 13 received prior short-duration paclitaxel-containing chemotherapy regimens. Eleven patients had adenocarcinoma and three squamous cell cancer. Patients completed a mean of two cycles (range one to eight) prior to disease progression. No major responses were observed. Toxicity was minimal and included grade 3/4 neutropenia in 14% of patients. One patient with adenocarcinoma demonstrated stable disease for 28 weeks. No major activity was observed in a population of previously treated patients. Ninety-six-hour paclitaxel in metastatic esophageal cancer is generally well tolerated with minimal toxicity; however, it is ineffective in previously treated patients. Further evaluation of this schedule of paclitaxel in combination with concurrent radiotherapy, where its radiosensitizing potential may be useful, is ongoing in locally advanced esophageal cancer.


A method of intermittent occlusion and chemotherapy infusion of the hepatic artery.
A method of intermittent occlusion of the hepatic artery and chemotherapy infusion has been developed using a catheter introduced into the hepatic artery, with interruption of the blood flow accomplished by inflation of the balloon. This method is less likely than ligation of the hepatic artery to produce massive liver necrosis, and it ensures adequate perfusion of the tumor tissue with the chemotherapeutic agents.


Prognostic Implications of Left Ventricular Global Longitudinal Strain in Predialysis and Dialysis Patients.
Chronic kidney disease (CKD) is a worldwide growing epidemic associated with an increased risk of cardiovascular morbidity and mortality. Left ventricular (LV) global longitudinal strain (GLS) is a measure of LV systolic function associated with prognosis in the general population. However, little is known about the association between LV GLS and survival in patients with CKD. The aim of the present study was to investigate the prognostic implications of LV GLS in predialysis and dialysis patients specifically. LV GLS was measured in a retrospective cohort of predialysis and dialysis patients (CKD stage 3b to 5) who underwent clinically indicated echocardiography between 2004 and 2015. Patients were divided into 4 groups according to quartiles of LV GLS: first quartile (LV GLS ≤10.6%, worst function), second quartile (LV GLS 10.7% to 15.1%), third quartile (LV GLS 15.2% to 17.8%), and fourth quartile (LV GLS ≥17.9%, best function). The primary end point was all-cause mortality. Of 304 patients (62 ± 14 years, 66% male), 65% were in predialysis and 35% in dialysis. During a median follow-up of 29 months (interquartile range 16 to 58 months), 34% of patients underwent renal transplantation and 36% died. Patients with LV GLS ≤10.6% showed significantly worse prognosis compared with the other groups (log-rank test, p <0.001). LV GLS ≤10.6% was significantly associated with increased risk of all-cause mortality (hazard ratio 2.18, 95% CI 1.17 to 4.06, p = 0.014) after correcting for age, gender, albumin levels, atrial fibrillation, and renal transplantation. In conclusion, in predialysis and dialysis patients, severely impaired LV GLS is independently associated with an increased risk of mortality.


Identifying abnormal parathyroid glands in the thyroid uptake area using technetium-99m-sestamibi and factor analysis of dynamic structures.
A rapid (25 min) single tracer scintigraphic method to localize parathyroid gland abnormalities was evaluated in 24 patients with hyperparathyroidism. Scintigraphy was performed with 99mTc-sestamibi prior to surgery. A 25-min dynamic series centered on the neck was acquired immediately after injection of 99mTc-MIBI. Two planar static views were obtained after 1 and 2 hr. To identify abnormal parathyroid tissue in the thyroid uptake area, a factor analysis of dynamic structure (FADS) was applied to the dynamic acquisition. The results were compared to the analysis of the two planar static views. FADS demonstrated abnormal uptake of the tracer in the thyroid area for 26 of the 31 parathyroid glands found to be abnormal at surgery (5/6 adenomas, 21/25 hyperplastic glands). In three cases, FADS demonstrated parathyroid uptake despite the absence of parathyroid tissue at surgery. FADS revealed as specific and more sensitive than the visual analysis of the two static views, since only 13/30 glands were still visible after 1 hr, and 5/26 after 2 hr. Furthermore, a study with two static views was found to be less sensitive for the detection of hyperplastic glands. FADS99mTc-MIBI is performed in less time than existing scintigraphic protocols. It is a promising method to detect abnormal parathyroid glands in the cervical area with a single tracer.


