Interactions of flerobuterol, an antidepressant drug candidate, with beta adrenoceptors in the rat brain.
Interactions of dl-flerobuterol with central beta adrenoceptors were investigated. It inhibited the binding of [3H]CGP 12177, a selective beta adrenoceptor ligand, to membranes prepared from rat cerebral cortex, cerebellum, heart and lung. The affinity of dl-flerobuterol was very close in all tissues (Ki approximately 1 microM). In cerebral cortex, binding inhibition of [3H]CGP 12177 was stereospecific, l-flerobuterol (Ki = 483 nM) being 70-fold more potent than d-flerobuterol (Ki = 34 microM). Moreover, dl-flerobuterol (Ki = 926 nM) was 7-fold less potent than isoproterenol (Ki = 140 nM) to displace [3H]CGP 12177 binding, but 5-fold more potent than salbutamol (Ki = 4600 nM). Flerobuterol did not inhibit the radioligand binding to the other receptors at the highest concentration tested, thus leading to a very high beta adrenergic selectivity. Flerobuterol increased the concentration of cyclic AMP in slices of rat cerebral cortex in a dose-dependent manner; this effect was antagonized by atenolol and propranolol. Compared to isoproterenol or norepinephrine, which produced cyclic AMP maximal increases of 380 and 460%, respectively, it showed a weaker activity with a maximal stimulation obtained at 100 microM, corresponding to a cAMP increase of 140% over basal value (100%). These data revealed that flerobuterol possessed a beta adrenergic agonist activity. Moreover, it antagonized competitively the isoproterenol- or norepinephrine-stimulated accumulation of cAMP. At low concentrations of isoproterenol or norepinephrine, the stimulation of adenylate cyclase was only due to the action of flerobuterol, but at higher concentrations, the response of isoproterenol or norepinephrine was competitively blocked by flerobuterol. At 10 microM, isoproterenol surmounted fully this antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of intraspecimen spatial variation in tissue mineral density on the apparent stiffness of trabecular bone.
This study investigated the effects of intraspecimen variations in tissue mineral density(TMD) on the apparent-level stiffness of human trabecular bone. High-resolution finite element (FE) models were created for each of 12 human trabecular bone specimens,using both microcomputed tomography (lCT) and "gold-standard" synchrotron radiation lCT (SRlCT) data. Our results confirm that incorporating TMD spatial variation reduces the calculated apparent stiffness compared to homogeneous TMD models. This effect exists for both lCT- and SRlCT-based FE models, but is exaggerated in lCT based models. This study provides a direct comparison of lCT to SRlCT data and is thereby able to conclude that the influence of including TMD heterogeneity is overestimated in lCT-based models.


Sentinel Node Biopsy in Early Breast Cancer Patients with Palpable Axillary Node.
Sentinel lymph node biopsy is a reliable method for evaluation of the axillary lymph node status in early stage breast cancer patients with non-palpable lymph nodes. The present study evaluated the status of sentinel and non-sentinel lymph nodes in T1T2 patients with palpable axillary lymph nodes. One hundred and two women with early breast cancer were investigated in this study. Patients were selected for axillary sentinel lymph node biopsy and then surgery .Then the rates of false negative and true positive, and diagnostic accuracy of sentinel lymph nodes biopsy were evaluated. In addition, the hormone receptors status of the tumor was determined through IHC and data was analyzed in SPSS21. In this study, the mean age of the patients was 49 years, 85% had invasive ductal carcinoma in their pathology reports, 77% were ER/PR positive, 30% HER2 positive and 9.8% triple negative and 69% had KI67<14%. In frozen pathology, 15.7 and 84.3% were sentinel positive and negative, respectively, and in the final pathology, 41 and 58.8% were sentinel positive and negative, respectively. This difference arises from the false negative rate of the frozen pathology, which was about 31.3%. The sensitivity, specificity, and diagnostic accuracy of the frozen section were 24, 90 and 43%, respectively. Lymphovascular invasion is an important effective factor in the involvement of sentinel and non-sentinel lymph nodes. Statistical analysis showed that the probability of sentinel and non-sentinel lymph nodes involvement was higher in receptor positive patients and those with KI67>14% (p<0.002) whereas the rate of involvement was lower in triple negative patients. Sentinel node biopsy can be used in a significant percentage of breast cancer patients with palpable and reactive axillary lymph nodes.


Autoimmunity after liver transplantation: a frequent event but a rare clinical problem.
Autoantibodies are frequently detected after liver transplantation (LT), but their role is unclear. This study was designed to address three points: autoantibody prevalence pre-LT and over time up to five yr after LT, identification of possible predictors of autoantibody formation, and correlation between autoantibodies and graft dysfunction. To these aims, we retrospectively evaluated 92 consecutive LT recipients for whom prospectively stored frozen sera were available for autoantibodies assessment by immunofluorescence. The overall autoantibody prevalence resulted significantly higher after LT than before LT (64% vs. 27%, p < 0.001 and 35.9% vs. 8.7%, p < 0.001 considering cutoff titer of ≥ 1:80 and ≥ 1:160, respectively). Recipient gender, donor age and gender, and indication for LT and main immunosuppressant (cyclosporine vs. tacrolimus) were not associated with the presence of autoantibodies. Patients with graft dysfunction had a significantly higher autoantibody prevalence irrespective of the etiology of liver injury as compared to those patients with persistently normal liver biochemistry, but only for cutoff titers ≥ 1:160 (p = 0.004). No cases of de novo autoimmune hepatitis were observed. In conclusion, autoantibodies are very frequently detected after LT also at high titers and their association with graft dysfunction likely represents an aspecific indicator of liver injury.


[Genetic markers in thyroid autoimmune diseases].
Autoimmune disorders of the thyroid such as Graves' disease and Hashimoto's thyroiditis are the most common autoimmune diseases in the Western world. The frequent occurrence of both diseases in members of the same family indicates the influence of common genetic factors generally predisposing to thyroid autoimmunity. Common susceptibility loci have been mapped to the HLA region on chromosome 6p21 (HLA DR, HLA DQ), to chromosome 2q33 (CTLA4) and possibly to chromosome 8q24 (thyroglobulin). Additional susceptibility is conferred by genomic variants of the vitamin D system (vitamin D receptor and CYP1 alpha hydroxylase). Since these polymorphisms prevail also in healthy relatives they are necessary but not sufficient cofactors. The higher prevalence of thyroid autoimmune disease in women cannot be explained by susceptibility genes. The observation of microchimerisms in thyroid tissue might explain that an immunisation by fetal-maternal interaction can lead to thyroid autoimmunity in HLA risk combinations.


Effects of Tauroursodeoxycholic Acid and Alpha-Lipoic-Acid on the Visual Response Properties of Cat Retinal Ganglion Cells: An In Vitro Study.
To investigate the effects of tauroursodeoxycholic acid (TUDCA) and alpha-lipoic-acid (ALA) on the visual response properties of cat retinal ganglion cells (RGCs) in wholemount retinas. Young adult cats were divided into three groups: control, ALA, and TUDCA. In vitro single-unit extracellular recordings were performed on wholemount retinas to objectively evaluate the visual response properties of RGCs prior and post to antioxidant treatment. The visual responses properties of RGCs, including receptive field size, luminance threshold, and contrast sensitivity, were collected online and analyzed off-line with Axon Pclamp9. Most of the RF sizes were larger than those plotted prior to the 60 minutes dark adaptation. The luminance threshold was elevated in the control group (no treatment) but reduced post ALA treatment and significantly reduced post TUDCA treatment. The contrast threshold was significantly elevated in the control group (no treatment) and clearly elevated post ALA treatment but effectively sustained post TUCDA treatment. Retinal neurocircuitry deteriorates in wholemount retinas, resulting in abnormal visual response properties in RGCs. Alpha-lipoic-acid and TUDCA exerted beneficial neuroprotective effects by activating the antioxidant pathway, partially restoring the functionality of retinal neurocircuitry and significantly improving the visual response properties of RGCs. However, TUDCA appears to be more effective than ALA in reducing irradiance thresholds and improving contrast sensitivity.


