Gilteritinib as Bridging and Posttransplant Maintenance for Relapsed Acute Myeloid Leukemia with FLT3-ITD Mutation Accompanied by Extramedullary Disease in Elderly.
A 69-year-old woman was diagnosed with acute myeloid leukemia (AML) with an FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation. Complete remission (CR) was achieved after induction therapy, but AML resulted in a hematological relapse two months after the consolidation chemotherapy. Relapse was accompanied by multiple skin lesions that demonstrated leukemic cell infiltration as well as a drooping right eyelid with extroversion of the eye due to right oculomotor palsy. Gilteritinib was started as salvage therapy, and bone marrow blasts decreased to 0.8% after one month. Two months later, the eye symptoms improved, and the patient underwent cord blood transplantation (CBT). The skin lesions disappeared after the conditioning regimen, and the patient achieved CR status with complete donor chimerism at day 28. Gilteritinib was restarted as posttransplant maintenance therapy on day 53 of CBT. No adverse events other than mild hepatotoxicity were observed, and the patient was alive and in CR status, while continuing gilteritinib at one year and seven months after CBT. Bridging and posttransplant maintenance therapy with gilteritinib may be a promising therapeutic option for relapsed AML with the FLT3-ITD mutation in elderly patients.


Absolute rate coefficients and branching percentages for the reactions of POxCly- + N (4S(3/2)) and POxCly- + O (3P) at 298 K in a selected-ion flow tube instrument.
The absolute rate coefficients and product ion branching percentages at 298 K for the reactions of several POxCly- species with atomic nitrogen (N (4S(3/2))) and atomic oxygen (O (3P)) have been determined in a selected-ion flow tube (SIFT) instrument. POxCly- ions are generated by electron impact on POCl3 in a high-pressure source. O atoms are generated by quantitative titration of N atoms with NO, where N atoms are produced by microwave discharge on N2. The experimental procedure allows for the determination of rate coefficients for the reaction of the reactant ion with N (4S(3/2)) and O (3P) as well as with N2 and NO. None of the ions react with N2 or NO, giving an upper limit to the rate coefficient of <5 x 10(-12) cm3 molecules(-1) s(-1). POCl3- and POCl2- do not react with N atoms, giving an upper limit to the rate coefficient of <1 x 10(-11) cm3 molecules(-1) s(-1). The major product ion for POCl3- and POCl2- reacting with O involves loss of Cl from the reactant ion, accounting for >85% of the products. PO2- is a minor product (<or=4%) from POCl2- + O. Only PO2Cl- reacts with both N and O, directly giving PO2- and PO3- as major products. In addition, calculations of the structures and energies for PO2N, PO2N-, and NCl have been performed at the G3 level of theory to obtain estimates for the energetics of the PO2Cl- reactions. PO2-, PO3-, and PO2Cl2- are all unreactive with both N and O. Comparisons of the reactivity of POxCly- ions with O atoms are made to previous reactivity studies of these ions. In particular, routes that yield the very stable PO2- and PO3- ions are discussed.


Herpes simplex virus thymidine kinase-green fluorescent protein fusion gene: new tool for gene transfer studies and gene therapy.
Green fluorescent protein (GFP) and herpes simplex virus type-I thymidine kinase (TK) are commonly used markers in gene transfer studies. The latter gene has also proven to be an effective tool in cancer "suicide" gene therapy. To facilitate rapid and reliable selection of cells expressing TK, we constructed a plasmid expressing a TK-green fluorescent protein fusion gene (TK-GFP). In this fusion gene, the expression of each component is coupled to one another, permitting accurate determination of the percentage of cells expressing TK by detecting the green fluorescence produced by GFP. Transfection of the fusion plasmid to mammalian cells revealed that the construct is fully functional, making the cells both fluorescent and sensitive to ganciclovir.


Thermally Activated Delayed Fluorescence Pendant Copolymers with Electron- and Hole-Transporting Spacers.
To study the effect of hole- and electron-transporting spacers in copolymers on the thermally activated delayed fluorescence (TADF) properties and device efficiency of copolymers, two series of copolymers PCzPT-x and POPT-x have been designed and synthesized successfully. In these copolymers, 2-(10H-phenothiazin-10-yl)dibenzothiophene-S,S-dioxide units give green-yellow TADF, while hole-transporting 9-(4-vinylphenyl)-9H-carbazole units or electron-transporting diphenyl(4-vinylphenyl)phosphine oxide act as spacers or hosts. Their thermal, electrochemical, photophysical, and electroluminescent properties and theoretical calculations are systematically investigated to illustrate the relationships between molecular structures and photophysical properties. By optimizing the upconversion and radiative decay rate and managing the energy transfer, a green-yellow device based on POPT-25 achieves a maximum external quantum efficiency of 5.2%, a current efficiency of 16.8 cd/A, and a power efficiency of 7.8 lm/W with CIE coordinates of (0.36, 0.50). Moreover, an external quantum efficiency of 3.5% at the practical luminescence of 100 cd/m2 is obtained.


Use of Artificial Neural Network for the Simulation of Radon Emission Concentration of Granulated Blast Furnace Slag Mortar.
In this study, an artificial neural networks study was carried out to predict the quantity of radon of Granulated Blast Furnace Slag (GBFS) cement mortar. A data set of a laboratory work, in which a total of 3 mortars were produced, was utilized in the Artificial Neural Networks (ANNs) study. The mortar mixture parameters were three different GBFS ratios (0%, 20%, 40%). Measurement radon of moist cured specimens was measured at 3, 10, 30, 100, 365 days by sensing technology for continuous monitoring of indoor air quality (IAQ). ANN model is constructed, trained and tested using these data. The data used in the ANN model are arranged in a format of two input parameters that cover the cement, GBFS and age of samples and, an output parameter which is concentrations of radon emission of mortar. The results showed that ANN can be an alternative approach for the predicting the radon concentration of GBFS mortar using mortar ingredients as input parameters.


[Antibody dynamics in growing birds experimentally infected or naturally sick with white diarrhea].
Serologic studies were carried out with growing birds, aged 37-70 days, experimentally and spontaneously infected with Salmonella gallinarum and Salmonella pullorum, respectively. More positively reacting birds were found by means of the whole-blood agglutination reaction with typhoid-pullorum test than in the study of the same birds when aged 6-7 months. The investigation of birds when young is also advantageous in that there are no losses of eggs, it is more readily carried out, and the infected flocks could as early as the first selection be intended for market production, being replaced with healthy flocks. It is believed that certain changes in the programme for the control on pedigree and reproduction flocks would be purposeful, the first investigation for pullorum disease being carried out when the birds are aged 40-70 days and not when 6-7 months old.


Effect of lyophilization and storage of liver 9,000xg supernatant fraction on the metabolism of imipramine in several species of animals.
Effects of lyophilization and storage of liver 9,000xg supernatant fraction on the activity of drug metabolizing enzymes in some species of animals were studied. Imipramine metabolizing enzyme activity and the content of cytochrome P-450 were stable for, at least, one month without any loss of the activity when lyophilized liver 9,000xg supernatant fraction of some animal species, i.e., rat, mouse, guinea pig, rabbit and dog, was stored under reduced pressure in a deep freezer (-20 degrees C). There were no differences of imipramine metabolism between lyophilized liver 9,000xg supernatant fraction which was kept in a deep freezer for one month and a fresh fraction which was prepared immediately before determinations of the enzyme activity and cytochrome P-450. The data presented here indicated that the lyophilized preparation of the liver 9,000xg supernatant as well as the fresh preparation can be used for the determination of the drug metabolizing enzyme activity.


Changes in urinary excretions of cadmium, copper, and zinc in Japanese workers.
The authors undertook this study to determine changes in the daily concentration of cadmium, copper, and zinc in Japanese workers' urine over a 13-year period from 1985 to 1998. The workers were aged between 20 and 59 years. The authors studied 277 subjects in 1985, 320 in 1993, and 292 in 1998, for a total of 889 (464 men and 425 women). Although. in both men and women, urinary excretions of cadmium and copper were lower in 1993 and 1998 than in 1985, they were not substantially lower in 1998 than in 1993. The authors observed no marked changes between 1985, 1993, and 1998 regarding the excretion of zinc in any of the age groups in either men or women. Furthermore, the excretion of urinary cadmium in 1998 still exceeded the tolerable limit levels in the general population of the investigated region in Japan. This fact suggests the necessity of further nationwide investigation and comprehensive measures to reduce cadmium exposure in Japanese society.


Correlation of COVID-19 Receptors with Neutrophils and Their Role in the Adherence of Co-Infected Bacteria.
The COVID-19 caused by the SARS-CoV-2 virus has an impact on all aspects of patient care. Since the onset of this disease pandemic in 2019, numerous studies have been published which have attempted to identify virus receptors in the upper respiratory tract, such as nasal, oropharynx, and lung and their role in coinfection of bacterial adherence. In this study, the level of m RNA for platelet-activating factor receptor (PAF-R) and angiotensin-converting enzyme 2 receptor (ACE2-R) were detected in the whole blood of COVID-19 patients and controlled by using real-time reverse transcription-polymerase chain reaction technique. The results of the expression level of the PAF-R gene were higher in patients (43 ± 12.5) than in the healthy control (40 ± 2.1). Moreover, the expression level of ACE2-R was significantly (0.0001) increased in patients (27.5±6.2), compared to the control group. In addition, there was an elevation of neutrophils (79.6±17.6%) and PAF-R level (43%) in COVID-19 patients in comparison to the control (40) with a positive correlation between these factors (r=0.8769, P=0.0001). Nasopharyngeal epithelial cells showed a higher adherence rate (86%) to both bacteria isolates (Streptococcus pneumonia and Staphylococcus aureus) in patients than in the control group. Increased expression of PAF-R and ACE2-R genes in COVID-19 patients and co-infected bacteria disease could be the factors for the SARS-CoV-2 virus to enter the cells of the host.


[Circadian rhythms in endocrinology].
The function and fission properties of every cell in the organism follow a distinct rhythm. The synchronization of all these peripheral rhythms is controlled by a superordinate "master-clock", which is located in the nucleus suprachiasmaticus of the hypothalamus. Endocrine systems, aside from the autonomic nervous system, serve as efferent signals to transmit the rhythm to peripheral organs. The measurement of time-dependent changes in circulating hormone concentrations allows conclusions concerning the functionality of circadian rhythms and therefore represents a central approach in endocrine research. Regarding the interpretation of diurnal changes, one has to keep in mind that apart from the light/dark cycle other factors like the sleep/wake cycle or food intake also clearly influence the secretory activity of many endocrine organs. The dissociation of intrinsic circadian rhythms from other influencing factors requires the performance of costly and well-controlled experimental studies. Moreover, because of the complex interactions between hormones it is necessary to assess diurnal changes in activity of various endocrine systems in parallel. Only such an approach enables to understand the impact of endocrine rhythms on the complexly regulated homeostasis of e.g. glucose metabolism or the immune system.