Parents' willingness to pay for biologic treatments in juvenile idiopathic arthritis.
Biologic therapies are considered the standard of care for children with the most severe forms of juvenile idiopathic arthritis (JIA). Inconsistent and inadequate drug coverage, however, prevents many children from receiving timely and equitable access to the best treatment. The objective of this study was to evaluate parents' willingness to pay (WTP) for biologic and nonbiologic disease-modifying antirheumatic drugs (DMARDs) used to treat JIA. Utility weights from a discrete choice experiment were used to estimate the WTP for treatment characteristics including child-reported pain, participation in daily activities, side effects, days missed from school, drug treatment, and cost. Conditional logit regression was used to estimate utilities for each attribute level, and expected compensating variation was used to estimate the WTP. Bootstrapping was used to generate 95% confidence intervals for all WTP estimates. Parents had the highest marginal WTP for improved participation in daily activities and pain relief followed by the elimination of side effects of treatment. Parents were willing to pay $2080 (95% confidence interval $698-$4065) more for biologic DMARDs than for nonbiologic DMARDs if the biologic DMARD was more effective. Parents' WTP indicates their preference for treatments that reduce pain and improve daily functioning without side effects by estimating the monetary equivalent of utility for drug treatments in JIA. In addition to evidence of safety and efficacy, assessments of parents' preferences provide a broader perspective to decision makers by helping them understand the aspects of drug treatments in JIA that are most valued by families.


Prevalence of spondyloarthritis in Terceira, Azores: a population based study.
To determine the prevalence of spondyloarthritis (SpA) in the Caucasian population of Terceira Island, Azores. Study subjects were recruited from people over the age of 50 years from one half of the island of Terceira (n=24 561). Seventy eight men and 78 women from each five year age group were selected, giving a total of 468 men and 468 women available for study, of whom 490 agreed to take part. These subjects were assessed by dorsal, lumbar, and pelvic radiography. Radiological sacroiliitis was identified in eight patients on whom sacroiliac computed tomography scans were performed. HLA class I typing by polymerase chain reaction with sequence-specific primers was carried out in seven cases. SpA was present in eight subjects (1.6%, 95% CI 0.8 to 2.7%), including seven men (2.7%) and one woman (0.4%). Three (1.2% ) male patients with definite ankylosing spondylitis were HLA-B27 positive. Only one person had a previous diagnosis of SpA. These data complement previous studies in European countries on SpA prevalence and establish an estimate of the overall prevalence of SpA in a southern European population.


Treatment of aggressive behavior problems in boys with intellectual disabilities using zuclopenthixol.
Disruptive or challenging behavior problems pose a threat to children and adolescents with intellectual disabilities and their caregivers. Psychopharmacological treatment is mostly studied with new-generation antipsychotics and has been criticized for adverse side effects. This study examined the effect of the classic antipsychotic zuclopenthixol. A total of 39 boys (ages 8.0-17.11 years) with learning disabilities were included and examined for a response to zuclopenthixol during a 6 week period of open label treatment. Doses started low and were adapted individually. From responders, zuclopenthixol was randomly withdrawn for 12 weeks. Responses to withdrawal were observed by external raters using the Modified Overt Aggression Scale. Of all patients included into the study, 15 were not randomized because of insufficient therapeutic effect, adverse event, or noncompliance. Kaplan-Meier estimations showed less aggressive behavior problems for the continuing subgroup (n=9) than in the placebo group (n=15). Individual doses stayed <10 mg/day. Zuclopenthixol proved to be effective in reducing challenging behavior in boys even at low doses.