The Impact of Sacral Neuromodulation on Sexual Dysfunction.
Sacral neuromodulation (SNM) is a well-established treatment in several urinary and bowel dysfunctions, nevertheless its role on sexual dysfunction remains unclear. We evaluate the impact of SNM on sexual function and its association with age at SNM, functional diagnosis and post-void residual urine (PVR) before SNM. Patients who had SNM were retrospectively analyzed. Sexual function was assessed before and after treatment with the International Index of Erectile Function (IIEF-5) for men and the Female Sexual Function Index (FSFI) for women. IIEF-5 and FSFI were also associated with age at SNM, functional diagnosis, and PVR. Fifteen females and 9 males, with a median age of 41 years (26-72 years), median follow-up 20.7 months (2-53 months) were enrolled. IIEF-5 improved in 4 patients (p = 0.06), and FSFI total score in 5 (p = 0.2). There was significant association between functional diagnosis and FSFI total score (p = 0.05), and FSFI specific domains of arousal (p = 0.03), lubrication (p = 0.04), and satisfaction (p = 0.03), with significant improvement showed in patients with detrusor overactivity with impaired contractility. Although gains observed in IIEF-5 and FSFI were modest, our preliminary results show that SNM may have favorable impact on sexual function.


Unraveling haplotype errors in the DFNA33 locus.
Genetic heterogeneity makes it difficult to identify the causal genes for hearing loss. Studies from previous decades have mapped numerous genetic loci, providing critical supporting evidence for gene discovery studies. Despite widespread sequencing accessibility, many historically mapped loci remain without a causal gene. The DFNA33 locus was mapped in 2009 and coincidentally contains ATP11A, a gene recently associated with autosomal dominant hearing loss and auditory neuropathy type 2. In a rare opportunity, we genome-sequenced a member of the original family to determine whether the DFNA33 locus may also be assigned to ATP11A. We identified a deep intronic variant in ATP11A that showed evidence of functionally normal splicing. Furthermore, we re-assessed haplotypes from the originally published DFNA33 family and identified two double recombination events and one triple recombination event in the pedigree, a highly unlikely occurrence, especially at this scale. This brief research report also serves as a call to the community to revisit families who have previously been involved in gene mapping studies, provide closure, and resolve these historical loci.


Modulation of naive CD4 T cell activation with altered peptide ligands: the nature of the peptide and presentation in the context of costimulation are critical for a sustained response.
Altered peptide ligands containing single amino acid substitutions have the potential to be used for modulating immune function. Using a panel of moth cytochrome c peptides, we demonstrate that different phases of naive CD4 T cell response are alternately modulated depending on altered peptide ligand dose and accessory molecule expression by APC. Weak agonists presented at high concentration, and with costimulation, efficiently induced early phase naive T cell activation as assessed by IL-2R/CD69 expression, but could only promote sufficient IL-2 for a short-lived proliferative response. In contrast, strong agonists and heteroclitic peptides induced early phase T cell activation even at low concentrations with costimulation, and allowed sustained IL-2 secretion and proliferation. In the absence of accessory molecule help, early and late phase activation was impaired with weak agonists, whereas strong agonists partially compensated for a lack of costimulation for early phase activation, and also promoted enhanced IL-2 with sustained proliferation. These studies support the hypothesis that the naive T cell response will be determined by the balance between provision of accessory molecule help and the affinity of peptide/MHC complexes for individual TCRs, and suggest that extended IL-2 production is the main facet of naive CD4 activation that is affected by altering the nature of the peptide.


Intraocular pressure, cup-disc ratio, and steroid responsiveness in retinal detachment.
A review of the literature failed to indicate whether the high incidence of open angle glaucoma in patients with nontraumatic rhegmatogenous retinal detachment is due to common genetic determinants. The diurnal variation of intraocular pressure, the cup-disc C/D ratio, and the intraocular response to topically applied corticosteroids were studied in 30 subjects with unilateral, nontraumatic, rhegmatogenous retinal detachment. The results indicate that 20% of the subjects were high steroid responders and that 53% had a C/D ratio greater than 0.3. We shall discuss the relationship of these findings to the multifactorial inheritance of open angle glaucoma.


Patterns of motor activity in the isolated nerve cord of the octopus arm.
The extremely flexible octopus arm provides a unique opportunity for studying movement control in a highly redundant motor system. We describe a novel preparation that allows analysis of the peripheral nervous system of the octopus arm and its interaction with the muscular and mechanosensory elements of the arm's intrinsic muscular system. First we examined the synaptic responses in muscle fibers to identify the motor pathways from the axial nerve cord of the arm to the surrounding musculature. We show that the motor axons project to the muscles via nerve roots originating laterally from the arm nerve cord. The motor field of each nerve is limited to the region where the nerve enters the arm musculature. The same roots also carry afferent mechanosensory information from the intrinsic muscle to the axial nerve cord. Next, we characterized the pattern of activity generated in the dorsal roots by electrically stimulating the axial nerve cord. The evoked activity, although far reaching and long lasting, cannot alone account for the arm extension movements generated by similar electrical stimulation. The mismatch between patterns of activity in the isolated cord and in an intact arm may stem from the involvement of mechanosensory feedback in natural arm extension.


Motivational strategies for returning patients with low back pain to usual activities: A survey of physiotherapists working in Australia.
Timely resumption of usual activities is integral to successful functional outcomes in individuals with low back pain (LBP). Little is known about how physiotherapists motivate their patients achieve this. This study examined physiotherapists' knowledge, reported usage and training in a set of 12 motivational strategies. The results of an online cross sectional survey of 170 Australian physiotherapists were compared descriptively, and potential associations between therapist training and strategy use, confidence and perceived effectiveness analysed. Participants considered it extremely important to motivate individuals with LBP to return to usual activities and most commonly reported managing this aspect of treatment exclusively. Active goal setting was the most recognised motivational strategy and transtheoretical based counselling the least recognised. Provision of verbal information and praise/encouragement were reported as the most frequently used strategies. The most common reasons for not using a familiar motivational strategy were time constraints and lack of training. Training in active goal setting was associated with greater use, confidence and perceived effectiveness and was most commonly perceived as moderately effective. Cognitive behavioural therapy was well recognised and training associated with greater use and confidence but not perceived effectiveness. Motivational interviewing was known to approximately half of respondents, consistent with its infancy in LBP and training was not associated with use, confidence or perceived effectiveness. Further research into clearly defined, time efficient and physiotherapy specific motivational interventions for individuals ambivalent to returning to usual activities following an episode of low back pain, may help address the issues identified by the current survey.


Bose-Einstein condensation of strontium.
We report on the attainment of Bose-Einstein condensation with ultracold strontium atoms. We use the (84)Sr isotope, which has a low natural abundance but offers excellent scattering properties for evaporative cooling. Accumulation in a metastable state using a magnetic-trap, narrowline cooling, and straightforward evaporative cooling in an optical trap lead to pure condensates containing 1.5 x 10(5) atoms. This puts (84)Sr in a prime position for future experiments on quantum-degenerate gases involving atomic two-electron systems.