Interplay of Homogeneous Reactions, Mass Transport, and Kinetics in Determining Selectivity of the Reduction of CO2 on Gold Electrodes.
Gold electrocatalysts have been a research focus due to their ability to reduce CO2 into CO, a feedstock for further conversion. Many methods have been employed to modulate CO2 reduction (CDR) vs hydrogen evolution reaction (HER) selectivity on gold electrodes such as nano-/mesostructuring and crystal faceting control. Herein we show that gold surfaces with very different morphologies (planar, leaves, and wires) lead to similar bell-shaped CO faradaic efficiency as a function of applied potential. At low overpotential (E > -0.85 V vs standard hydrogen electrode (SHE)), HER is dominant via a potential quasi-independent rate that we attribute to a rate limiting process of surface dissociation of competent proton donors. As overpotential is increased, CO faradaic efficiency reaches a maximal value (near 90%) because CO production is controlled by an electron transfer rate that increases with potential, whereas HER remains almost potential independent. At high overpotential (E < -1.2 V vs SHE), CO faradaic efficiency decreases due to the concurrent rise of HER via bicarbonate direct reduction and leveling off of CDR as CO2 replenishment at the catalyst surface is limited by mass transport and homogeneous coupled reactions. Importantly, the analysis shows that recent attempts to overcome mass transport limitations with gas diffusion electrodes confront low carbon mass balance owing to the prominence of homogeneous reactions coupled to CDR. The comprehensive kinetics analysis of the factors defining CDR vs HER on gold electrodes developed here provides an activation-driving force relationship over a large potential window and informs on the design of conditions to achieve desirable high current densities for CO2 to CO conversion while maintaining high selectivity.


Pharmacokinetics of sifuvirtide in treatment-naive and treatment-experienced HIV-infected patients.
The pharmacokinetics assessment in two clinical studies of sifuvirtide (a novel HIV fusion inhibitor) was first reported in Chinese HIV patients. Nineteen treatment-naive HIV patients were treated with s.c.(subcutaneous injection) sifuvirtide [10 or 20 mg q.d.(quaque die)] for 28 days in study 1, and eight treatment-experienced HIV patients were treated with s.c. sifuvirtide (20 mg q.d.) in combination with HAART drugs (lamivudine, didanosine, and Kaletra) for 168 days in study 2. In study 1, T1/2 was 17.8 ± 3.7 h for 10 mg group and 39.0 ± 3.5 h for 20 mg group; the mean Cmax of last dose was 498 ± 54 ng/mL for 10 mg group and 897 ± 136 ng/mL for 20 mg group. In study 2, T1/2 was 6.71 ± 2.17 h in treatment-experienced patients. Cmax was 765 ± 288 ng/mL after last 168th dosage. Sifuvirtide showed improved clinical pharmacokinetics characteristics compared with Enfuvirtide, and showed very different pharmacokinetic characteristics between treatment-naive and treatment-experienced patients. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:4038-4047, 2014.


Natural fluctuations of an electropore show fractional Lévy stable motion.
Until now a stable long-lived electronanopore could be generated in a lipid membrane only under current-clamp conditions, and stochastic properties of a single nanopore have been studied by the chronopotentiometry. The current-clamp experiment introduces negative feedback, which could be responsible for the electropore fluctuations and observed 1/fB power spectrum. A new electroporation method, chronoamperometry after current clamp (CACC), prevents irreversible rupture of the membrane and eliminates the feedback by clamping the voltage after previous electroporation. The experiments show that the electropore size can also be stabilized under constant potential. The electropore fluctuations do not need feedback to appear. The fluctuations are self-similar with a short memory. CACC provides an effective tool for studying the natural dynamics of an electropore in various environments, which was tested with Na+ and Al3+ ions. Comparison between chronopotentiometry and CACC reveals that the feedback mainly shortens the memory of the stochastic fluctuations. Statistical analysis shows that the conductance fluctuations can be approximately modeled as a fractional Lévy stable motion for a small hydrophilic electropore, which tends to fractional Brownian motion when the electropore increases its size. A hypothesis is presented that this transition reflects a more regular shape of big nanopores.


Design and Study of PEG Linkers That Enable Robust Characterization of PEGylated Proteins.
Several PEGylated therapeutic proteins are approved drugs, and more are under development. However, the synthesis and characterization of these bioconjugates, especially heterogeneous mixtures of PEGylated proteins, are challenging. The present study focuses on the development of PEG linkers that can be installed through biocatalytic route and render much simpler and insightful analytical characterization of PEG-protein conjugates. This linker enables traditional peptide mapping assay to determine protein sequence coverage, natural PTMs, and PEG attachment sites. Novel PEG linkers are cleavable during traditional sample preparation, leaving behind reporter amino acids to allow the determination of PEG attachment sites by peptide mapping. Products of transglutaminase-catalyzed bioconjugation of 5K PEG to Interferon α-2b were analyzed, and K31, K134, and K164 were identified as the PEGylation sites; the former two being newly determined sites demonstrates the sensitivity of the approach. In another instance, conjugation sites on Interleukin-2-PEG conjugation were found to be K31, K47, K48, and K75.


Promoting balance and jumping skills in children with Down syndrome.
The purpose of this study was to investigate the changes in balance and qualitative and quantitative jumping performances by 20 children with Down syndrome (3 to 6 years) on jumping lessons. 30 typical children ages 3 to 6 years were recruited as a comparison group. Before the jumping lesson, a pretest was given subjects for balance and jumping skill measures based on the Motor Proficiency and Motor Skill Inventory, respectively. Subjects with Down syndrome received 3 sessions on jumping per week for 6 weeks but not the typical children. Then, a posttest was administered to all subjects. Analysis of covariance showed the pre- and posttest differences on scores for floor walk, beam walk, and horizontal and vertical jumping by subjects with Down syndrome were significantly greater than those for the typical children.


Anaesthetic implications of Nager syndrome.
Nager acrofacial dysostosis is an oromandibular hypogenesis syndrome with associated limb abnormalities. Although it shares some phenotypic features with Treacher-Collins syndrome, it is recognized as a separate disorder. The physical features of Nager syndrome include down slanted palpebral fissures, malar hypoplasia, a high nasal bridge, atretic external auditory canals, cleft palate and micrognathia. Preaxial limb malformations include absent or hypoplastic thumbs, hypoplasia of the radius and shortened humeral bones. Of primary concern to the anaesthetist are the midface and mandibular manifestations which may complicate perioperative airway management. These problems may also manifest in the postoperative period with airway obstruction. Associated defects have included vertebral malformations with reports of cervical spine involvement, congenital cardiac defects and upper limb defects affecting the preaxial or radial side. We describe a 7-year-old boy with Nager syndrome who required anaesthetic care during placement of a syringopleural shunt for drainage of a spinal cord syrinx. The perioperative implications of this disorder are reviewed.


Peroxisome proliferator-activated receptor (PPAR)gamma can inhibit chronic renal allograft damage.
Chronic inflammation and fibrosis are the leading causes of chronic allograft failure. The nuclear receptor peroxisome proliferator-activated receptor (PPAR)gamma is a transcription factor known to have antidiabetogenic and immune effects, and PPARgamma forms obligate heterodimers with the retinoid X receptor (RXR). We have reported that a retinoic acid (RAR)/RXR-agonist can potently influence the course of renal chronic allograft dysfunction. In this study, in a Fischer to Lewis rat renal transplantation model, administration of the PPARgamma-agonist, rosiglitazone, independent of dose (3 or 30 mg/kgBW/day), lowered serum creatinine, albuminuria, and chronic allograft damage with a chronic vascular damage score as follows: 35.0 +/- 5.8 (controls) vs. 8.1 +/- 2.4 (low dose-Rosi; P < 0.05); chronic tubulointerstitial damage score: 13.6 +/- 1.8 (controls) vs. 2.6 +/- 0.4 (low dose-Rosi; P < 0.01). The deposition of extracellular matrix proteins (collagen, fibronectin, decorin) was strikingly lower. The expression of transforming growth factor-beta1 was inhibited, whereas that of bone morphogenic protein-7 (BMP-7) was increased. Intragraft mononuclear cells and activated fibroblast numbers were reduced by 50%. In addition, the migratory and proliferative activity of these cells was significantly inhibited in vitro. PPARgamma activation diminished the number of cells expressing the proinflammatory and fibrogenic proteoglycan biglycan. In macrophages its secretion was blocked by rosiglitazone in a predominantly PPARgamma-dependent manner. The combination of PPARgamma- and RAR/RXR-agonists resulted in additive effects in the inhibition of fibrosis. In summary, PPARgamma activation was potently immunosuppressive and antifibrotic in kidney allografts, and these effects were enhanced by a RAR/RXR-agonist.


Amelioration of the salt-stressed root growth of rice and normalization of the Na+ distribution between the shoot and root by (S)-alpha-methylbenzyl-2-fluoro-4-methylphenylurea.
Optically active alpha-methylbenzyl phenyl ureas (MBPUs) show diverse plant physiological properties. Experiments were conducted to evaluate the salt-stress response of just-germinated rice seedlings supplemented with the S-enantiomer of MBPUs by assessing the growth and Na+ content. This study indicates that S-MBPUs served as a unique stress reliever for just-germinated young seedlings of rice injured by salinity. NaCl severely affected the root growth of rice seedlings. Concomitant treatment with S-MBPUs effectively ameliorated the growth inhibition of rice by NaCl. Glycine betaine (GB) did not act as a reliever of the NaCl stress. The addition of S-alpha-methylbenzyl 2-fluoro-4-methylphenyl urea (7, denoted as S-FM) to the saline medium ameliorated not only the root growth but also the protein content and dry weight of roots depending upon its concentration. The protein content, Na+ content and growth rate were correlated to each other with a positive relationship. The Na+ distribution ratio (S/R(Na+)) between the shoot and root increased with increasing concentration of NaCl when added alone, viz. with increasing growth reduction. A concomitant treatment with S-FM (7), however, resulted in the S/R(Na+) value becoming smaller with growth amelioration. This indicates that S-FM (7) controlled the translation of Na+ from the roots to shoots. S-FM (7) would have influenced some inherent functions connected with the Na+ behavior in the rice plant, although details of the mechanism for normalization of the S/R(Na+) ratio are still not clear.