Field trial of the efficacy of a combination of imidacloprid and permethrin against Tunga penetrans (sand flea, jigger flea) in dogs in Brazil.
In a field trial in Brazil 17 dogs penetrated by females of the jigger flea, Tunga penetrans, were topically treated with a combination of 10% imidacloprid and 50% permethrin (Advantix), while 17 dogs remained untreated. The follow-up controls on days 7, 14, 21 and 28 post-treatment clearly showed that, beginning from day 7, the flea load in treated dogs decreased, so that most of the dogs became free of tungiasis lesions, while in the untreated group the flea load remained high. Since the dogs distribute the flea eggs throughout the village, leading to a high incidence of tungiasis in humans, treatment of dogs probably also decreases the number of cases of tungiasis in the latter.


[Tests of stimulation of calcitonin secretion. Value in medullary cancer of the thyroid].
The detection of high circulating levels of calcitonin is a most valuable procedure to diagnose advanced cases of medullary carcinoma of the thyroid. However, the diagnosis of a primitive tumor in the early stages of development (as in cases of the familial form of the disease) or of a metastasis following ablation of the tumor is more difficult. In the latter cases, the levels of circulating calcitonin may be within normal limits, and for diagnosis one must then resort to tests to stimulate the secretion of calcitonin. We are reporting from our personal experiences the advantages, disadvantages and inconveniences of the three most well-known tests. All patients responded positively to administration of calcium or pentagastrin. The alcohol test, however, produced inconsistent results.


Management of patients with poor-prognosis nonseminomatous germ cell cancer.
The treatment and outcome of 57 patients with poor-prognosis metastatic nonseminomatous germ cell cancer were reviewed. The patients were treated between 1980 and 1986. Poor-prognosis patients were characterized by the presence of at least one of the following findings: (1) retroperitoneal tumor mass greater than 10 cm; (2) greater than 3 lung metastases, the largest being greater than 2 cm; (3) extrapulmonary, extralymphatic, metastases; and (4) extragonadal primary tumor. The intended treatment consisted of cisplatin-based combination chemotherapy followed by secondary surgery. From 1980 to 1983 a modified Einhorn regimen was used (cisplatin 100 mg/m2 per cycle; CVB). In case of unacceptable vinblastine toxicity, this drug was substituted by VP-16 (500 mg per m2 per cycle; BEP20). From October 1983 the intention was to replace at least 3 of the CVB/BEP20 cycles by BEP60 cycles (days 1-3: cisplatin 60 mg/m2, days 1-3: VP-16 120 mg/m2; days 1, 5, 15: bleomycin 30 mg). There were 33 patients in the CVB/BEP20 group and 24 patients in the BEP60 group. Two patients of the CVB/BEP20 group and 6 patients of the BEP60 group were not evaluable for response, but are included in the survival analysis. The reasons for exclusion from response evaluation were that these patients could not receive the intended chemotherapy in appropriate doses due to severely reduced pretreatment general condition or due to early death. Fourteen patients with multiple lung metastases but no other poor-prognosis criteria had a 93% survival indicating that they did not represent poor-prognosis germ cell cancer. After excluding these 14 patients, the 4-year survival was 58% for 19 CVB/BEP20 patients and 72% for BEP60 patients. This difference did not reach the level of statistical significance in this limited series. The introduction of high-dose cisplatin had thus not led to clearly superior treatment results as compared to CVB/BEP20.


Upper bounds on maximum likelihood for phylogenetic trees.
We introduce a mechanism for analytically deriving upper bounds on the maximum likelihood for genetic sequence data on sets of phylogenies. A simple 'partition' bound is introduced for general models. Tighter bounds are developed for the simplest model of evolution, the two state symmetric model of nucleotide substitution under the molecular clock. This follows earlier theoretical work which has been restricted to this model by analytic complexity. A weakness of current numerical computation is that reported 'maximum likelihood' results cannot be guaranteed, both for a specified tree (because of the possibility of multiple maxima) or over the full tree space (as the computation is intractable for large sets of trees). The bounds we develop here can be used to conclusively eliminate large proportions of tree space in the search for the maximum likelihood tree. This is vital in the development of a branch and bound search strategy for identifying the maximum likelihood tree. We report the results from a simulation study of approximately 10(6) data sets generated on clock-like trees of five leaves. In each trial a likelihood value of one specific instance of a parameterised tree is compared to the bound determined for each of the 105 possible rooted binary trees. The proportion of trees that are eliminated from the search for the maximum likelihood tree ranged from 92% to almost 98%, indicating a computational speed-up factor of between 12 and 44.