The use of Robertsonian translocations in the mouse for studies on non-disjunction.
In the mouse, gametes with gross chromosome duplications and deficiencies can complement each other to give viable zygotes (with some notable exceptions involving particular chromosomes). These complementation-type offspring can be recognised in intercrosses between translocation heterozygotes in which one parent is homozygous for a recessive genetic marker not carried by the other. This system has beeN used by Lyon and colleagues (1976) to study non-disjunction in heterozygotes for tobacco mouse and laboratory-derived Robertsonian translocations. Although non-disjunction is frequent in the former group, still higher frequencies are needed for a workable test system in which wild type mice are treated and mated to a tester stock generating many aneuploid gametes. Possible approaches include (1) use of semidominant markers, (2) marking both arms, (3) combining two or three independent Robertsonians in the tester stock, (4) use of compounds of Robertsonians wih monobrachial homology, since these give very high frequencies of non-disjunction, (5) generation of a compound of three Robertsonians with tribrachial homology, which should produce aneuploid gametes only. This last seems the most promising approach, if the compound proves fertile, and would be analogous to the isochromosome system of Drosophila.


Identification of a flavonoid C-glycoside as potent antioxidant.
Flavonoids have been documented to have good antioxidant activities in vitro. However, reports on the cellular antioxidant activities of flavonoid C-glycosides are very limited. In this work, an apigenin C-glycoside was purified from Artocarpus heterophyllus by column chromatography and was identified to be 2″-O-β-D-xylosylvitexin by nuclear magnetic resonance spectroscopy. The cellular antioxidant activity and anticancer activity of 2″-O-β-D-xylosylvitexin were evaluated for the first time. The quantitative structure-activity relationship was analysed by molecular modeling. Apigenin presented an unexpected cellular antioxidation behaviour. It had an antioxidant activity at low concentration and a prooxidant activity at high concentration, whereas 2″-O-β-D-xylosylvitexin showed a dose-dependent cellular antioxidant activity. It indicated that C-glycosidation improved the cellular antioxidation performance of apigenin and eliminated the prooxidant effect. The ortho-dihydroxyl at C-3'/C-4' and C-3 hydroxyl in the flavonoid skeleton play important roles in the antioxidation behaviour. The cell proliferation assay revealed a low cytotoxicity of 2″-O-β-D-xylosylvitexin.


Sirtuin activators mimic caloric restriction and delay ageing in metazoans.
Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.


[Bacteremia induced by labor. Is prophylaxis for infective endocarditis necessary?].
To characterize the occurrence of bacteremia during delivery and to verify the necessity of prophylaxis against infective endocarditis. The authors collected hemoculture of 100 women, 15,30 and 45 minutes after delivery. The data were collected from May 1992 until May 1993. The positive hemocultures were followed by antibiogram. Seven hemocultures were positive: six for Staphylococcus, one for Candida sp, Penicilium sp, Clandosporum sp and Aspergillus sp that were found in association. Four patients had prematures amniorrhexis, longer than 6 hours before delivery (p < 0.05). Six patients had labor longer than 6 hours after admission (p < 0.05). The authors did not observe differences related to vaginal delivery with or without forceps or cesarean section. The samples were all sensible to cefalotin at the antibiogram. Labor and delivery is a high risk procedure for bacteremia and so for ineffective endocarditis in susceptible patients. The statistical analysis recognize as risk factors labor longer than 6 hours inside the hospital and premature amniorrhexis. We propose the use of intravenous cefalotin 1g 60 minutes before expulsion and repeated 6 and 12 hours later.


Modulation of propagation from an ectopic focus by electrical load and by extracellular potassium.
We previously developed a technique (R. Kumar, R. Wilders, R. W. Joyner, H. J. Jongsma, E. E. Verheijck, D. A. Golod, A. C. G. van Ginneken, and W. N. Goolsby. Circulation 94: 833-841, 1996) for study of a mathematical model cell with spontaneous activity, viz. a "real-time" simulation of a rabbit sinoatrial node cell (SAN model cell; R. Wilders, H. J. Jongsma, and A. C. van Ginneken. Biophys. J. 60: 1202-1216, 1991) simultaneously being electrically coupled via our "coupling clamp" [H. Sugiura and R. W. Joyner. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H1591-H1604, 1992] circuit to a real, isolated ventricular myocyte. We now apply this technique to investigate effects of coupling conductance (Gc), cell size, and the modulation of membrane potential by elevated extracellular potassium concentration on the ability of an ectopic focus, represented by the SAN model cell, to successfully drive a ventricular cell. Values of Gc and the relative sizes of the two cells define three possible outcomes: 1) spontaneous pacing of the SAN model cell but not driving of the ventricular cell, 2) cessation of spontaneous pacing, or 3) pacing of the SAN model cell and driving of the ventricular cell. Below a critical size of the SAN model cell only the first two of these outcomes is possible. Above this critical size there is a range of Gc that allows successful operation of the system as an ectopic focus. Elevation of extracellular potassium concentration from 4 to 8 mM increases both the lower bound and upper bound of Gc for this range. Elevation of extracellular potassium concentration, as commonly observed in myocardial ischemia, may have effects on either inhibiting or releasing from inhibition an ectopic focus.


Temperature dependent soret spectral band shifts accompany human CN-mesohemoglobin assembly.
The interaction between human apohemoglobin A and CN-Mesohemin, a monomeric non-native heme derivative, was probed by Soret spectrophotometric titrations in 0.05 M potassium phosphate buffer, pH 7 at varied temperatures. Hypsochromic shifts in the absorbance maxima were observed at all temperatures below 10 degrees C. First derivative spectroscopy of CN-Mesohemin titrations was used to provide further evidence of a spectral shift upon CN-Mesohemoglobin assembly. Findings of Soret Spectral shifts demonstrate a preference for the alpha chain heme site by CN-Mesohemin indicative of semi-alpha-hemoglobin intermediate formation. CN-Mesohemin, a derivative with peripheral 2,4 ethyl groups, does not possess the extended conjugation seen for native CN-Protohemin with its 2,4 vinyl groups. Indeed, reduced polarity of CN-Mesohemin over that of CN-Protohemin resulted in distinct temperature dependencies. Molecular visualization and protein-ligand interaction analysis targeted a functionally diverse residue unique to the alpha-chain. Tyrosine-42 (a polar/non-polar amino acid) appeared to play a prominent role in the assembly process.


A Multimodality Image Guided Precision Radiation Research Platform: Integrating X-ray, Bioluminescence, and Fluorescence Tomography With Radiation Therapy.
Small animal irradiation is crucial to the investigation of radiobiological mechanisms. The paradigm of clinical radiation therapy is trending toward high-precision, stereotactic treatment. However, translating this scheme to small animal irradiation is challenging owing to the lack of high-quality image guidance. To overcome this obstacle, we developed a multimodality image guided precision radiation platform. The platform consists of 4 modules: x-ray computed tomography (CT), bioluminescence tomography (BLT), fluorescence molecular tomography (FMT), and radiation therapy. CT provides animal anatomy and material density for radiation dose calculation, as well as body contour for BLT and FMT reconstruction. BLT and FMT provide tumor localization to guide radiation beams and molecular activity to evaluate treatment outcome. Furthermore, we developed a Monte Carlo-based treatment planning system (TPS) for 3-dimensional dose calculation, calibrated it using radiochromic films sandwiched in a water-equivalent phantom, and validated it using in vivo dosimeters surgically implanted into euthanized mice (n = 4). Finally, we performed image guided irradiation on mice bearing orthotopic breast and prostate tumors and confirmed radiation delivery using γH2AX histology. The Monte Carlo-based TPS was successfully calibrated by benchmarking simulation dose against film measurement. For in vivo dosimetry measured in the euthanized mice, the average difference between the TPS calculated dose and measured dose was 3.86% ± 1.12%. Following the TPS-generated treatment plan, we successfully delivered 20 Gy dose to an animal bearing an orthotopic prostate tumor using 4 BLT-guided radiation beams and 5 Gy dose to an animal bearing an orthotopic breast tumor using a single FMT-guided radiation beam. γH2AX histology presented significantly more DNA damage in irradiated tumors and thus validated the dose delivery accuracy. Combined with Monte Carlo TPS, this multimodality CT/BLT/FMT image guided small animal radiation platform can specifically localize tumors, accurately calculate dose distribution, precisely guide radiation delivery, and molecularly evaluate treatment response. It provides an advanced toolset for radiobiology and translational cancer research.