[Expression of human follicle stimulating hormone in insect cells].
To study the expression of hFSH in insect cells, the cDNA encoding the hFSH beta chain was cloned by overlapping-PCR using human chromosome DNA extracted from placental tissue as template. Then we constructed expression vector pVL1393/hFSH beta using an unfused protein nuclear polyhedrosis virus (AcNPV) expression vector. The insect cells (SF9) were cotransfected with the expression vector and nuclear polyhedrosis linearized virus DNA, and recombinant viruses AcNPV-hFSH beta were collected. The beta subunit of hFSH expressed in plasma of the SF9 cells was detected by Western blot analysis, and showed apparent molecular masses of 21 kDa. After coinfecting SF9 cells with recombinant viruses AcNPV-hFSH beta and AcNPV-hCG alpha, secreted heterodimer of hFSH was detected by Western blot under non-reducing conditions. The apparent molecular weight of heterodimer was about 33 kDa.


Predictors of gangrenous necrotizing enterocolitis and extent of disease. Early laparotomy versus peritoneal drainage.
Evaluation of known predictors of gangrene in neonates with necrotizing enterocolitis (NEC) and identification of those suggestive of severe disease, requiring expeditious laparotomy rather than primary peritoneal drainage as a definitive treatment. This is a retrospective review of data collected from the medical records of newborns with confirmed NEC, treated at the Maternity and Children's Hospital, Dammam, Kingdom of Saudi Arabia, from May 1993 to May 2004. Fifty-five cases were selected for the study, 23 had successful medical management and 32 underwent laparotomy. Of this group, 15 had peritoneal drainage prior to laparotomy. Nine known clinical, radiological and laboratory features suspicious of bowel perforation or gangrene were evaluated. The operated group was classified according to the extent of disease into isolated, multifocal or pan intestinal and the distribution of these 9 criteria was calculated for each of the 3 groups. Comparison was then carried out between the group with isolated NEC and those with extensive disease. Isolated NEC was present in 8 (25%), multifocal NEC in 19 (59%) and pan intestinal NEC in 5 (16%) of the operated cases. Pneumoperitoneum and palpable abdominal mass were the most specific and predictive signs of perforated or gangrenous bowel in NEC. Severe pneumatosis intestinalis and gasless abdomen were also highly specific and predictive of the same but had a low prevalence. Abdominal wall erythema, persistent metabolic acidosis, portal vein air, gasless abdomen and severe pneumatosis intestinalis were found to be associated with severe or extensive gangrene. Palpable abdominal mass and fixed dilated loops were increased in cases of isolated NEC. Portal vein air was associated with the highest mortality. Pneumoperitoneum, though the only absolute evidence of bowel perforation, cannot predict the extent of disease. Peritoneal drainage is a useful stabilizing procedure but the presence of any of the above mentioned criteria which are associated with severe disease necessitate a quick decision in favor of laparotomy. The absence of these signs, however, cannot rule out extensive or progressive NEC and failure to improve after peritoneal drainage also requires an emergency laparotomy, regardless of birth weight or gestational age.


The Translational Value of Psychophysiology Methods and Mechanisms: Multilevel, Dynamic, Personalized.
It has been nearly 15 years since Kazdin and Nock published methodological and research recommendations for understanding mechanisms of change in child and adolescent therapy. Their arguments and enthusiasm for research on mechanisms of behavior change (MOBCs) resonated across disciplines and disorders, as it shined a light on the crucial importance of understanding how and for whom treatments instigate behavior change and how therapeutic mechanisms might be extended to "situations and settings of everyday life." Initial efforts focused on how psychotherapy works and linear models, yet the use of theory to guide the study of mechanisms, and laboratory experiments to manipulate them, is broadly applicable. This article considers dynamic physiological processes that support behavior change. Specifically, it examines the utility of psychophysiological methods to measure and promote behavior change. Moreover, it embeds the baroreflex mechanism, a well-defined heart-brain feedback loop, within the theories and strategies of MOBC research. Individuals' subjective and expressive experience of change does not always align with their physiological reactivity. Thus, behavior change may be best understood when concurrently assessed across multiple biobehavioral levels. Further, behavior is initiated in the moment, often before conscious deliberation, suggesting that multilevel behavior change research may benefit from real-time methodological designs. Last, substance use trajectories vary widely, suggesting that different MOBCs are more or less active in individuals depending on their personal constituency and the functional need that their substance use serves; thus, methods that are amenable to personalized modeling approaches are important.


Effect of transfer of donor corneal tissue from McCarey-Kaufmann medium to Optisol-GS on corneal endothelium.
The purpose of this study is to evaluate the effect of transfer of donor corneal tissue from McCarey-Kaufmann (MK) medium to Optisol-GS on corneal endothelium. This was a prospective, randomized comparative study. Twenty paired human donor corneal tissues of optical quality were retrieved. One tissue of the pair was preserved in Optisol-GS preservative medium (Group A) and other tissue of the pair in MK medium (Group B) at the time of corneoscleral disc excision. Within 12 h of retrieval, each cornea was evaluated using slit-lamp biomicroscopic examination and specular microscopic analysis. Group B corneas were transferred to Optisol-GS medium within 48-53 h of retrieval. Specular analysis of the paired corneas was repeated 3 h after transferring to Optisol-GS. On day 7 of storage, specular analysis of both the tissues was repeated. The average age of the donor at the time of death was 29 years (16-68 years). The reduction in endothelial cell count, from baseline, in Groups A and B was 5.5% and 5.8% (P = 0.938) on the 3rd day and 8.2% and 12.6% (P = 0.025) on the 7th day, respectively, postretrieval. The coefficient of variation (CV) increased by 36% (P = 0.021) and hexagonality reduced by 19% (P = 0.007) on day 7. All tissues retained an endothelial cell density higher than the accepted critical level for penetrating keratoplasty. Significant endothelial cell loss was noted while transferring tissues from one medium to another, necessitating the need for reevaluation of transferred tissues before utilization.


Functional annotation and analysis of the Ornithodoros moubata midgut genes differentially expressed after blood feeding.
The argasid tick Ornithodoros moubata is the main vector of the African swine fever and the human relapsing fever in Africa. As part of the host-parasite-pathogen interface, the tick midgut expresses key proteins for tick survival and tick-borne pathogen transmission. Accordingly, midgut proteins are potential targets for the development of new drugs and vaccines aimed at tick control, and obtaining proteomic and transcriptomic data from the O. moubata midgut would facilitate the identification of such target candidates. With this aim, we have assembled and characterized the midgut transcriptome of O. moubata females before and 48h after a blood meal, and identified the genes that are differentially expressed in the midgut after feeding. Overall, 23,863 transcripts were obtained, and of them, 9,164 were identified and annotated. The most represented molecular functions were catalytic and binding activities, and the most represented biological processes were metabolic, cellular and single-organism processes. KEGG analysis of the annotated sequences assigned up to 3,053 of them to 130 active pathways, among which, the top 30 pathways were mostly metabolic routes. Differential expression analysis between unfed and fed ticks detected 8,026 Differentially Expressed Genes (DEGs), 4,093 up-regulated and 3,933 down-regulated, respectively. The biological significance of these DEGs was further investigated using the KEEG, Pfam and GO databases. The functional groups of the genes/proteins predicted to be involved in the processes of blood digestion, nutrient transport and metabolism, and in responses related to defence and oxidative stress are discussed in more detail. This work reports the first midgut transcriptome analysis of an argasid tick species, and provides a wealth of novel molecular information about the argasid machinery involved in blood feeding and digestion. This information represents a starting point for the development of alternative strategies for tick control.


Transposition-mediated DNA re-replication in maize.
Every DNA segment in a eukaryotic genome normally replicates once and only once per cell cycle to maintain genome stability. We show here that this restriction can be bypassed through alternative transposition, a transposition reaction that utilizes the termini of two separate, nearby transposable elements (TEs). Our results suggest that alternative transposition during S phase can induce re-replication of the TEs and their flanking sequences. The DNA re-replication can spontaneously abort to generate double-strand breaks, which can be repaired to generate Composite Insertions composed of transposon termini flanking segmental duplications of various lengths. These results show how alternative transposition coupled with DNA replication and repair can significantly alter genome structure and may have contributed to rapid genome evolution in maize and possibly other eukaryotes.


Anticancer activity of graphene oxide-reduced graphene oxide-silver nanoparticle composites.
In the present study, a chemical route was employed to synthesize graphene oxide (GO)-reduced graphene oxide (rGO)-Ag nanoparticle (AgNP) composites from graphite and AgNO3 using vitamin C as reducing agent. Powder X-ray diffraction pattern and field emission scanning electron microscope images revealed that the AgNP were uniformly distributed on the surface of GO and rGO nanosheets. For the first time, the cytotoxicity of GO, rGO, AgNP, GO-AgNP and rGO-AgNP composites were examined against human lung cancer A549 cells using MTT assay and reported quantitatively. The rGO-AgNP showed significant cytotoxicity activity with an IC50 value of 30μg/mL towards A549 cells which is higher than that of GO (180μg/mL), rGO (160μg/mL) and GO-AgNP (100μg/mL). Compared to AgNP (6μg/mL), rGO-AgNP shows partial agglomeration of AgNP on rGO sheets, which reduces the interaction between rGO-AgNP and A549 cells leading to lesser anticancer activity than AgNP. The interaction between rGO and AgNP leads to increase in the material biocompatibility, reducing the toxicity and corrosive characteristic.


Ovalbumin is synthesized in mouse cells transformed with the natural chicken ovalbumin gene.
The entire chicken ovalbumin gene, accompanied by genomic DNA sequences flanking both termini of the gene and three copies of the herpes simplex virus thymidine kinase gene, has been cloned in plasmid pBR322. This recombinant plasmid was linearized and used to transform thymidine kinase-deficient mouse cells. Thymidine kinase-positive transformants were selected by their ability to grow in the hypoxanthin/aminopterin/thymidine (HAT) medium. The entire ovalbumin gene integrated into high molecular weight DNA within all the transformants and retained its original sequence organization. In all of the transformants examined, a protein identified as chicken ovalbumin by immunoreactivity was detected within the cells. It is estimated that between 1000 and 100,000 molecules of chicken ovalbumin were produced per mouse cell in each of these transformants. Our results demonstrate that the mouse cellular machinery can be utilized to accurately express genetic information encoded in a cloned gene from a different eukaryotic organism into its specific protein product.


Efficacy of a nerve stimulator in regional analgesia; experience in a resident training programme.
Forty interscalene brachial plexus regional blocks and twenty sciatic-femoral lower limb blocks were performed by 1st and 2nd year anaesthesia residents. Nerve trunk location was equally but randomly divided between use of a peripheral nerve stimulator and reliance on paraesthesiae. The stimulator group were sedated prior to nerve block while the non-stimulator group were similarly sedated after nerve block. There was no significant difference either in the number of needle insertions required for nerve location, or in the success rate, between stimulator and non-stimulator techniques. It is concluded that the stimulator is not a useful adjunct for nerve location, except in those patients who are unable to co-operate in eliciting paraesthesia. In such patients the stimulator permits a comparable success rate.