Predictive performance of serum procalcitonin for the diagnosis of bacterial meningitis after neurosurgery.
Postoperative bacterial meningitis (PBM) is a serious potential complication after neurosurgery. Early diagnosis and introduction of antimicrobial therapy are necessary to reduce the rate of fatal outcomes from PBM. However, PBM is not easily differentiated from postoperative aseptic meningitis (PAM), which usually has favorable clinical outcomes. Serum procalcitonin (S-PCT) has been found to be a useful marker for distinguishing community-acquired bacterial from viral meningitis. We investigated the predictive performance of S-PCT for PBM in patients who underwent neurosurgery. Between September 2009 and August 2010, we prospectively collected data from patients who underwent neurosurgery and had cerebrospinal fluid (CSF) pleocytosis within 14 days of surgery. Based on the CSF culture results, patients were categorized as either PBM or PAM cases. We compared the laboratory test results including S-PCT levels between PBM and PAM cases, and investigated the predictive performance of S-PCT for PBM. During the study period, PBM and PAM occurred in 14 and 64 patients, respectively. There was no significant difference in CSF profiles between PBM and PAM cases. S-PCT level ≥ 0.15 ng/mL (50.0% vs. 20.0%, P = 0.07) and C-reactive protein (CRP) level ≥ 2.5 mg/dL (75.0% vs. 46.5%, P = 0.16) tended to be more frequent in PBM than in PAM cases. A blood white blood cell (B-WBC) count ≥ 9,500/mm(3) was more frequently found in PBM cases (85.7% vs. 50.8%, P = 0.02) than in PAM cases. For the diagnosis of PBM, an S-PCT level ≥ 0.15 ng/mL had a specificity of 80.0%. The combined criteria of a CRP level ≥ 2.5 mg/dL, B-WBC count ≥ 9,500/mm(3), and an S-PCT level ≥ 0.15 ng/mL had the highest specificity (92.6%) of all the criteria. An S-PCT level ≥0.15 ng/mL had low sensitivity (50.0%), and the combined criteria of CRP level ≥ 2.5 mg/dL, B-WBC count ≥ 9,500/mm(3), and S-PCT level ≥ 0.15 ng/mL had an improved sensitivity of 85.7%. However, the sensitivity did not significantly differ from that of a B-WBC count ≥ 9,500/mm(3) (85.7%). S-PCT showed limited performance for the diagnosis of postoperative meningitis. However, it could be a useful adjunct for the improvement of diagnostic sensitivity when used in combination with other inflammatory markers.


Pharmacological implications of ipriflavone against environmental metal-induced neurodegeneration and dementia in rats.
Long-term exposure to environmental neurotoxic metals is implicated in the induction of dementia and cognitive decline. The present study aims to illustrate the therapeutic role of ipriflavone as a synthetic isoflavone against environmental metal-induced cognitive impairment in rats. Dementia was induced by a mixture of aluminum, cadmium, and fluoride for 90 days followed by ipriflavone for a further 30 days. Metal-treated animals exhibited abnormal behaviors in the Morris water maze task. Neuropathological biomarkers including oxidative stress (TBARS, NO, SOD, GPX, GST, and GSH), inflammation (TNF- α, IL-6, and IL-1β), neurotransmission (AChE and MAO), and insulin resistance (insulin, insulin receptor, and insulin-degrading enzyme) were altered, which consequently elevated the level of amyloid-β42 and tau protein in the hippocampus tissues inducing neuronal injury. Ipriflavone significantly (P < 0.05) ameliorated the neurobehavioral abnormalities and the cognitive dysfunction biomarkers via antioxidant/anti-inflammatory mechanism. Moreover, ipriflavone downregulated the mRNA expression level of amyloid precursor protein and tau protein, preventing amyloid plaques and neurofibrillary tangle aggregation at P < 0.05. A molecular docking study revealed that ipriflavone has a potent binding affinity towards AChE more than donepezil and acts as a strong AChE inhibitor. Our data concluded that the therapeutic potential of ipriflavone against dementia could provide a new strategy in AD treatment.