Chaotic model and memory in single calcium-activated potassium channel kinetics.
Ion channels are pores formed by proteins and responsible for carrying ion fluxes through cellular membranes. The ion channels can assume conformational states thereby controlling ion flow. Physically, the conformational transitions from one state to another are associated with energy barriers between them and are dependent on stimulus, such as, electrical field, ligands, second messengers, etc. Several models have been proposed to describe the kinetics of ion channels. The classical Markovian model assumes that a future transition is independent of the time that the ion channel stayed in a previous state. Others models as the fractal and the chaotic assume that the rate of transitions between the states depend on the time that the ionic channel stayed in a previous state. For the calcium activated potassium channels of Leydig cells the R/S Hurst analysis has indicated that the channels are long-term correlated with a Hurst coefficient H around 0.7, showing a persistent memory in this kinetic. Here, we applied the RS analysis to the opening and closing dwell time series obtained from simulated data from a chaotic model proposed by L. Liebovitch and T. Tóth [J. Theor. Biol. 148, 243 (1991)] and we show that this chaotic model or any model that treats the set of channel openings and closings as independent events is inadequate to describe the long-term correlation (memory) already described for the experimental data.


Neuroblastoma adenylate cyclase. Role of 2-chloroadenosine, prostaglandin E1, and guanine nucleotides in regulation of activity.
Neuroblastoma adenylate cyclase is activated by 2-chloroadenosine, prostaglandin E1, and 5'-guanylylimidodiphosphate [GMP-P(NH)P]. However, the process of activation by the first two compounds is different from that induced by the third. Prostaglandin E1 and 2-chloroadenosine activation is rapid, producing elevated activities which are constant throughout a 20-min assay. In contrast, GMP-P(NH)P activation is slow and although the activity is elevated within 1 min, it continues to increase for up to 12 min before attaining a maximal constant value. Activation is more rapid when either prostaglandin E1 or 2-chloroadenosine is present with GMP-P(NH)P. Activation of the enzyme by GMP-P(NH)P appears to be retarded by endogenous nucleotides as suggested by the following observations: (a) if the enzyme is incubated at 30 degrees with 5 mM MgCl2 for 5 to 7 min, GMP-P(NH)P then produces maximal activation without a detect able lag; (b) if, during this incubation, nucleotides, a nucleotide regenerating system, or EDTA (instead of MgCl2) are present, subsequent GMP-P(NH)P activation is slow; and (c) in the assays which contain a nucleotide regenerating systm and MgATP as substrate, the Km for GMP-P(NH)P is 6 +/- 2 muM. However, in the assays using MgAMP-P(NH)P as substrate but no nucleotide regenerating system, the Km is 0.5 +/- 0.2 muM. GPD and GTP do not replace GMP-P(NH)P as an enzyme activator in any of our assays systems, and in fact, are potent inhibitors of GMP-P(NH)P enzyme activation. Prostaglandin E1 and 2-chloradensine do not alter significantly the Km for GMP-P(NH)P but do decrease the ensyme's sensitivity of GDP. Proposed is a hysteretic model of neuroblastoma adenylate cyclase, which shows the enzyme responding slowly to rapid changes in GMP-P(NH)P concentration due to the slow displacement of the tightly bound endogenous guanine nucleotides by GMP-P(NH)P. Additionally, prostaglandin E1 and 2-chloroadenosine increase the rate of GMP-P(NH)P activation by decreasing the enzyme's affinity for these endogenous guanine nucleotides.


Self-reported and parent-reported pain for common painful events in high-functioning children and adolescents with autism spectrum disorder.
Previous research suggests that children with autism spectrum disorders (ASD) are at a higher risk for painful experiences, but there is limited research examining pain in children with ASD. The current study examined self-reported and parent-reported pain in 20 high-functioning youth with ASD (17 boys; 3 girls) and 20 typically developing controls (16 boys; 4 girls) ranging in age from 9 to 18 years and matched on age and IQ. Participants with and without ASD rated their hypothetical pain in a series of pictures depicting common childhood situations. They also rated the amount of pain they would expect to feel (using the Faces Pain Scale-Revised and a Numeric Rating Scale) in a series of validated hypothetical pain situations depicted in cartooned images (eg, scraping knee on sidewalk). Parents rated the amount of pain they would expect their child to show in each of the same cartoon stimuli. There were no significant differences between pain vignette ratings of youth with ASD and their non-ASD peers or in the ratings provided by their parents. High-functioning youth with ASD were able to successfully use both of the self-report scales to rate pain. This is the first study to successfully obtain self-report of pain from youth with ASD. Implications for the understanding of pain and pain assessment in high-functioning youth with ASD are discussed.


Increased Sphingosine Kinase 1 Expression Is Associated with Poor Prognosis in Human Solid Tumors: A Meta-Analysis.
PubMed, Web of Science, Embase, CNKI, and Wanfang databases were thoroughly searched for eligible studies, in which the relationship between SPHK1 expression and cancer prognosis was evaluated. Hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled to estimate the impact of SPHK1 expression on cancer patients' survival. Odds ratios (ORs) and 95% CIs were combined to assess the association between SPHK1 expression and clinicopathological characteristics of cancer patients. The certainty of evidence was evaluated by Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria. Thirty studies comprising 32 cohorts with 5965 patients were included in this meta-analysis. The outcomes indicated that elevated SPHK1 expression was associated with worse overall survival (OS) (HR = 1.71, 95% CI: 1.45-2.01, P < 0.001) and disease-free survival (DFS) (HR = 1.34, 95% CI: 1.13-1.59, P = 0.001). What is more, SPHK1 overexpression was significantly correlated with certain phenotypes of tumor aggressiveness, such as clinical stage (OR = 2.07, 95% CI: 1.39-3.09, P < 0.001), tumor invasion (OR = 2.16, 95% CI: 1.47-3.18, P < 0.001), lymph node metastasis (OR = 2.04, 95% CI: 1.71-2.44, P < 0.001), and distant metastasis (OR = 3.16, 95% CI: 2.44-4.09, P < 0.001). The quality of the evidence for both OS and DFS was low. Increased SPHK1 expression is related to poor prognosis in human cancers and may serve as a promising prognostic marker and therapeutic target for malignant patients. However, conclusions need to be treated with caution because of lack of high quality of evidence.


Cerebral infarction in a patient with congenital complete heart block.
Stokes-Adams attacks are fairly common in children with congenital complete heart block, but the occurrence of cerebral infarction is quite unusual. We present the case of a 13-year-old boy with congenital heart block and an embolic stroke involving the cerebral artery. Echocardiography revealed no valvular regurgitation, hypokinetic segments, mural thrombus, or myxoma. Electrocardiographic monitoring demonstrated good response of ventricular rate to exercise and no episodes of atrial or ventricular dysrhythmia. It is assumed that embolism occurred due to bradycardia.


Syntheses and structural properties of rare earth carbodiimides.
Crystalline samples of rare earth carbodiimides were synthesized by solid-state metathesis reactions of rare earth trichlorides with lithium cyanamide in sealed silica ampules. Two distinct structures were determined by single-crystal X-ray diffraction. The structure determined for Sm2(CN2)3 [C2/m, Z = 2, a = 14.534(2) A, b = 3.8880(8) A, c = 5.2691(9) A, beta = 95.96(2) degrees , R1 = 0.0267, and wR2 = 0.0667] was assigned for RE2(CN2)3 compounds with RE = Y, Pr, Nd, Sm, Gd, Tb, Dy, Ho, and Er, and the structure determined for Lu2(CN2)3 [R32, Z = 3, a = 6.2732(8) A, c = 14.681(2) A, R1 = 0.0208, and wR2 = 0.0526] was assigned for the smallest rare earth ions with RE = Tm, Yb, and Lu by powder X-ray diffraction. Both types of crystal structures are characterized by layers of [NCN](2-) ions whose arrangements can be derived from the motif of a closest packed layer of sticks. These layers alternate with layers of rare earth ions in a one-by-one sequence. Different tilting arrangements of the N-C-N-axes relative to the stacking directions (c) and different arrangements of RE3+ ions within metal atom layers account for the two distinct structures in which Sm3+ and Lu3+ ions adopt the coordination numbers 7 and 6, respectively.