Gene expression analyses reveal metabolic specifications in acute O2 -sensing chemoreceptor cells.
Glomus cells in the carotid body (CB) and chromaffin cells in the adrenal medulla (AM) are essential for reflex cardiorespiratory adaptation to hypoxia. However, the mechanisms whereby these cells detect changes in O2 tension are poorly understood. The metabolic properties of acute O2 -sensing cells have been investigated by comparing the transcriptomes of CB and AM cells, which are O2 -sensitive, with superior cervical ganglion neurons, which are practically O2 -insensitive. In O2 -sensitive cells, we found a characteristic prolyl hydroxylase 3 down-regulation and hypoxia inducible factor 2α up-regulation, as well as overexpression of genes coding for three atypical mitochondrial electron transport subunits and pyruvate carboxylase, an enzyme that replenishes tricarboxylic acid cycle intermediates. In agreement with this observation, the inhibition of succinate dehydrogenase impairs CB acute O2 sensing. The responsiveness of peripheral chemoreceptor cells to acute hypoxia depends on a 'signature metabolic profile'. Acute O2 sensing is a fundamental property of cells in the peripheral chemoreceptors, e.g. glomus cells in the carotid body (CB) and chromaffin cells in the adrenal medulla (AM), and is necessary for adaptation to hypoxia. These cells contain O2 -sensitive ion channels, which mediate membrane depolarization and transmitter release upon exposure to hypoxia. However, the mechanisms underlying the detection of changes in O2 tension by cells are still poorly understood. Recently, we suggested that CB glomus cells have specific metabolic features that favour the accumulation of reduced quinone and the production of mitochondrial NADH and reactive oxygen species during hypoxia. These signals alter membrane ion channel activity. To investigate the metabolic profile characteristic of acute O2 -sensing cells, we used adult mice to compare the transcriptomes of three cell types derived from common sympathoadrenal progenitors, but exhibiting variable responsiveness to acute hypoxia: CB and AM cells, which are O2 -sensitive (glomus cells > chromaffin cells), and superior cervical ganglion neurons, which are practically O2 -insensitive. In the O2 -sensitive cells, we found a characteristic mRNA expression pattern of prolyl hydroxylase 3/hypoxia inducible factor 2α and up-regulation of several genes, in particular three atypical mitochondrial electron transport subunits and some ion channels. In addition, we found that pyruvate carboxylase, an enzyme fundamental to tricarboxylic acid cycle anaplerosis, is overexpressed in CB glomus cells. We also observed that the inhibition of succinate dehydrogenase impairs CB acute O2 sensing. Our data suggest that responsiveness to acute hypoxia depends on a 'signature metabolic profile' in chemoreceptor cells.


[Gastroprotective action of corticotropin-releasing factor (CRF): involvement of glucocorticoids and CRF receptors type 2].
The stress response involves the activation of two corticotropin-releasing factor (CRF) receptors types 1 and 2. The pituitary type 1 CRF receptors represent the primary receptors to activate the hypothalamic-pituitary-adrenocortical axis and, consequently, glucocorticoid production. Exogenous CRF induces an increase in glucocorticoid production and may protect the gastric mucosa against stress-induced injury. Here we examined contribution of glucocorticoids and CRF receptors type 2 to gastroprotective effect of exogenous CRF. Gastric injury was induced by 3 him-mobilization (at 10 degrees C) in conscious rats or 3.5 h gastric ischemia-reperfusion in anaesthetized rats. Intraperitoneal administration of CRF at the doses of 1.25 or 2.5 Mg/kg increased plasma corticosterone levels and suppressed the occurrence of gastric erosion induced by each stimulus. Metyrapone injected before CRF caused an inhibition of CRF-induced corticosterone response and prevented the protective effect of CRF on the gastric mucosa against erosion caused by immobilization (at 10 degrees C). However, metyrapone injection did not influence the protective effect of CRF on the gastric mucosa against ischemia-reperfusion-induced lesion. The protective effect of CRF on the gastric mucosa against ischemia-reperfusion-induced lesion was prevented by the nonselective CRF receptor antagonist astressin and selective type 2 CRF receptor antagonist astressin2-B. The results obtained suggest that exogenous CRF may protect the gastric mucosa against injury through involvement of glucocorticoids and also through CRF receptors type 2.


Septicemia without sepsis: inherited disorders of nuclear factor-kappa B-mediated inflammation.
Septicemia is a life-threatening condition that may lead to sepsis and even septic shock. This cascade is usually accompanied by a pronounced inflammatory response, leading to high body temperature and elevated levels of laboratory markers of inflammation. However, this response can be significantly diminished in children with inherited disorders of nuclear factor (NF)-kappa B-mediated immunity. Three disease-causing genes involved in NF-kappa B activation have been identified: NEMO, IKBA, and IRAK4. Patients with anhidrotic ectodermal dysplasia and immunodeficiency, which is caused by mutations in NEMO and IKBA, have sparse hair, dry skin, and conical teeth and are at increased risk of severe infections caused by pyogenic bacteria and atypical mycobacteria. Patients with interleukin-1 receptor-associated kinase-4 deficiency are at increased risk of invasive disease due to pyogenic bacteria. An underlying defect in NF- kappa B activation should be suspected in children with bacterial septicemia accompanied by mild signs of inflammation.


Automated and manual serum free thyroxine assays evaluated with equilibrium dialysis.
Two fully automated serum FT4 assays (Ciba Corning: ACS-180; Abbott Diagnostics: IMx) and two manual/semiautomated assays (Wallac: Delfia; Diagnostic Products Corp.: Coat-A-Count) were compared with a FT4 reference method based on equilibrium dialysis (ED) using routine clinical samples (n = 105-150). For the full range of FT4 concentrations the correlation with ED was good (r = 0.932-0.959), except for Coat-A-Count (r = 0.852), a single-step analogue-type method. Analytical inaccuracy of the automated methods at low FT4 concentrations was revealed by the differential plot: the IMx assay overestimated concentrations < 10 pmol l-1 and the ACS-180 assay concentrations < 6 pmol l-1. The between-assay CVs for the automated methods were not better than for the non-automated assays indicating problems of calibration curve stability for the automated assays.


Evaluation of the prevalence and risk factors for colonization by vancomycin-resistant Enterococcus among patients on dialysis.
Vancomycin-resistant Enterococcus (VRE) has been reported among long-term dialysis patients, although risk factors for VRE colonization are not well defined. This study aims to appraise the prevalence and risk factors for VRE colonization among patients on long-term dialysis therapy, as well as the mechanisms for dissemination of vancomycin resistance. This is a cross-sectional survey of 320 patients on long-term dialysis therapy at 2 hospitals of the Federal University of São Paulo from June 2001 to March 2003. Fecal samples were collected from each patient once a week for 1 month. Samples with positive test results for VRE were submitted to molecular typing through automated ribotyping. VRE prevalence was 14.4%. There were significant associations between VRE and dialysis type (hemodialysis, P = 0.04), number of hospitalizations (P = 0.03), low hemoglobin level (P = 0.03), and leukocytosis (P = 0.05). Among samples with VRE (n = 56), 25% were Enterococcus faecium; 10.7%, Enterococcus casseliflavus; 57.1%, Enterococcus gallinarum; and 3.6%, Enterococcus faecalis. All samples isolated were sensitive to teicoplanin, except for E faecium samples, which were strongly resistant, although 9 of 14 patients with this isolate presented the same ribogroup (111-S-4). Typing of 6 samples from 8 dialysis patients with E gallinarum was performed, showing a predominant ribogroup (112-S-4). Hospital environment, hemodialysis, anemia, and leukocytosis appear to be associated with VRE colonization. These results suggest that dissemination of these bacteria among patients on long-term dialysis therapy may be taking place.


Properties of rabies strain ("Pasteur Potsdam") adapted to primary dog kidney cells.
The Pasteur strain of fixed rabies virus (Pasteur Institute Paris, passage 2061 in rabbit brain) was adapted by alternate passages to primary dog kidney cells. The adapted rabies virus designated as "Pasteur Potsdam" developed no CPE and yielded four harvests with a titre of 5.5-7.0 (log MICLD50/ml). The strain could be grown in BHK 21/S13, CER and N2a neuroblastoma cells. In the cultures of BHK 21/S13 cells the virus titered 6.0-8.5 (log MICLD50/ml). In SDS PAGE its G protein migrated faster than that of the ERA strain. The inactivated antigen induced interferon in mice. The strain was identified by anti-rabies immunoglobulin. The harvested material showed an antigenic value of 0.4 IU/ml. The virus was not pathogenic after s.c. and i.p. inoculations to mice, rats, Syrian hamsters, and rabbits and after i.m. inoculation to Syrian hamsters and rats.


Bioactive secondary metabolites from new endophytic fungus Curvularia. sp isolated from Rauwolfia macrophylla.
Over the last decades, endophytic fungi represent a new source of pharmacologically active secondary metabolites based on the underlying assumption that they live symbiotically within their plant host. In the present study, a new endophytic fungus was isolated from Rauwolfia macrophylla, a medicinal plant from Cameroon. The fungus showed a highest homology to Curvularia sp. based on complete nucleotide sequence data generated from the internal transcribed spacer (ITS) of ribosomal DNA region. Large scale fermentation, working-up and separation of the strain extract using different chromatographic techniques afforded three bioactive compounds: 2'-deoxyribolactone (1), hexylitaconic acid (2) and ergosterol (3). The chemical structures of compounds 1-3 were confirmed by 1 and 2D NMR spectroscopy and mass spectrometry, and comparison with corresponding literature data. Biologically, the antimicrobial, antioxidant activities and the acetylcholinesterase inhibitory of the isolated compounds were studied.


Heat damage and repair in the Escherichia coli nucleoid: kinetics based on sedimentation analysis.
Changes in the structure of the Escherichia coli nucleoid during heat damage and repair were followed by sedimentation analysis in neutral sucrose gradients. Heating at 50 degrees C results first in a decrease in the sedimentation coefficient of the isolated nucleoid. Increasing the heating time, a subsequent increase in sedimentation coefficient is observed. After a heat shock (i.e. 4 min at 50 degrees C), a short incubation at 25 degrees C (i.e. 5 min) allows the nucleoid to repair and return to the sedimentation coefficient of control unheated nucleoids. The nucleoids heated at 50 degrees C for longer periods and incubated afterwards at 25 degrees C demonstrate a different pattern of structural repair. They associate with protein in the first stage of the repair period.