Endolymphatic sac surgery: analysis of 100 operations.
One hundred endolymphatic mastoid shunt operations in 89 patients with classical Menière's disease were analysed. The disease was bilateral in 18 patients (20%). The patients were carefully pre-selected by a comprehensive protocol of audiovestibular and metabolic investigations. All patients had definite electrophysiological evidence of endolymphatic hydrops with an enhanced negative summating potential on transtympanic electrocochleography. The surgical results were analysed both by the original American Academy of Ophthalmology and Otolaryngology Guidelines (AA00, 1972) and the more recent modifications of the American Academy of Otolaryngology, Head and Neck Surgery (AA-HNS, 1985). Control of the vertigo was achieved in 81% of the patients overall, in 88% of the patients with unilateral disease and in 63% of the patients with bilateral disease. A significant hearing improvement was obtained in 19% of patients, no change in 55% and hearing became worse in 26%. Tinnitus improved in 38% of patients, was unchanged in 52% and became worse in 10%. Disability was assessed and there was no disability in 44% of the patients post-operatively, some degree of disability in 48% but only 8% were severely disabled and unable to sustain gainful employment.


Comparison of Cinnamon Essential Oils from Leaf and Bark with Respect to Antimicrobial Activity and Sensory Acceptability in Strawberry Shake.
Cinnamon leaf and bark essential oils have long been used as natural preservatives and flavoring agents in foods. This study determined antimicrobial effects of leaf and bark of cinnamon essential oils (CEOs) against 2 foodborne pathogens, Salmonella Typhimurium (S.T.) and Listeria monocytogenes (L.m.), at 2 initial bacterial levels (4- and 9-log CFU/mL) in strawberry shakes. The antimicrobial study of CEOs at 0.1% and 0.5% in strawberry shakes against S.T. and L.M. showed a significant difference (P < 0.05) in log reductions of both bacterial growth at low (4-log CFU/mL) and high (9-log CFU/mL) initial bacterial levels. Addition of 0.5% CEOs into strawberry shakes at 4 °C completely inhibited both bacteria after a period of 8 d storage. Shelf-life study showed that acidity and total solid content were not affected during storage. The strawberry shakes containing bark CEO had higher ratings of sensory acceptability compared to leaf CEO, with or without the addition of 1% masking agent. In conclusion, this study demonstrated that CEO derived from bark was better than that from leaf in terms of their antimicrobial activity and sensory aspect. This study demonstrates that essential oils derived from cinnamon bark and leaf have the potential to be used as natural antimicrobial ingredient in milk beverages with respect to sensory aspect. This finding promotes the acceptance of natural antimicrobials among consumers, while providing enhanced safer products to the food industry application.


Meconium microbiota types dominated by lactic acid or enteric bacteria are differentially associated with maternal eczema and respiratory problems in infants.
Culture-dependent methods have shown that meconium, the newborn's first intestinal discharge, is not sterile, but the diversity of bacteria present in this material needs to be further characterized by means of more sensitive molecular techniques. Our aims were to characterize molecularly the meconium microbiota in term infants, to assess whether it contributes to the future microbiota of the infants' gastrointestinal tract, and to evaluate how it relates to lifestyle variables and atopy-related conditions. We applied high-throughput pyrosequencing of the 16S rRNA gene to study the meconium microbiota in twenty term newborns from a Spanish birth cohort. For comparison, we characterized the microbiota in fecal samples from seven pregnant women days before delivery and in two series of infant samples spanning the first seven months of life. We also compared our data with vaginal and skin microbiota characterized in independent studies. Different types of meconium microbiota were defined based on taxonomic composition and abundance and their associations with different factors were statistically evaluated. The meconium microbiota differs from those in adult feces, vagina and skin, but resembles that of fecal samples from young infants. Meconium samples clustered into two types with different bacterial diversity, richness and composition. One of the types was less diverse, dominated by enteric bacteria and associated with a history of atopic eczema in the mother (P = 0.038), whereas the second type was dominated by lactic acid bacteria and associated with respiratory problems in the infant (P = 0.040). Our findings suggest that the meconium microbiota has an intrauterine origin and participates in gut colonization. Although based on a small population sample, our association analyses also suggest that the type of bacteria detected in meconium is influenced by maternal factors and may have consequences for childhood health.