Differential influence of stromal fibroblasts from different breast tissues on human breast tumour cell growth in nude mice.
The influence of human stromal fibroblasts cultured from normal, non-malignant and malignant breast tissues on in vivo growth of human breast tumour cells was studied. Earlier appearance and increased incidence were observed when low cell inocula of breast MDA-MB 231 tumour cells were coinjected with fibroblasts from either normal or non-malignant mammary tissue. However, at higher cell inoculations the appearance of MDA-MB tumours was delayed while the incidence was reduced. Coinjected fibroblasts derived from breast tumours did not modify MDA-MB tumour growth. The tumourigenic MCF-7 and non-tumourigenic NPM14-T4/9 breast cell lines were not affected by the presence of normal breast fibroblasts. These results indicate that fibroblasts can influence the behavior of tumour cells in vivo but the effects depend on the type and the proportions of coinoculated cells.


Accuracy of training recommendations based on a treadmill multistage incremental exercise test.
Competitive runners will occasionally undergo exercise in a laboratory setting to obtain predictive and prescriptive information regarding their performance. The present research aimed to assess whether the physiological demands of lab-based treadmill running (TM) can simulate that of over-ground (OG) running using a commonly used protocol. Fifteen healthy volunteers with a weekly mileage of ≥ 20 km over the past 6 months and treadmill experience participated in this cross-sectional study. Two stepwise incremental tests until volitional exhaustion was performed in a fixed order within one week in an Outpatient Clinic research laboratory and outdoor athletic track. Running velocity (IATspeed), heart rate (IATHR) and lactate concentration at the individual anaerobic threshold (IATbLa) were primary endpoints. Additionally, distance covered (DIST), maximal heart rate (HRmax), maximal blood lactate concentration (bLamax) and rate of perceived exertion (RPE) at IATspeed were analyzed. IATspeed, DIST and HRmax were not statistically significantly different between conditions, whereas bLamax and RPE at IATspeed showed statistical significance (p < 0.05). Apart from RPE at IATspeed, IATspeed, DIST, HRmax and bLamax strongly correlate between conditions (r = 0.815-0.988). High reliability between conditions provides strong evidence to suggest that running on a treadmill are physiologically comparable to that of OG and that training recommendations and be made with assurance.


A new generation of food-borne pathogen detection based on ribosomal RNA.
Listeria and Salmonella detection assays for food and environmental surfaces that target ribosomal RNA (rRNA) have been developed. The large number of rRNA molecules in bacteria enabled the development of molecular assays that use enrichment times as short as 12 hours for Salmonella and 24 hours for Listeria. These assays run on a fully automated molecular pathogen detection system, which provides walk-away capability and produces 300 assay results in eight hours.


Ammonium hydroxide modulated synthesis of high-quality fluorescent carbon dots for white LEDs with excellent color rendering properties.
A novel type of aqueous fluorescent carbon dot (CD) was synthesized using citric acid as the only carbon source via an ammonium hydroxide modulated method, providing a blue color gamut. The amino group is considered to be the key factor in the high fluorescence of CDs and a model is established to investigate the mechanism of fluorescence. In addition, white light-emitting diodes (WLEDs) are fabricated by utilizing the prepared CDs and rare earth luminescent materials (SrSi2O2N2:Eu and Sr2Si5N8:Eu) as color conversion layers and UV-LED chips as the excitation light source. The WLEDs produce bright white light with attractive color rendering properties including a color rendering index of up to 95.1, a CIE coordinate of (0.33, 0.37), and a T c of 5447 K under a 100 mA driven current, indicating that the CDs are promising in the field of optoelectronic devices.


Predicting Zoonotic Risk of Influenza A Viruses from Host Tropism Protein Signature Using Random Forest.
Influenza A viruses remain a significant health problem, especially when a novel subtype emerges from the avian population to cause severe outbreaks in humans. Zoonotic viruses arise from the animal population as a result of mutations and reassortments, giving rise to novel strains with the capability to evade the host species barrier and cause human infections. Despite progress in understanding interspecies transmission of influenza viruses, we are no closer to predicting zoonotic strains that can lead to an outbreak. We have previously discovered distinct host tropism protein signatures of avian, human and zoonotic influenza strains obtained from host tropism predictions on individual protein sequences. Here, we apply machine learning approaches on the signatures to build a computational model capable of predicting zoonotic strains. The zoonotic strain prediction model can classify avian, human or zoonotic strains with high accuracy, as well as providing an estimated zoonotic risk. This would therefore allow us to quickly determine if an influenza virus strain has the potential to be zoonotic using only protein sequences. The swift identification of potential zoonotic strains in the animal population using the zoonotic strain prediction model could provide us with an early indication of an imminent influenza outbreak.


General and abdominal adiposity in a representative sample of Portuguese adults: dependency of measures and socio-demographic factors' influence.
The aims of this study were: (i) to estimate the dependency between BMI and waist:height ratio (WHtR) as measures of general and abdominal adiposity, and (ii) to evaluate the influence of socio-demographic factors on both measures and on their dependency in risk classification. Data from a cross-sectional study conducted in 2009 among a representative sample of 3529 Portuguese adults were used. Height, weight and waist were measured and socio-demographic data (sex, age, education level, occupational status, marital status, region of residence) were obtained. Using logistic regression, crude and adjusted OR for high general (BMI≥25·0 kg/m²) and abdominal (WHtR≥0·5) adiposity, and for incompatible classification between them, were calculated. Above half (50·8%) of the respondents had high BMI and 42·1% had high WHtR, and the rates were higher in men than in women. There was an inverse association between education level and both adiposity measures. The lowest prevalence of high general and abdominal adiposity was observed in students and singles, whereas the highest was found in retired, widowed and respondents from Azores, Madeira and Alentejo. Nearly a quarter of respondents (24·0%) were incompatibly classified by BMI and WHtR, with higher prevalence in men than in women and in low- than in high-educated people. Future surveys should focus on developing at least sex-specific cut-offs for both measures. Implementation of effective strategies for preventing and reducing high adiposity levels in Portugal should be directed primarily to men, older, low-educated individuals, as well as those living in the islands and poor regions of the country.