Comparison of multiple X-ray fluorescence techniques for elemental analysis of particulate matter collected on air filters.
This work reports on qualitative and semi-quantitative elemental analysis of particulate matter (PM) collected on PTFE membrane filters, for a source apportionment study conducted in Brescia (Italy). Sampling was undertaken in a residential area where an increase in Mn emissions has been highlighted by previous studies. Filters are measured by means of X-ray Fluorescence (XRF) based techniques such as micro-XRF and grazing incidence XRF using synchrotron radiation, Mo or W excitation sources, after applying an automatized sample preparation method. A heterogeneous distribution in PM shape, size and composition was observed, with features typical of anthropogenic sources. XRF measurements performed at various incidence angle, on large areas and different experimental setup were reproducible. The results demonstrate a successful comparison of the various XRF instrumentation, and the decrease in Mn content with the distance away from the identified emission source. This work highlights the potentialities of the presented approach to provide a full quantitative analysis, and ascertain its suitability for providing a direct, fast, simple and sensitive elemental analysis of filters in source apportionment studies and screening purposes.


Transcriptome of swarming Proteus mirabilis.
Swarming motility by the urinary tract pathogen Proteus mirabilis has been a long-studied but little understood phenomenon. On agar, a P. mirabilis colony grows outward in a bull's-eye pattern formed by consecutive waves of rapid swarming followed by consolidation into shorter cells. To examine differential gene expression in these growth phases, a microarray was constructed based on the completed genome sequence and annotation. RNA was extracted from broth-cultured, swarming, and consolidation-phase cells to assess transcription during each of these growth states. A total of 587 genes were differentially expressed in broth-cultured cells versus swarming cells, and 527 genes were differentially expressed in broth-cultured cells versus consolidation-phase cells (consolidate). Flagellar genes were highly upregulated in both swarming cells and consolidation-phase cells. Fimbriae were downregulated in swarming cells, while genes involved in cell division and anaerobic growth were upregulated in broth-cultured cells. Direct comparison of swarming cells to consolidation-phase cells found that 541 genes were upregulated in consolidate, but only nine genes were upregulated in swarm cells. Genes involved in flagellar biosynthesis, oligopeptide transport, amino acid import and metabolism, cell division, and phage were upregulated in consolidate. Mutation of dppA, oppB, and cysJ, upregulated during consolidation compared to during swarming, revealed that although these genes play a minor role in swarming, dppA and cysJ are required during ascending urinary tract infection. Swarming on agar to which chloramphenicol had been added suggested that protein synthesis is not required for swarming. These data suggest that the consolidation phase is a state in which P. mirabilis prepares for the next wave of swarming.


Activated perilobular, not periacinar, pancreatic stellate cells contribute to fibrogenesis in chronic alcoholic pancreatitis.
The authors investigated the role of activated perilobular, not periacinar, pancreatic stellate cells, in fibrogenesis in chronic pancreatitis, based on the distribution of myofibroblasts. Twenty-four patients with clinically diagnosed chronic alcoholic pancreatitis were studied histopathologically, immunohistochemically and quantitatively. In all cases, fibrosis was patchily distributed in the perilobular, or interlobular, areas, accompanied by a cirrhosis-like appearance; it had extended into the intralobular area in advanced cases. Seven patients had a massive or confluent loss of exocrine tissue, resulting in extensive interlobular fibrosis; the more extensive the interlobular fibrosis, the smaller the lobules. Immunoreactivity to alpha-smooth muscle actin, a myofibroblast marker, was found mostly in the same areas of the fibrosis, mainly the interlobular, and less often the periacinar, areas; the average percentage area of perilobular myofibroblasts was significantly higher than that of periacinar myofibroblasts in 20 randomly selected lobules (P > 0.001), in which the average value for the former was 38.03% (range: 13.54-61.32%; SD, 13.8%) and that for the latter was 4.85% (range 0.90-9.57%; SD, 2.22%). Fibrosis also immunostained positive for collagen types I and III. In conclusion, activated perilobular, not periacinar, pancreatic stellate cell contribute to fibrogenesis in chronic pancreatitis.


Reduced toxicological manifestations of cisplatin following encapsulation in folate grafted albumin nanoparticles.
Cisplatin is one of the most potent chemotherapeutic agents acting against a variety of tumors, however, its use is mainly limited due to the dose limiting toxicities and acquired resistance to cisplatin. Folate functionalized albumin nanoparticles were developed for targeted delivery of drug to limit the adverse effects of cisplatin. Cisplatin loaded nanoparticles functionalized with folate (CP-FA-BSA-NPs) were developed and characterized for various parameters. In order to investigate the targeting ability of folate conjugated nanoparticles, in vitro cellular uptake study was performed in folate receptor over expressing cells (MCF-7). Further, blood urea nitrogen (BUN) level, plasma creatinine level, body weight and kidney weight of the mice were measured followed by histopathological examination of various tissues to have an insight into the potential of developed formulation in the reduction of drug associated adverse effects. The cellular uptake studies demonstrated higher internalization of folate conjugated nanoparticles as compared to plain counterpart (CP-BSA-NPs). Following two cycles of cisplatin treatment, a week apart, BUN and plasma creatinine level were found to be significantly higher in case of free cisplatin as compared to saline, CP-BSA-NPs and CP-FA-BSA-NPs treated groups. Body weight and kidney weight of free cisplatin treated mice were significantly reduced as compared to other group. Histopathological examination of kidney from CP-BSA-NPs and CP-FA-BSA-NPs treated groups revealed no kidney damage, however, a sign of nephrotoxicity was observed in the case of free cisplatin. The results demonstrated the potential of developed formulation in reducing the adverse effects of cisplatin.


Potential of acoustic imaging in the detection of nanometer gaps.
The potential of the water-immersion and dry-contact acoustic imaging techniques for detecting nanometer gaps embedded in silicon is studied. The sensitivity for detecting gaps of over 10 nm in height is governed only by the lateral resolution of the imaging and is independent of the height of the gap.


Wildlife collection for scientific purposes.
Illegal transfer of wildlife has 2 main purposes: trade and scientific research. Trade is the most common, whereas scientific research is much less common and unprofitable, yet still important. Biopiracy in science is often neglected despite that many researchers encounter it during their careers. The use of illegally acquired specimens is detected in different research fields, from scientists bioprospecting for new pharmacological substances, to taxonomists working on natural history collections, to researchers working in zoos, aquariums, and botanical gardens. The practice can be due to a lack of knowledge about the permit requirements in different countries or, probably most often, to the generally high level of bureaucracy associated with rule compliance. Significant regulatory filters to avoid biopiracy can be provided by different stakeholders. Natural history collection hosts should adopt strict codes of conduct; editors of scientific publications should require authors to declare that all studied specimens were acquired legally and to cite museum catalog numbers as guarantee of best practices. Scientific societies should actively encourage publication in peer-reviewed journals of work in which specimens collected from the wild were used. The International Commission on Zoological Nomenclature could require newly designated types based on recently collected specimens to be accompanied by statements of deposition in recognized scientific or educational institutions. We also propose the creation of an online platform that gathers information about environmental regulations and permits required for scientific activities in different countries and respective responsible governmental agencies and the simplification of the bureaucracy related to regulating scientific activities. This would make regulations more agile and easier to comply with. The global biodiversity crisis means data need to be collected ever faster, but biopiracy is not the answer and undermines the credibility of science and researchers. It is critical to find a modus vivendi that promotes compliance with regulations and scientific progress.


Treatment of cervical carcinoma with methotrexate, bleomycin and vincristine.
Seventeen patients with squamous cell carcinoma of the cervix received a combination of methotrexate, bleomycin, and vincristine. Oral methotrexate and parenteral bleomycin were given every week and intravenous vincristine was given every other week. Eight patients had partial response and one patient had a complete response. This study strongly supports the effectiveness of methotrexate, bleomycin, and vincristine against cervical malignancy.


Primary peripheral adenoid cystic carcinoma of the lung. A case report.
We report a rare case of peripheral adenoid cystic carcinoma of the lung, showing unusual pathological and clinical features, namely rapid growth, local aggressive behaviour, huge tumour size, no endobronchial component or submucosal infiltration, and a rapidly progressive clinical course. Extensive surgery resulted in considerable palliation of symptoms, but not in prolonged survival. The reported case emphasizes the malignant potential of peripheral adenoid cystic carcinoma of the lung.


[Detection of surface EMG signal using active electrode].
Research of surface electromyogram(EMG) signal is important in rehabilitation medicine, sport medicine and clinical diagnosis, accurate detection of signal is the base of quantitative analysis of surface EMG signal. In this article were discussed how to reduce possible noise in the detection of surface EMG. Considerations on the design of electrode unit were presented. Instrumentation amplifier AD620 was employed to design a bipolar active electrode for use in surface EMG detection. The experiments showed that active electrode could be used to improve signal/noise ratio, reduce noise and detect surface EMG signal effectively.


[Pilonidal Sinus -- Primary Closure also in Case of Abscess?].
After excision of pilonidal sinus treatment consists either in open procedure or primary closure. We present the results of 45 consecutive patients (male 29, female 16, age 32 +/- 13 years), who underwent surgery between September 2001 and December 2002. Fourteen patients had simple fistula without infection, 18 had fistulas with putride secretion and 13 had abscess. Primary closure with direct suture was performed in 34 patients (76 %: 13 x simple fistula, 13 x fistula with putride secretion, 8 x abscess). Eleven patients were treated by layopen procedure and secondary wound healing. Wound infection occurred in 13 patients (7 x superficial, 6 x deep). Mean time of postoperative treatment was 15 +/- 3 days after closure and primary healing and 66 +/- 15 days after open proce dure or secondary healing. Mean time out of work was 19 +/- 10 respectively 52 +/- 19 days. A recurrence of fistula occurred in eight patients after primary closure (18 %) and none after open procedure. Also in cases of pilonidal sinus with infection, primary wound closure can be carried out even though the rate of recurrences is higher than after open procedure. A successful primary closure significantly reduces time of illness and time out of work.