Detection of novel QTLs qDTH4.5 and qDTH6.3, which confer late heading under short-day conditions, by SSR marker-based and QTL-seq analysis.
Heading date is one of the most important traits in rice breeding. It is governed by multiple genes, including known quantitative trait loci (QTLs). In general, almost all japonica cultivars, including Nipponbare, head early under short-day (SD) conditions, but some indica cultivars, including Kasalath, head late. To explain this difference, we identified QTLs controlling heading date under SD conditions. We used NILs, CSSLs, and BILs from a cross between Nipponbare and Kasalath, and evaluated days to heading (DTH) under SD conditions. No NILs or CSSLs showed late heading, but two BILs (BIL-55 and BIL-78) had almost the same DTH as Kasalath. We developed an F2 population from a cross between BIL-55 and Nipponbare and performed QTL analysis using SSR markers. The late-heading phenotype was controlled by two known genes and at least two novel QTLs on chromosomes 4 and 6, named qDTH4.5 and qDTH6.3. These QTLs were confirmed by QTL-seq. The QTLs and polymorphisms detected here will provide useful information for further genetic studies and breeding under SD conditions at lower latitudes.


Photophysical and laser emission studies of 8-polyphenylene-substituted BODIPY dyes in liquid solution and in solid polymeric matrices.
In our search for efficient and photostable laser dyes, four new dyes with the basic structure of the commercial BODIPY laser dye PM567, with either an 8-diphenylene or an 8-p-triphenylene group, both substituted at the terminal polyphenylene position with an acetoxymethyl (dyes P2Ar1Ac and P3Ar1Ac, respectively) or a methacryloyloxymethyl group (dyes P2Ar1MA and P3Ar1MA, respectively), have been synthesized. The photophysical and lasing properties of the dyes have been studied both dissolved in liquid solvents (acetoxymethyl dyes) and incorporated into solid polymeric matrices, in the latter case as solutions (acetoxymethyl dyes) or as copolymers with methyl methacrylate (methacryloyloxymethyl dyes). In liquid solution, the photophysics of P2Ar1Ac and P3Ar1Ac is scarcely affected by the number (two or three) of p-phenylene units. Quantum mechanical calculations reveal that the p-phenylene units in these dyes are twisted ca. 37 degrees each other, an that the first 8-p-phenylene group stands nearly perpendicular to the aromatic BODIPY plane, resulting in electronic decoupling of the two chromophores. P2Ar1Ac exhibits a somewhat lower photodegradation quantum yield under UV and visible irradiation, if compared with P3Ar1Ac or with PM567, likely because of its also lower rate constant for the reaction with in situ-generated singlet molecular oxygen. Both acetoxymethyl dyes emit laser radiation in solution in all the solvents tried, under transversal pumping at 532 nm. In ethyl acetate, with a dye concentration of 0.80 x 10(-3) M, laser efficiencies as high as 80% have been observed. When the 8-polyphenylene dyes were incorporated into solid poly(methyl methacrylate) (PMMA) matrices, as solutions or as copolymers, the fluorescence emission increased with respect to that of the parent PM567 dye dissolved in the same matrix, and lasing efficiencies in the range 18-31% were obtained, with good photostability. The dye P2Ar1Ac dissolved in PMMA was found to exhibit the best overall laser behavior, with a good balance between efficiency and photostability.