Epidemiology and outcome of pressure injuries in critically ill patients with chronic obstructive pulmonary disease: A propensity score adjusted analysis.
Pressure injuries are a frequent complication in intensive care unit (ICU) patients, especially in those with comorbid conditions such as chronic obstructive pulmonary disease (COPD). Yet no epidemiological data on pressure injuries in critically ill COPD patients are available. To assess the prevalence of ICU-acquired pressure injuries in critically ill COPD patients and to investigate associations between COPD status, presence of ICU-acquired pressure injury, and mortality. This is a secondary analysis of prospectively collected data from DecubICUs, a multinational one-day point-prevalence study of pressure injuries in adult ICU patients. We generated a propensity score summarizing risk for COPD and ICU-acquired pressure injury. The propensity score was used as matching criterion (1:1-ratio) to assess the proportion of ICU-acquired pressure injury attributable to COPD. The propensity score was then used in regression modeling assessing the association of COPD with risk of ICU-acquired pressure injury, and examining variables associated with mortality (Cox proportional-hazard regression). Of the 13,254 patients recruited to DecubICUs, 1663 (12.5%) had documented COPD. ICU-acquired pressure injury prevalence was higher in COPD patients: 22.1% (95% confidence interval [CI] 20.2 to 24.2) vs. 15.3% (95% CI 14.7 to 16.0). COPD was independently associated with developing ICU-acquired pressure injury (odds ratio 1.40, 95% CI 1.23 to 1.61); the proportion attributable to COPD was 6.4% (95% CI 5.2 to 7.6). Compared with non-COPD patients without pressure injury, mortality was no different among patients without COPD but with pressure injury (hazard ratio [HR] 1.07, 95% CI 0.97 to 1.17) or COPD patients without pressure injury (HR 1.13, 95% CI 1.00 to 1.27). Mortality was higher among COPD patients with pressure injury (HR 1.35, 95% CI 1.15 to 1.58). Critically ill COPD patients have a statistically significant higher risk of pressure injury. Moreover, those that develop pressure injury are at higher risk of mortality. As such, pressure injury may serve as a surrogate for poor prognostic status to help clinicians identify patients at high risk of death. Also, delivery of interventions to prevent pressure injury are paramount in critically ill COPD patients. Further studies should determine if early intervention in critically ill COPD patients can modify development of pressure injury and improve prognosis.


Clinical scoring for diagnosis of acute lower abdominal pain in female of reproductive age.
Background. Obstetrics and gynecological conditions (OB-GYNc) are difficult to be differentiated from appendicitis in young adult females presenting with acute lower abdominal pain. Timely and correct diagnosis is clinically challenging. Method. A retrospective data analysis was performed on 542 female patients who were admitted to a tertiary care hospital with a chief complaint of acute lower abdominal pain. Diagnostic indicators of appendicitis and OB-GYNc were identified by stepwise multivariable polytomous logistic regression. Diagnostic performances of the scores were tested. Result. The developed clinical score is comprised of (1) guarding or rebound tenderness, (2) pregnancy, (3) sites of abdominal tenderness, (4) leukocytosis, (5) peripheral neutrophils ≥75%, and (6) presence of diarrhea. For diagnosis of appendicitis, the area under the ROC curve was 0.8696, and the sensitivity and specificity were 89.25% and 70.00%. For OB-GYNc, the corresponding values were 0.8450, 66.67%, and 94.85%, respectively. Conclusion. The clinical scoring system can differentiate the diagnosis of acute lower abdominal pain in young adult females. Time spent for diagnosis at the emergency room may be shortened, and the patients would be admitted to the appropriate departments in less time.


Effect of hydrocortisone on intravenous glucose tolerance in small-for-gestational-age infants.
The effects of hydrocortisone (H) hemisuccinate (10 mg/kg) on intravenous glucose tolerance (1 g/kg) was studied in eight full term small-for-gestational-age (SGA) infants and compared to seven control infants at mean age of 41 h. After H, the rate of glucose disappearance was (mean +/- SD) 0.92 +/- 0.27 vs 1.24 +/- 0.31% min in controls (p less than 0.01). Glucose space was similar after H: 449 +/- 62 ml/kg and in the control group 468 +/- 75 ml/kg. At 5 and 15 min, although higher in the H group, mean plasma glucose was not significantly different. The difference became significant at 30 min (t = 2.00; p = 0.05), 45 (t = 2.298; p less than 0.05) and 60 min (t = 2.48; p less than 0.02). Plasma insulin concentration did not change after glucose injection in the control group. After H administration, plasma insulin increased: the basal median value was less than 5 mU/ml (range less than 5-18) and at 60 min it rose to 30 mU/ml (range 7.5-89). These data suggest that in newborn infants corticoids induce a reduced peripheral uptake of glucose independent of insulin secretion.


Genomic determinants in advanced endometrial cancer patients with sustained response to hormonal therapy- case series and review of literature.
The incidence of endometrial cancer is increasing, however treatment options for advanced disease are limited. Hormonal therapy has demonstrated positive outcomes for Stage IV EC. Next generation sequencing (NGS) has increased our understanding of molecular mechanisms driving EC. In this case series, we selected six patients at our institution with Stage IV, hormone receptor positive, endometrial cancer currently being treated with hormonal therapy. All patients achieved SD for at least ≥ 1.5 years. We studied NGS data on all six patients to assess for any common genomic marker which could predict the SD of at least 1.5 years achieved in this group. Institutional Review Board (IRB) approval was obtained from Staten Island University Hospital and Northwell Health, New York. PTEN, PIK3CA, PIK3R1, and ARID1A mutations were found in 83%, 67% 50%, and 67% of patients respectively. TP53 and FGFR2 were both found in 50% of patients. All patients were positive for estrogen and/or progesterone receptor (ER+ and/or PR+). We did not find any one common mutation that could have predicted the observed response (or SD of ≥1.5 years) to hormone therapy. However, our data reflects the prevalence of various mutations reported in literature: (1) Hormone Receptor status is a positive prognostic indicator (2) PTEN/PIK3CA mutations can occur concurrently in EC (3) ARID1A coexists with PTEN (4) FGFR and PTEN pathways may be interlinked. We suggest NGS be employed frequently in patients with endometrial cancer to identify targetable mutations. Additional larger studies are needed to characterize the interplay between mutations.


CD-ROM.
What makes CD-ROM attractive or unattractive in the library setting? What are its advantages or disadvantages? How will the technology develop? What has been the experience of libraries who have tested and introduced CD-ROM products to their users? The following two-part article addresses these questions. Part 1 explores the development of disk technology, its advantages and disadvantages and potential library applications. The actual testing and use of one of the CD-ROM products, PsycLIT, is the focus of Part II.


Spatial Learning and Memory-What's TLE Got To Do With It?
Cognitive impairment is a significant comorbidity of epilepsy. At present, the molecular/cellular mechanisms that underlie these cognitive impairments remain unknown. It seems likely that a complete understanding at the molecular/cellular level will require the use of rodent models. A number of rodent models of epilepsy are used to study cognition in a variety of behavioral tasks. This review presents a brief overview of two commonly used tasks (the Morris water maze and the radial arm maze) that have been used to assess spatial learning/memory in two chemoconvulsant models of temporal lobe epilepsy.


[Comparison of protective effects of eight ethyl acetate extracts from Eclipta prostrate on NHBE cells based on component structure theory].
To analyze and compare the protective effects of active components in different ethyl acetate extracts (EAEEPs) from Eclipta prostrate, in order to study the comparison of materials bases protecting normal human bronchial epithelial (NHBE) cells. The MTT assay was taken to compare the protective effect of different EAEEPs on cigarette smoke extracts (CSE) -induced NHBE cells. The ultra-performance liquid chromatography (UPLC) was applied to analyze the content of phenolic acid, coumaric grass ether and flavonoid in EAEEPs. According to the results, all of the eight EAEEPs (0-200 mg x L(-1)) showed certain protective effect on NHBE cells, with statistical difference. Specifically, the total mass of EAEEP VII (89.15 mg x L(-1)) and EAEEP VIII (57.44 mg x L(-1)), which showed the strongest activity, was not the highest, while EAEEP III (132.25 mg x L(-1)) displayed the highest total mass. In the combination with the "component structure" theory, the analysis showed a significant difference in the mass structure among phenolic acid, coumaric grass ether and flavonoid in EAEEP VIII and EAEEP VIII, which were 1.0: 1. 0: 0.5 and 1.0: 1.9: 0.8, respectively. The results suggested a specific optimal "component structure" relationship may exist in EAEEP, which could provide reference for the material base study and quality control.