Genomic Breakpoint Characterization and Transcriptome Analysis of Metastatic, Recurrent Desmoplastic Small Round Cell Tumor.
Desmoplastic small round cell tumor (DSRCT) is a rare pediatric cancer caused by the EWSR1-WT1 fusion oncogene. Despite initial response to chemotherapy, DSRCT has a recurrence rate of over 80% leading to poor patient prognosis with a 5-year survival rate of only 15-25%. Owing to the rarity of DSRCT, sample scarcity is a barrier in understanding DSRCT biology and developing effective therapies. Utilizing a novel pair of primary and recurrent DSRCTs, we present the first map of DSRCT genomic breakpoints and the first comparison of gene expression alterations between primary and recurrent DSRCT. Our genomic breakpoint map includes the lone previously published DSRCT genomic breakpoint, the breakpoint from our novel primary/recurrent DSRCT pair, as well as the breakpoints of five available DSRCT cell lines and five additional DSRCTs. All mapped breakpoints were unique and most breakpoints included a 1-3 base pair microhomology suggesting microhomology-mediated end-joining as the mechanism of translocation fusion and providing novel insights into the etiology of DSRCT. Through RNA-sequencing analysis, we identified altered genes and pathways between primary and recurrent DSRCTs. Upregulated pathways in the recurrent tumor included several DNA repair and mRNA splicing-related pathways, while downregulated pathways included immune system function and focal adhesion. We further found higher expression of the EWSR1-WT1 upregulated gene set in the recurrent tumor as compared to the primary tumor and lower expression of the EWSR1-WT1 downregulated gene set, suggesting the EWSR1-WT1 fusion continues to play a prominent role in recurrent tumors. The identified pathways including upregulation of DNA repair and downregulation of immune system function may help explain DSRCT's high rate of recurrence and can be utilized to improve the understanding of DSRCT biology and identify novel therapies to both help prevent recurrence and treat recurrent tumors.


Self-reported Gesture Interpretation and Performance Deficits in Individuals at Clinical High Risk for Psychosis.
Deficits in performing and interpreting communicative nonverbal behaviors, such as gesture, have been linked to varied psychopathology and dysfunction. Some evidence suggests that individuals at risk for psychosis have deficits in gesture interpretation and performance; however, individuals with internalizing disorders (eg, depression) may have similar deficits. No previous studies have examined whether gesture deficits in performance and interpretation are specific to those at risk for psychosis. Additionally, the underlying mechanisms (eg, cognition) and consequences (eg, functioning) of these deficits are poorly understood. This study examined self-reported gesture interpretation (SRGI) and performance (SRGP) in those at clinical high risk for psychosis (CHR; N = 88), those with internalizing disorders (INT; N = 51), and healthy controls (HC; N = 53). Participants completed questionnaires, clinical interviews, and neurocognitive tasks. Results indicated that the CHR group was characterized by significantly lower SRGI scores than the HC or INT groups (d = 0.41); there were no differences among groups in SRGP. Within CHR participants, greater deficits in SRGP were associated with lower verbal learning and memory (r = -.33), but not general intelligence or processing speed. Furthermore, gesture deficits were associated with higher cross-sectional risk for conversion to a full psychotic disorder in the CHR group. Overall, these findings suggest that specific subdomains of gesture may reflect unique vulnerability for psychosis, self-report may be a viable assessment tool in understanding these phenomena, and gesture dysfunction may signal risk for transition to psychosis.


Emerging noninvasive treatments of nonmelanoma skin cancers.
Nonmelanoma skin cancer (NMSC) is the most common malignancy worldwide, and the incidence continues to increase. Originally, treatment options for NMSCs largely relied on destructive and surgical methods. Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) commonly are treated with cryosurgery, electrodesiccation and curettage, or more definitive surgical options. Over time, topical agents such as 5-fluorouracil, imiquimod, ingenol mebutate, and various forms of aminolevulinic acid (ALA) for photodynamic therapy (PDT) were included for superficial lesions as well as field treatment. The development of oral hedgehog (Hh) inhibitors such as vismodegib offered a promising alternative to patients with advanced disease. Each treatment has its own specific indications and side effects, thus there is always room for novel therapeutic approaches. We review new and potential treatments for NMSCs since 2018 including topical sonidegib, cemiplimab, taladegib, posaconazole, radiation therapy (RT), combination RT with vismodegib, PDT, and laser therapies.


Generation, characterisation, and applications of atomic and molecular alignment and orientation.
The gas phase is generally defined as a state of matter in which atoms or molecules are in constant, rapid, random Brownian motion. However, a range of techniques exist for preparing distributions of gas phase atoms and molecules whose motion is far from random, and whose orientation in space is well defined. In this Perspective, we will explore the nature of atomic and molecular alignment and orientation, the various techniques by which samples of spatially oriented species may be prepared and characterised, and some of the ways in which oriented molecules are being exploited to further our knowledge of molecular structure and dynamics.


Mortality after near-miss obstetric complications in Burkina Faso: medical, social and health-care factors.
To investigate mortality in women in Burkina Faso in the 4 years following a life-threatening near-miss obstetric complication and to identify the medical, social and health-care-related causes of death. In total, 1014 women were recruited after hospital discharge and followed for up to 4 years: 337 had near-miss complications and 677 had uncomplicated pregnancies. Significant differences in mortality between the groups were assessed using Fisher's exact test. The medical causes of death were identified from medical records and verbal autopsy data; social and health-care-related factors associated with death were identified from interviews with the deceased women's relatives. In the 4 years, 15 (5.3%) women died in the near-miss group and 5 (0.9%) died after uncomplicated pregnancies (P < 0.001). More than half the deaths after a near miss, but none after an uncomplicated delivery, were pregnancy-related. Indirect factors contributed to many of these deaths, particularly human immunodeficiency virus infection. Relatives' accounts suggested that the high cost and poor quality of health care, a lack of follow-up care and an unmet need for contraception contributed to the excess mortality in the near-miss group. Women in Burkina Faso who initially survived a near-miss obstetric complication had an increased risk of all-cause and pregnancy-related death in the ensuing 4 years. The likelihood of survival over the longer term could be increased by offering a continuum of care that addresses the indirect and social causes of death and supplements the emergency intrapartum obstetric care provided by current safe motherhood programmes.


Widespread Pain and Central Sensitization in Adolescents with Signs of Painful Temporomandibular Disorders.
To investigate the associations between signs of painful temporomandibular disorders (TMD) and number of tender points (TPs) and fibromyalgia in adolescents, as well as the relationship between TPs and pressure-pain threshold (PPT) in individuals presenting with local, regional, or widespread pain as a way to investigate the presence of central sensitization (CS). The sample consisted of 690 Brazilian adolescents with and without signs of painful TMD, aged 12 to 14 years old. Painful TMD was classified according to the Research Diagnostic Criteria for TMD (RDC/TMD) Axis I. The criteria established by Yunus were applied to assess juvenile fibromyalgia and TPs. Mann-Whitney and chi-square tests were applied to test the associations between signs of painful TMD and demographic variables. Regression models were used to estimate the association between signs of painful TMD and number of TPs and to determine which additional predictive variables were associated with TPs. Regression analyses were performed to test the associations between PPT values and number of TPs. Fisher test was used to estimate the association between signs of painful TMD and FM. Significant associations between signs of painful TMD and the number of TPs (P < .001), as well as between TPs and the PPT values for local, regional, and widespread pain (P < .001), were found. No association between signs of painful TMD and fibromyalgia was found (P = .158). Individuals with signs of painful TMD presented with more TPs compared to pain-free adolescents. Moreover, the higher the number of TPs, the lower the PPT. This finding suggests that adolescents with signs of painful TMD are at increased risk of presenting with CS.


[Circadian chronotherapy for Walker-256 of Wistar rat].
The tumor growth of Walker-256, 10(7) cells of which were implanted into Wistar rat's hindpaw s.c. were measured regularly at 7.00, A. M. and 7.00, P. M. The tumor growth ratios during day (TG-day) and night (TG-night) were 3.8 +/- 3.4%, 29.4 +/- 9.3%, (Tumor Vol < 250 mm3, p < 0.05), 9.6 +/- 4.4%, 30.4 +/- 8.1%, (250 mm3 < T. V. < 750 mm3, p < 0.05) respectively. After tumor vessels formed. TG-day and TG-night were 19.4 +/- 6.1%, 26.6 +/- 5.3%, (750 mm3 < T. V., p > 0.05) respectively. This data showed us circadian rhythms of the tumor growth of Walker-256 which didn't form tumor vessels. Walker-256 and body weight of Wistar rats given 5mg/kg/day of 5-FU p. o. at 7.00, A. M. (day therapy) or at 7.00 P. M. (night therapy) from the second day to the eighth day were 250.5 +/- 31.5 mm3 (n = 8), 62.8 +/- 55.8 mm3 (n = 8) (p < 0.05) (no treatment group: 1,616.0 +/- 321.0 mm3, n = 9) and 111.2 +/- 82.2 g, 156.3 +/- 3.1 g (p < 0.05) respectively. This method of therapy could be appreciated as the chronotherapy.


One-stage extreme lateral interbody fusion and percutaneous pedicle screw fixation in lumbar spine tuberculosis.
We explored the efficacy of minimal invasive surgery including one-stage debridement and intervertebral fusion through extreme lateral channel (XLIF) combined with lateral or percutaneous posterior pedicle screw fixation for the treatment of lumbar spine tuberculosis. Twenty two patients with lumbar tuberculosis who underwent surgery with XLIF technique and internal fixation were included in the study. Their data about operative time, intraoperative blood loss, bone fusion, kyphosis correction, and clinical recovery were retrospectively collected and analyzed. The mean intraoperative blood loss was 249.8±27.8 ml and the operative time 347.5±20.7 min. At the final follow-up, 11 to 15 months postoperatively, ESR and CRP were normal and pain (VAS) and Oswestry disability index (ODI) were significantly reduced (23.0±-3.1 vs 0.6±-0.7 and 57.2±-1.6 vs 6.4±-1.2 respectively) compared to preoperative values. Progression of the kyphotic deformity was effectively prevented (mean Cobb angle 23.9° +/-1.9° vs 24.5° +/-1.4°, P>0.05). There was one failure of the fixation associated to poor therapy adherence. All the patients showed neurological recovery. Debridement and interbody fusion by extreme lateral channel combined with lateral or percutaneous posterior pedicle screw fixation effectively retained the spine stability and provided clinical and neurologic recovery in selected patients with lumbar spine tuberculosis.


Nano-Cracked Strain Sensor with High Sensitivity and Linearity by Controlling the Crack Arrangement.
Studies on wearable sensors that monitor various movements by attaching them to a body have received considerable attention. Crack-based strain sensors are more sensitive than other sensors. Owing to their high sensitivity, these sensors have been investigated for measuring minute deformations occurring on the skin, such as pulse. However, existing studies have limited sensitivity at low strain range and nonlinearity that renders any calibration process complex and difficult. In this study, we propose a pre-strain and sensor-extending process to improve the sensitivity and linearity of the sensor. By using these pre-strain and sensor-extending processes, we were able to control the morphology and alignment of cracks and regulate the sensitivity and linearity of the sensor. Even if the sensor was fabricated in the same manner, the sensor that involved the pre-strain and extending processes had a sensitivity 100 times greater than normal sensors. Thus, our crack-based strain sensor had high sensitivity (gauge factor > 5000, gauge factor (GF = (△R/R0)/ε), linearity, and low hysteresis at low strain (<1% strain). Given its high sensing performance, the sensor can be used to measure micro-deformation, such as pulse wave and voice.