Identification and characterization of human FCHO2 and mouse Fcho2 genes in silico.
FNBP1, FNBP1L, CIP4/TRIP10, FNBP2, SRGAP1/ARHGAP13, SRGAP2/ARHGAP14, ARHGAP4, FCHSD1, and FCHSD2 constitute the FCFBS superfamily characterized by FES-CIP4 homology (FCH) domain, Formin-binding FNBP1-FNBP2 homology (FBH) domain, and SRC homology 3 (SH3) domain. During genome-wide searching for human genes encoding FCH domain molecules, we identified the FCHO2 gene by using bioinformatics. DKFZp451B033 (AL831971.1) was the representative cDNA derived from human FCHO2 gene, while FLJ32208 (AK056770.1) was a chimeric cDNA generated by the recombination between FCHO2 and CSH1 genes. MGC63242 (BC052456.1) rather than 5832424M12 (AK031041.1) was the representative cDNA derived from mouse Fcho2 gene. FCHO2 gene, consisting of 26 exons, was mapped to human chromosome 5q13.2. Human FCHO2 (810 aa) showed 94.6% total-amino-acid identity with mouse Fcho2 (809 aa), and 50.4% total-amino-acid identity with human FCHO1. Drosophila CG8176 (NP_788613.1) and C. elegans 2B609 (NP_493947.1) were homologs of mammalian FCHO2 and FCHO1. FCHO-homologous (FOH) domain (codon 527-810 of human FCHO2) was identified as the novel domain conserved among FCHO homologs. Human FCHO2, FCHO1, Drosophila CG8176 and C. elegans 2B609 were found consisting of N-terminal FCH domain and C-terminal FOH domain. This is the first report on identification and characterization of evolutionarily conserved FCHO homologs as well as the novel FOH domain.


Various grain substrates for the production of fruiting bodies and bioactive compounds of the medicinal caterpillar mushroom, Cordyceps militaris (Ascomycetes).
In this study, several grains such as brown rice (Br), plumule rice (Pr), wheat (W) and pearl barley (Pb) supplemented with 1% (w/w) peptone (P), yeast extract (Ye), ammonia sulfate (As), and monosodium glutamate (Mg) as a nitrogen source, respectively, were used to produce fruiting bodies and bioactive compounds of two strains of Cordyceps militaris. Among these grain substrates, the substrate most suitable to mycelial growth was Pb+Ye for C. militaris H and L. The mushroom strains colonized this substrate in 12.8 and 12.6 days, respectively. For C. militaris L, the fewest days were required for primordial initiation on Br+Ye and Pr+P substrates. The highest yield and biological efficiency was observed with Pb substrate (25.16 g/bottle and 87.36%) and Br+P substrate (21.84 g/bottle and 75.83%) for C. militaris H and L, respectively. In the fruiting bodies of C. militaris H, the highest cordycepin content was cultivated on W+Mg substrate (25.07 mg/g), the highest mannitol content was cultivated with Pr+Mg (153.21 mg/g) and Pr (151.65 mg/g) substrates, and the highest adenosine content was cultivated with Pr+Ye (0.94 mg/g) and Pb+Ye (0.90 mg/g) substrates. In the fruiting bodies of C. militaris L, the highest cordycepin content was cultivated with W+Mg substrate (22.14 mg/g); the highest mannitol content was cultivated with Pb substrate (189.33 mg/g); and the highest adenosine content was cultivated with Pb+Ye substrate (0.71 mg/g).