Presentation of a major histocompatibility complex class 1-binding peptide by monocyte-derived dendritic cells incorporating hydrophobized polysaccharide-truncated HER2 protein complex: implications for a polyvalent immuno-cell therapy.
Recognition of the essential role of dendritic cells (DCs) as professional antigen-presenting cells has prompted investigators to search for methods to use DCs as natural adjuvants in immunotherapy. A number of antigenic oligopeptides, recognized by CD8(+) cytotoxic T lymphocytes (CTLs) specific for cancer cells, have been applied in clinical trials using DCs. Such a monovalent vaccine with a single epitope for a particular type of HLA class 1 molecule would be effective. However, a polyvalent vaccine might be more potent. We designed a novel protein delivery system consisting of hydrophobized polysaccharides complexed with target proteins. The truncated HER2 protein encompassing 147 N-terminal amino acids, including the 9-mer HER2p63-71 peptide (HER2p63), TYLPTNASL, the human homologue of an antigenic murine tumor rejection peptide, was prepared. We report here that HLA-A2402(+) DCs could incorporate hydrophobized polysaccharide-truncated HER2 protein complexes and process the protein to present major histocompatibility complex class 1-binding HER2p63 peptide. The complexes enter DCs by phagocytosis, and then the truncated protein is processed through a pathway similar to that for endogenous proteins. DCs sensitized by these complexes primed and boosted HER2p63-specific CD8(+) T cells in the context of HLA-A2402. Vaccination with DCs incorporating these complexes completely suppressed lung metastases in a HER2-expressing murine tumor model. We also generated 3 CD4(+) clones reactive with different HER2- derived 25-mer peptides from lymph node cells in mice treated with CHP/HER2-147. Thus, hydrophobized polysaccharide-protein complexes are promising candidates for the construction of polyvalent vaccines.


Chromosome breakage in lymphocytes from members of cancer families showing autosomal dominant inheritance.
We have conducted investigations on members of three families with increased predisposition to cancer which appears to be inherited as an autosomal dominant trait. The aim of our studies overall is to provide markers for the mutant genes involved, so that gene carriers may be monitored closely for signs of malignant disease. This paper reports on studies of chromosome breakage in lymphocytes from affected and at-risk family members and control subjects. No increase in spontaneous chromosome breakage was observed in family members compared with controls. An increased sensitivity to chromosome damage induced by the alkylating agent, N-methyl-N1-nitro-N-nitrosoguanidine (MNNG), was observed in three members from two families; one person was affected, the others at risk. These families included cases of osteosarcoma, in addition to various types of cancer of epithelial origin. Two members (one affected, one at-risk) of a third family showed increased sensitivity to the radio-mimetic agent, bleomycin. This family appeared to represent the cancer family syndrome. Whilst not conclusive at present, our results appear to justify investigation of members of cancer families with respect to sensitivity to chromosome breaking agents.


Does any therapy really work for neurocardiogenic syncope?
Effectiveness of a treatment for neurocardiogenic syncope can be defined in terms of symptom response, quality-of-life, healthcare utilization, treatment side effects and cost-effectiveness. Most trials have focused on syncope recurrence or burden, without assessing quality-of-life formally. Drug and device interventions are characterized by a dearth of randomized controlled trials, with those few of robust design demonstrating little impact on recurrence of syncope. General advice includes hydration, trigger recognition and counter pressure maneuvers to attenuate episodes. Lifestyle recommendations have limited comparative effectiveness evidence, but are favored due to lack of side effects and low cost. The frequency of syncope improves in many patients regardless of the intervention, although ultimate recurrence of syncope remains high. In the minority of patients seeking treatment due to recurrence, midodrine has reasonable supporting evidence for effectiveness with some evidence for beta-blockers in older age patients. Emerging evidence favors pacing in patients with asystole during spontaneous (as opposed to provoked) syncope. Combining long-term implantable cardiac monitoring, tilt and adenosine triphosphate testing may yet accurately define the optimal minority who benefit from pacing. In the remaining majority, pharmacologic and device interventions should be used sparingly until clear benefits are established. Better understanding of patient fears, beliefs and behaviors may help develop cognitive therapies and improve quality-of-life alongside the focus on physical symptoms.


Patient Perceptions of Surgeon Reimbursement in Total Ankle Arthroplasty.
The incidence of total ankle arthroplasty (TAA) for ankle osteoarthritis has increased in the Medicare population by approximately 16.37% each year. This study examines the patient perception of orthopedic surgeon reimbursement for TAA by Medicare. A total of 78 patients were surveyed anonymously at 2 foot and ankle clinics within an academic health care setting. The surveys were given anonymously before the patients were seen by an orthopedic surgeon. Surveys were returned to office staff who placed them in a collection box to ensure confidentiality. The average estimate of how much orthopedic surgeons should be reimbursed for TAA was $19 506 and the average estimate of how much orthopedic surgeons were actually reimbursed was $20 772. Fifty patients believed that orthopedic surgeons were under reimbursed, 9 believed that they were reimbursed appropriately, and 19 were unsure. Demographic variables such as age, sex, education level, income, and insurance status had no significant effect on the results. Most patients believed orthopedic surgeons are under reimbursed for TAA and that there is a lack of health care transparency regarding orthopedic reimbursement for TAA by Medicare.Levels of Evidence: Level V: Expert opinion.


Effect of changing the kilovoltage peak on radiographic caries assessment in digital and conventional radiography.
This study aimed to investigate the effect of changing the kilovoltage peak (kVp) on the radiographic assessment of dental caries. Seventy-five extracted posterior teeth with proximal caries or apparently sound proximal surfaces were radiographed with conventional E-speed films and a photostimulable phosphor system using 60 kVp and 70 kVp for the caries assessment. The images were evaluated by three oral radiologists and compared with the results of the stereomicroscope analysis. No statistically significant difference was found between 60 kVp and 70 kVp for the caries detection, determination of caries extension into dentin, and caries severity in either the conventional or the digital images. Good to very good inter-observer and intra-observer agreements were found for both kilovoltage values on the conventional and digital images. Changing the kilovoltage between 60 kVp and 70 kVp had no obvious effect on the detection of proximal caries or determination of its extension or severity.


Discovery of 5-chloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (AZD1480) as a novel inhibitor of the Jak/Stat pathway.
The myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are a heterogeneous but related group of hematological malignancies characterized by clonal expansion of one or more myeloid lineages. The discovery of the Jak2 V617F gain of function mutation highlighted Jak2 as a potential therapeutic target in the MPNs. Herein, we disclose the discovery of a series of pyrazol-3-yl pyrimidin-4-amines and the identification of 9e (AZD1480) as a potent Jak2 inhibitor. 9e inhibits signaling and proliferation of Jak2 V617F cell lines in vitro, demonstrates in vivo efficacy in a TEL-Jak2 model, has excellent physical properties and preclinical pharmacokinetics, and is currently being evaluated in Phase I clinical trials.


[Dual-chamber rate responsive cardiac pacing].
The authors describe in this report their first experience with the implantation of a rate responsive, dual chamber pacemaker. They emphasize the advantages of this type of pacemakers: the maintenance of AV-synchrony and the rate increase in response to exercise. Meanwhile they call attention on the complexity of the ECG interpretation.