Patient-derived tumor models are attractive tools to repurpose drugs for ovarian cancer treatment: pre-clinical updates.
Despite advances in understanding of ovarian cancer biology, the progress in translation of research findings into new therapies is still slow. It is associated in part with limitations of commonly used cancer models such as cell lines and genetically engineered mouse models that lack proper representation of diversity and complexity of actual human tumors. In addition, the development of de novo anticancer drugs is a lengthy and expensive process. A promising alternative to new drug development is repurposing existing FDA-approved drugs without primary oncological purpose. These approved agents have known pharmacokinetics, pharmacodynamics, and toxicology and could be approved as anticancer drugs quicker and at lower cost. To successfully translate repurposed drugs to clinical application, an intermediate step of pre-clinical animal studies is required. To address challenges associated with reliability of tumor models for pre-clinical studies, there has been an increase in development of patient-derived xenografts (PDXs), which retain key characteristics of the original patient's tumor, including histologic, biologic, and genetic features. The expansion and utilization of clinically and molecularly annotated PDX models derived from different ovarian cancer subtypes could substantially aid development of new therapies or rapid approval of repurposed drugs to improve treatment options for ovarian cancer patients.


Ouabain Induces DNA Damage in Human Osteosarcoma U-2 OS Cells and Alters the Expression of DNA Damage and DNA Repair-associated Proteins.
Ouabain, isolated from natural plants, exhibits anticancer activities; however, no report has presented its mechanism of DNA damage induction in human osteosarcoma cancer cells in vitro. The aim of this study was to investigate whether ouabain induces DNA damage and repair, accompanied with molecular pathways in human osteosarcoma cancer U-2 OS cells in vitro. The percentage of viable cell number was measured by flow cytometric assay; DNA damage was assayed by DAPI staining, comet assay, and agarose gel electrophoresis. DNA damage and repair associated protein expressions were assayed by western blotting assays. Ouabain reduced total cell viability, induced chromatin condensation, DNA fragmentation, and DNA damage in U-2 OS cells. Ouabain increased p-ATMSer1981, p-ATRSer428, and p53 at 2.5-10 μM, increased p-p53Ser15 at 10 μM; however, it decreased p-MDM2Ser166 at 2.5-10 μM. Ouabain increased p-H2A.XSer139, MDC-1, and PARP at 2.5-10 μM and BRCA1 at 5-10 μM; however, it decreased DNA-PK and MGMT at 2.5-10 μM in U-2 OS cells at 48 h treatment. Ouabain promoted expression and nuclear translocation of p-H2A.XSer139 in U-2 OS cells and this was confirmed by confocal laser microscopy. Ouabain reduced total viable cell number through triggering DNA damage and altering the protein expression of DNA damage and repair system in U-2 OS cells in vitro.


Development of an asthma management system in a pediatric emergency department.
Asthma is the leading chronic childhood disease with exacerbations resulting in urgent and emergency care visits. Guidelines adherence improves patient care but is suboptimal. A computerized guideline system can help improve compliance through automatic initiation and reminders to increase adherence. We designed a computerized management system for asthma care in the pediatric emergency department (ED). The system will be evaluated in two phases. The first phase evaluates a computerized diagnostic prompt using the ED's existing asthma protocol. The second phase evaluates a computerized asthma management system including temporal reminder elements for scoring and medication orders. The system was developed in conjunction with the pediatric ED multidisciplinary care team. The computerized system is entirely automatic and a prospective evaluation of the diagnostic component is ongoing.


Tel-Aviv-Heidelberg Three Generation Offspring Study: Genetic and environmental sources of variation and covariation among plasma lipids, lipoproteins, and apoliproteins.
Multivariate genetic analysis, implemented in the statistical package for pedigree analysis, FISHER, was carried out on a large sample of Israeli pedigrees to evaluate heritability and genetic correlations among an array of plasma lipids: total cholesterol (TCHL), triglycerides (TRIG), HDL-C and HDL2-C, HDL3-C, LDL-C and HDL-C%, apolipoproteins A and B (APO-A1 and APO-B), lipoprotein LP(a) and fibrinogen (FIBR). Multiple regression analysis showed that although sex, age, smoking and other study environmental factors, have a significant contribution to the variation of each plasma lipid, they exert little effect on covariation in lipids. Genes, however, are important factors of the variation and covariation in lipids. Thus, variance component analysis showed that the genetic component of the study variables, adjusted on age, sex and environmental factors, ranged between 31% for logarithm-transformed TRIG and 77% for plasma concentrations of LP(a). Coefficients of multiple genetic determination of the genetic variation of each variable attributable to all of the other variables, ranged from low values (<30%) for TRIG, LP(a) and FIBR, to moderate (64%) for HDL2-C. The genetic variation of each of the remaining variables was completely explained by variation in other lipids. The results of a factor analyses of phenotypic, genetic and environmental correlation matrices were similar and clearly identified several clusters of variables. The first included APO-A1, HDL-C, HDL2-C and HDL3-C, and the second-APO-B, LDL-C and THCL. Further analysis showed that it was probable the genetic component of variation of HDL3-C plasma concentration that fully depended on APO-A1, while those of LDL-C and TCHL fully depended on APO-B. The degree of correlation between TRIG, LP(a), FIBR and other variables, if any, was considerably lower. Am. J. Hum. Biol. 9:357-370, 1997. © 1997 Wiley-Liss, Inc.


Effect of application site of low-level laser therapy in random cutaneous flap viability in rats.
This study aimed to investigate the effect of diode laser (830 nm) irradiation on the viability of ischemic random skin flaps in rats, as well as to determine the most effective site for applying laser radiation to speed healing. Low-level laser therapy (LLLT) has recently been used to improve the viability of ischemic random skin flaps in rats. Seventy Wistar rats were used and divided into seven groups of 10 rats each: group 1, sham laser treatment; group 2, which received irradiation at 1 point 5 cm from the flap's cranial base; group 3, which received irradiation at 2 points (5 and 7.5 cm from the flap's base); group 4, which received irradiation at 3 points (2.5, 5 and 7.5 cm from the flap's base); group 5, which received irradiation at 1 point 2.5 cm from the flap's base; group 6, which received irradiation at 2 points (2.5 and 5 cm from the flap's base); and group 7, which received irradiation at 1 point 7.5 cm from the flap's base. The animals were subjected to laser therapy at an energy density of 36 J/cm(2) for 72 sec immediately after surgery, and one time on each of the four subsequent days. The percentage of necrotic skin flap area was calculated on the seventh postoperative day using a paper template. The results showed that the rats in group 5 had the highest increase in skin flap viability, with a statistically significant difference compared to the other groups. Statistically significant differences were not seen between any of the other groups. The diode laser was effective in increasing skin flap viability in rats, and laser irradiation of a point 2.5 cm from the cranial base flap was found to be the most effective.


6R-tetrahydrobiopterin perfusion enhances dopamine, serotonin, and glutamate outputs in dialysate from rat striatum and frontal cortex.
The effect of 6R-tetrahydrobiopterin (R-THBP) on neurotransmitter release was investigated using in vivo brain microdialysis in urethane-anesthetized rats. Perfusion of 1.0 mM R-THBP enhanced the level of dopamine output in dialysates collected from the striatum and frontal cortex. R-THBP perfusion also increased serotonin (striatum) and glutamate outputs (striatum and frontal cortex). Dopaminergic terminals in the striatum were destroyed unilaterally by continuous infusion of 6-hydroxydopamine (6-OHDA) using an osmotic minipump system. The effect of R-THBP administration on glutamate level was found to be almost completely suppressed in the 6-OHDA-lesioned side of striatum, while in the intact side of striatum the glutamate level in the dialysates responded normally to R-THBP perfusion. These results suggest that R-THBP may play a role in the mechanisms of release of dopamine, serotonin, and glutamate. The functioning of the catecholaminergic system probably mediates the increase in glutamate output due to R-THBP perfusion.


Benefits of epoetin alfa in anemic breast cancer patients receiving chemotherapy.
Breast cancer patients receiving chemotherapy often exhibit anemia, which contributes to symptoms such as fatigue, compromising quality of life (QOL). The present subset analysis assessed the effects of recombinant human erythropoietin (rHuEPO, epoetin alfa) on anemia and QOL in approximately 1300 patients with breast cancer, who were derived from 3 large, community-based clinical trials of epoetin alfa in anemic chemotherapy patients with various malignancies. Epoetin alfa effectively and safely corrected anemia and improved QOL scores on the Linear Analogue Self-Assessment, which measures energy, ability to perform daily activities, and QOL. Clinical, laboratory, and QOL improvements were qualitatively and quantitatively similar to those reported in the larger populations with various tumor types. The efficacy and safety of epoetin alfa did not vary according to dosing frequency (1 vs. 3 times weekly). Epoetin alfa is, therefore, effective and safe in the management of anemia in patients with breast cancer treated with chemotherapy.


Current Situation of Medication Adherence in Hypertension.
Despite increased awareness, poor adherence to treatments for chronic diseases remains a global problem. Adherence issues are common in patients taking antihypertensive therapy and associated with increased risks of coronary and cerebrovascular events. Whilst there has been a gradual trend toward improved control of hypertension, the number of patients with blood pressure values above goal has remained constant. This has both personal and economic consequences. Medication adherence is a multifaceted issue and consists of three components: initiation, implementation, and persistence. A combination of methods is recommended to measure adherence, with electronic monitoring and drug measurement being the most accurate. Pill burden, resulting from free combinations of blood pressure lowering treatments, makes the daily routine of medication taking complex, which can be a barrier to optimal adherence. Single-pill fixed-dose combinations simplify the habit of medication taking and improve medication adherence. Re-packing of medication is also being utilized as a method of improving adherence. This paper presents the outcomes of discussions by a European group of experts on the current situation of medication adherence in hypertension.


[Two cases of acute renal failure associated with non-fulminant acute hepatitis A].
Hepatitis A is generally regarded as a mild, self-limiting disease of the liver. Acute renal failure has rarely been reported in association with non-fulminant acute hepatitis A. Acute tubular necrosis is the most common form of renal injury in such patients. We recently experienced two cases of hepatitis A in which acute renal failure occurred early in the course of the illness and had a clinical course suggestive of acute tubular necrosis. In both patients, the clinical course of renal dysfunction was almost parallel to that of hepatic dysfunction. Hemodialysis was performed in patient 1 because of severe uremia despite maintaining urine output more than 2,000 mL per day. On the other hand, hemodialysis was not performed in patient 2 who showed a rapid recovery of renal dysfunction. The renal biopsy of patient 1 demonstrated typical findings of acute tubular necrosis on microscopy.