Class II restorations: influence of a liner with rubbery qualities on the occurrence and size of cervical gaps.
The aim of this study was to evaluate the ability of new rubbery liners, used as a cervical increment, to relieve contraction stress and thereby reduce the formation of cervical gaps in class II composite restorations. The investigated liners were made of polyester-acrylate (PE(1), PE(2) or PE(3)) or silicone-acrylate (S), mixed with UDMA, without (A, B, C, D) or with HEMA (AH, BH, CH, DH). A silanized filler was added to the mixture, DH, to give composites with 20, 40, 60, and 70% (w/w) of filler (DHF20, DHF40, DHF60, DHF70, respectively). The presence and width of cervical gaps were determined using a light microscope. Statistical analysis showed that six of the 12 rubbery liners (AH-DH, DHF20-DHF40) significantly decreased gap formation in comparison with the control group. In addition, the polymerization shrinkage, flow, and strain capacity of these liners were measured and the influence of these factors on gap formation was examined. Two- and three-dimensional regression analyses showed significantly negative linear correlations between gap formation and strain capacity, and between gap formation and flow, and a significantly positive linear correlation between gap formation and shrinkage.


Comparison of estrogen-induced hyperplasia to endometrial carcinoma.
Use of exogenous estrogens has been associated with endometrial cancer in a number of case-control studies. This observed association could be biased as a result of frequent misclassification of estrogen-induced hyperplasia as endometrial cancer. To evaluate this possibility, pathology slides from 233 patients with a hospital diagnosis of endometrial cancer were reviewed independently by two pathologists. The hospital diagnosis was confirmed by both pathologists in 86% of the cases, indicating that the misclassification of hyperplasia as carcinoma is uncommon.


Synergisms of genome and metabolism stabilizing antitumor therapy (GMSAT) in human breast and colon cancer cell lines: a novel approach to screen for synergism.
Despite an improvement of prognosis in breast and colon cancer, the outcome of the metastatic disease is still severe. Microevolution of cancer cells often leads to drug resistance and tumor-recurrence. To target the driving forces of the tumor microevolution, we focused on synergistic drug combinations of selected compounds. The aim is to prevent the tumor from evolving in order to stabilize disease remission. To identify synergisms in a high number of compounds, we propose here a three-step concept that is cost efficient, independent of high-throughput machines and reliable in its predictions. We created dose response curves using MTT- and SRB-assays with 14 different compounds in MCF-7, HT-29 and MDA-MB-231 cells. In order to efficiently screen for synergies, we developed a screening tool in which 14 drugs were combined (91 combinations) in MCF-7 and HT-29 using EC25 or less. The most promising combinations were verified by the method of Chou and Talalay. All 14 compounds exhibit antitumor effects on each of the three cell lines. The screening tool resulted in 19 potential synergisms detected in HT-29 (20.9%) and 27 in MCF-7 (29.7%). Seven of the top combinations were further verified over the whole dose response curve, and for five combinations a significant synergy could be confirmed. The combination Nutlin-3 (inhibition of MDM2) and PX-478 (inhibition of HIF-1α) could be confirmed for all three cell lines. The same accounts for the combination of Dichloroacetate (PDH activation) and NHI-2 (LDH-A inhibition). Our screening method proved to be an efficient tool that is reliable in its projections. The presented three-step concept proved to be cost- and time-efficient with respect to the resulting data. The newly found combinations show promising results in MCF-7, HT-29 and MDA-MB231 cancer cells.


Identification of medullary loci critical for neurogenesis of gasping.
We hypothesized that a discrete medullary locus, critical for gasping neurogenesis, could be identified. In decerebrate, cerebellectomized, vagotomized, paralyzed, and ventilated cats, activities of phrenic, hypoglossal, and recurrent laryngeal nerves were monitored. Gasping was induced by freezing the brain stem, via a fork thermode, at the pontomedullary junction. By reversible cooling of the medulla, chemical lesions with kainic acid, and radio-frequency lesions, a critical area for gasping neurogenesis was localized bilaterally 2-3 mm rostral to obex, 2.0-2.5 mm lateral to midline, and 3-4 mm ventral to medullary surface. Electrical stimulation in this area elicited premature gasps, whereas unilateral lesions or lidocaine injections eliminated gasping activities in all nerves. These procedures did not cause similar changes during eupnea. In apneusis, however, lidocaine injections markedly altered the pattern or caused apnea. We conclude that discharge of neurons in a discrete portion of the lateral tegmental field of medulla is required for gasping neurogenesis. Our results are consistent with these neurons comprising the central pattern generator for gasping.