The efficacy of intravesical bacillus Calmette-Guerin in the treatment of interstitial cystitis: long-term followup.
Interstitial cystitis is a severe debilitating bladder disease characterized by unrelenting pelvic pain and urinary frequency. A prospective, double-blind, placebo controlled study of the use of intravesical bacillus Calmette-Guerin (BCG) in the treatment of interstitial cystitis was recently completed with a mean followup of 8 months. Results demonstrated a 60% BCG response rate, compared to a 27% placebo response rate. We now report the long-term followup results of those patients who received intravesical BCG. Subjects randomized to receive BCG were followed at routine intervals with questionnaires and voiding diaries identical to those in the blinded study. Adverse events were closely monitored in the treatment and followup phases of the study. Subject baseline values were compared to followup data. Of the BCG responders mean followup was 27 months (range 24 to 33), and 8 of 9 (89%) continue to have an excellent response in all parameters measured. The global interstitial cystitis survey improved 70%, daily voids decreased 31%, nocturia improved 54%, mean voided volume increased 61%, pelvic pain decreased 81%, vaginal pain decreased 71%, urgency decreased 71% and dysuria decreased 82%. Overall well-being improved 54% and the Rand-36 quality of life survey overall improved 64%. In 86% of the patients (6 of 7) dyspareunia resolved. Of the initial BCG nonresponders there was no significant difference in interstitial cystitis symptomatology from baseline to last followup, suggesting that BCG does not worsen interstitial cystitis symptoms. No long-term adverse events from BCG were noted. Intravesical Tice BCG is safe, effective and durable in the treatment of interstitial cystitis. Of those patients who received only 6 weekly treatments and responded favorably 89% continue to have an excellent response with followup ranging from 24 to 33 months.


[Rapid Recanalization of Cerebral Venous Sinus Thrombosis Secondary to Severe Dehydration:A Case Report].
A 41-year-old healthy man presented with sudden disturbance of consciousness and convulsion during a marathon. Computed tomography revealed a lateral sinus sign in the posterior fossa, and magnetic resonance(MR)venography revealed a flow gap in the posterior part of the superior sagittal sinus and bilateral transverse sinus, although the other MR image sequences were normal. Laboratory data revealed dehydration, acute kidney failure, and rhabdomyolysis. Owing to immediate correction of dehydration, clinical symptoms and radiological abnormality improved rapidly. Cerebral venous sinus thrombosis(CVST)is a rare condition, accounting for <1% of all stroke cases. In all cases, CVST cannot cause cerebral infarction or hemorrhagic change but in any case, may present a transient ischemic attack-like event because of rapid spontaneous recanalization. Therefore, CVST may occur more frequently than expected.


Effects of dietary Lactobacillus rhamnosus JCM1136 and Lactococcus lactis subsp. lactis JCM5805 on the growth, intestinal microbiota, morphology, immune response and disease resistance of juvenile Nile tilapia, Oreochromis niloticus.
The present study aimed to evaluate the individual and combined effects of Lactobacillus rhamnosus (LR) JCM1136 and Lactococcus lactis subsp. lactis (LL) JCM5805 on the growth, intestinal microbiota, intestinal morphology, immune response and disease resistance of juvenile Nile tilapia (Oreochromis niloticus). A total of 720 apparently healthy juvenile Nile tilapia (0.20 ± 0.05 g) were randomly divided into four equal groups. Fish were fed with a basal diet (CK) supplemented with JCM1136 (LR), JCM5805 (LL), and JCM1136 + JCM5805 (LR+LL) at 1 × 108 CFU/g basal diet for 6 weeks, followed by a basal diet for 1 week. After 6 weeks of feeding, the LL treatment significantly increased the growth and feed utilization of Nile tilapia when compared with the CK. Light microscopy and transmission electron microscopy images of the midgut revealed that probiotic supplementation significantly increased gut microvilli length and microvilli density compared to CK. The transcript levels of several key immune-related genes in the mid-intestine and liver of fish were analyzed by means of quantitative polymerase chain reaction (qPCR) at the end of the sixth week. The results showed the following: when compared to CK group, fish in LR had significantly increased transcript levels of IFN-γ, lyzc, hsp70 and IL-1β in the intestine; LL fish showed significantly increased expressions of TNF-α, IFN-γ, lyzc, hsp70 and IL-1β in the intestine and liver; and intestine lyzc, hsp70 and IL-1β and liver TNF-α, IFN-γ, hsp70 and IL-1β were significantly increased in LR+LL fish. Following a 6-week period of being fed probiotics or a control diet, the tilapia were challenged with an intraperitoneal injection of 20 μl of the pathogenic Streptococcus agalactiae (WC1535) (1 × 105 CFU/ml). The survival rates of the probiotic-fed groups were significantly higher than that of the CK group, and the LL group had the highest survival rate. High-throughput sequencing revealed a significantly higher presence of JCM5805 in the guts of LL fish during the period of probiotic application, but this was no longer detected in all LL samples 1 week post cessation of probiotic administration. Cessation of probiotic administration led to disorders of individual gut microbes within the LR and LL groups. Statistical analysis (LEfSe) demonstrated that three phyla, namely, Bacteroidetes, Fusobacteria and Actinobacteria were enriched in the CK group, while the abundance of Proteobacteria was greater in the probiotic-fed fish. At the genus level, Plesiomonas, which includes potential pathogens of fish, were significantly decreased in the probiotic-fed groups. In contrast, a significant increase of Rhizobium and Achromobacter, which can produce a variety of enzymes with cellulolytic and pectolytic activity, were observed in fish fed with probiotics, indicating that dietary probiotics were helpful in the propagation of some probiotic bacteria. Our data revealed that JCM1136 and JCM5805, as a feed additive at 108 CFU/g feed, could improve intestinal morphology, enhance immune status and disease resistance, and affect the gut microbiota of tilapia; thus, these additives could be used as probiotics for juvenile Nile tilapia. JCM5805 was more effective than JCM1136 or the mixture of the two for promoting the growth, enhancing the immune status and disease resistance of tilapia.


Neophobia is negatively related to reversal learning ability in females of a generalist bird of prey, the Chimango Caracara, Milvago chimango.
In an ever-changing environment, the ability to adapt choices to new conditions is essential for daily living and ultimately, for survival. Behavioural flexibility allows animals to maximise survival and reproduction in novel settings by adjusting their behaviour based on specific information and feedback acquired in their current environments. However, a growing body of evidence indicates that an individual's personality type can limit the extent to which the individual might behave flexibly, by influencing the way an individual pays attention to novelty and how much information it collects and stores, which in turn affects the individual's decision-making and learning process. In this study, the behavioural flexibility of a generalist predator, the Chimango Caracara, Milvago chimango, was analysed using the reversal learning paradigm, focusing on the comparison between age classes, and the relation of learning flexibility with a personality trait, the level of neophobia. Due to the low number of male individuals captured, this study was carried out only with female birds. The results showed that age had no significant effect either on the acquisition of a stimulus-reward association, or on the capacity of reversing this previously learned association. Reversal of the response was a harder task for these birds in comparison with the initial acquisition process. The individual's performances in the learning tasks seemed to be uncorrelated with each other, suggesting that they involve different neural mechanisms. Contrary to the general pattern observed in the majority of previous work on personality and cognition in non-human animals, the level of neophobia did not correlate with the initial associative learning performance in both adults and juveniles, yet it showed a significant negative relationship with reversal learning ability, mainly in the regressive phase of this task, for the two age classes. Our results suggest that the predatory and generalist lifestyle of female individuals of M. chimango along with the selective pressures of the environment of the individuals studied might play a critical role in the degree and direction of the linkage between novelty response and learning flexibility observed in this study.


Preparation of stable isotope-labeled 2-nitrobenzaldehyde derivatives of four metabolites of nitrofuran antibiotics and their comprehensive characterization by UV, MS, and NMR techniques.
A convenient method is presented for the preparation of the carbon-13-labeled 2-nitrobenzaldehyde derivatives of the nitrofuran metabolites 3-amino-2-oxazolidinone (AOZ), semicarbazide (SC), 1-aminohydantoin (AH), and 3-amino-5-morpholinomethyl-2-oxazolidinone (AMOZ), with the purpose of using them as internal standards for the quantification of trace levels of nitrofuran residues by liquid chromatography-tandem mass spectrometry in foods of animal origin. The synthesis encompasses the nitration of [1,2,3,4,5,6-(13)C(6)]toluene prior to chromyl compound-mediated oxidation of the methyl group into the corresponding aldehyde. The four metabolites of nitrofuran antibiotics were derivatized independently with the resulting ring-labeled 2-nitrobenzaldehyde (NBA) to obtain the target compounds. Both the isotopically enriched and native substances were used to perform a comprehensive fragmentation study by electrospray ionization (ESI) collision-induced dissociation (CID) mass spectrometry (MS). Full characterization of the nitrofuran derivatives was accomplished with ultraviolet (UV) and exhaustive nuclear magnetic resonance (NMR) analysis. A major advantage of the described procedure is that it can be extended to the preparation of other carbon-13-labeled derivatives of metabolites of nitrofuran antibiotics.


Dissecting the mechanism of Epac activation via hydrogen-deuterium exchange FT-IR and structural modeling.
Exchange proteins directly activated by cAMP (Epac) make up a family of cAMP binding domain-containing proteins that play important roles in mediating the effects of cAMP through the activation of downstream small GTPases, Ras-proximate proteins. To delineate the mechanism of Epac activation, we probed the conformation and structural dynamics of Epac using amide hydrogen-deuterium (H-D) exchange coupled with Fourier transform infrared spectroscopy (FT-IR) and structural modeling. Our studies show that unlike that of cAMP-dependent protein kinase (PKA), the classic intracellular cAMP receptor, binding of cAMP to Epac does not induce significant changes in overall secondary structure and structural dynamics, as measured by FT-IR and the rate of H-D exchange, respectively. These results suggest that Epac activation does not involve significant changes in the amount of exposed surface areas as in the case of PKA activation, and conformational changes induced by cAMP in Epac are most likely confined to small local regions. Homology modeling and comparative structural analyses of the CBDs of Epac and PKA lead us to propose a model of Epac activation. On the basis of our model, Epac activation by cAMP employs the same underlying structural principal utilized by PKA, although the detailed structural and conformational changes associated with Epac and PKA activation are significantly different. In addition, we predict that during Epac activation the first beta-strand of the switchboard switches its conformation to a alpha-helix, which folds back to the beta-barrel core of the CBD and interacts directly with cAMP to form the base of the cAMP-binding pocket.