Cigarette Smoke Extract Inhibits Platelet Aggregation by Suppressing Cyclooxygenase Activity.
The results of studies that were performed to determine whether cigarette smoking affects platelet function have been controversial, and the effects of nicotine- and tar-free cigarette smoke extract (CSE) on platelet function remain to be determined. The aim of this study was to determine the effect of CSE on platelet aggregation and to clarify the mechanism by which CSE affects platelet function. CSE inhibited murine platelet aggregation induced by 9,11-dideoxy-9α,11α-methanoepoxy-prosta-5Z,13E-dien-1-oic acid (U-46619), a thromboxane (TX) A 2 receptor agonist, and that induced by collagen with respective IC 50 values of 1.05 ± 0.14% and 1.34 ± 0.19%. A similar inhibitory action of CSE was also observed in human platelets. CSE inhibited arachidonic acid-induced TXA 2 production in murine platelets with an IC 50 value of 7.32 ± 2.00%. Accordingly, the inhibitory effect of CSE on collagen-induced aggregation was significantly blunted in platelets lacking the TXA 2 receptor compared with the inhibitory effect in control platelets. In contrast, the antiplatelet effects of CSE in platelets lacking each inhibitory prostanoid receptor, prostaglandin (PG) I 2 receptor and PGE 2 receptor subtypes EP 2 and EP 4 , were not significantly different from the effects in respective control platelets. Among the enzymes responsible for TXA 2 production in platelets, the activity of cyclooxygenase (COX)-1 was inhibited by CSE with an IC 50 value of 1.07 ± 0.15% in an uncompetitive manner. In contrast, the activity of TX synthase was enhanced by CSE. The results indicate that CSE inhibits COX-1 activity and thereby decreases TXA 2 production in platelets, leading to inhibition of platelet aggregation.


Preparation and photoactivation of caged fluorophores and caged proteins using a new class of heterobifunctional, photocleavable cross-linking reagents.
The design, synthesis, and spectroscopic and chemical properties of four members of a new class of heterobifunctional photocleavable (caged) cross-linking reagents were described. One of the two reactive groups of the cross-linker reacted with amino groups to form the corresponding photolabile carbamates. Amino group containing compounds or proteins caged with these reagents can be coupled through the thiol reactive oxirane group of the cross-linker to a different biomolecule or to a thiol-derivatized surface. The 3,4-dimethoxy-6-nitrophenyl photoisomerization group of the reagent was physically and chemically isolated from the cross-linking functionality, and the high extinction coefficient and red-shifted action spectrum of this chromophore make it suitable for photoactivation applications of caged compounds on surfaces or in living cells. The bifunctional, photocleavable cross-linking reagents were used to prepare a thiol reactive caged rhodamine 110. The new reagents and conjugation procedures described may be used as part of a general procedure to cage the activity of proteins by physically masking binding sites.


Indirect cavernous carotid fistula in a 12-year-old girl.
We present a very rare case of indirect cavernous carotid fistula (CCF) in a 12-year-old girl. Indirect CCF is extremely rare in the paediatric population. A 12-year-old girl presented with a 7-month history of frontal headaches and intermittent left-sided proptosis. On examination, she had dilated and engorged scleral veins on the left eye, mild dysdiadochokinesia and past pointing on the left side. A brain computer tomography with contrast, brain magnetic resonance imaging (MRI) and interventional radiography (IR) cerebral angiogram confirmed the diagnosis of CCF. The CCF was embolized and a follow-up brain MRI and an IR cerebral angiogram were conducted over the course of 8 months that revealed no evidence of residual CCF. CCF, though rare in the paediatric population, should be highly considered in the differential diagnosis when dilated scleral veins, proptosis and dysdiadokinesis are present in the clinical setting. Prompt treatment has good prognostic results.


Exploration of the visibility of patient input in final recommendation documentation for three health technology assessment bodies.
Health technology assessment (HTA) recommendations informed by patient concerns are seen to ensure democracy and legitimacy. We explored how written and oral patient involvement in two HTAs was reported on in publicly available final recommendations and discussion summaries of appraisal committees from three HTA bodies. We aimed to gain insights into how patient input was utilized by appraisal committees to better understand the goals of patient involvement and how these are being achieved. In each of the three HTA bodies, templated submission questionnaires provide a formal process for seeking written patient group input. Additionally, the National Institute for Health and Care Excellence (NICE) selects patient experts to provide a templated submission and attend appraisal committee meetings. For Scottish Medicines Consortium (SMC), a patient advocate and clinician combined meeting (PACE) discussed the cancer drug, referred to in the final recommendation. The discussion summaries of all appraisal committees contained references to patient involvement. Where two mechanisms for patient involvement were provided, oral input from the expert patients and PACE were more clearly documented than information from written patient group submissions. NICE reports focused on the perspective of the patient expert. The SMC report highlighted feedback from the PACE throughout. We suggest that the lack of clear reporting on the use of patient group input in deliberations and therefore accountability to patient groups limits progress in patient involvement in HTA. Patient groups may therefore not have a clear understanding of what information they can best provide to inform deliberations, and in reporting back to members.


Effect of acetaldehyde and cyanamide on the metabolism of formaldehyde by hepatocytes, mitochondria, and soluble supernatant from rat liver.
Formaldehyde can be metabolized primarily by two different pathways, one involving oxidation by the low-Km mitochondrial aldehyde dehydrogenase, the other involving a specific, glutathione-dependent, formaldehyde dehydrogenase. To estimate the roles played by each enzyme in formaldehyde metabolism by rat hepatocytes, experiments with acetaldehyde and cyanamide, a potent inhibitor of the low-Km aldehyde dehydrogenase were carried out. The glutathione-dependent oxidation of formaldehyde by 100,000g rat liver supernatant fractions was not affected by either acetaldehyde or by cyanamide. By contrast, the uptake of formaldehyde by intact mitochondria was inhibited 75 to 90% by cyanamide. Acetaldehyde inhibited the uptake of formaldehyde by mitochondria in a competitive fashion. Formaldehyde was a weak inhibitor of the oxidation of acetaldehyde by mitochondria, suggesting that, relative to formaldehyde, acetaldehyde was a preferred substrate. In isolated hepatocytes, cyanamide, which inhibited the oxidation of acetaldehyde by 75 to 90%, produced only 30 to 50% inhibition of formaldehyde uptake by cells as well as of the production of 14CO2 and of formate from [14C]formaldehyde. The extent of inhibition by cyanamide was the same as that produced by acetaldehyde (30-40%). In the presence of cyanamide, acetaldehyde was no longer inhibitory, suggesting that acetaldehyde and cyanamide may act at the same site(s) and inhibit the same formaldehyde-oxidizing enzyme system. These results suggest that, in rat hepatocytes, formaldehyde is oxidized by cyanamide- and acetaldehyde-sensitive (low-Km aldehyde dehydrogenase) and insensitive (formaldehyde dehydrogenase) reactions, and that both enzymes appear to contribute about equally toward the overall metabolism of formaldehyde.


A novel Wnt5a-Frizzled4 signaling pathway mediates activity-independent dendrite morphogenesis via the distal PDZ motif of Frizzled 4.
The morphology of the dendritic tree is critical to neuronal function and neural circuit wiring. Several Wnt family members have been demonstrated to play important roles in dendrite development. However, the Wnt receptors responsible for mediating this process remain largely elusive. Using primary hippocampal neuronal cultures as a model system, we report that Frizzled4 (Fzd4), a member of the Fzd family of Wnt receptors, specifically signals downstream of Wnt5a to promote dendrite branching and growth. Interestingly, the less conserved distal PDZ binding motif of Fzd4, and not its conserved proximal Dvl-interacting PDZ motif, is required for mediating this effect. We further showed that Dvl signaled parallel to and independent of Fzd4 in promoting dendrite growth. Unlike most previously described pathways, Wnt5a/Fzd4 signaling promoted dendrite development in an activity-independent and autocrine fashion. Together, these results provide the first identification of a Wnt receptor for regulating dendrite development in the mammalian system, and demonstrate a novel function of the distal PDZ motif of Fzd4 in dendrite morphogenesis, thereby expanding our knowledge of the complex roles of Wnt signaling in neural development.


The tumor suppressor gene H-Rev107 functions as a novel Ca2+-independent cytosolic phospholipase A1/2 of the thiol hydrolase type.
H-Rev107 is a protein that was previously cloned as a negative regulator of proto-oncogene Ras and classified as a class II tumor suppressor. Its structural similarity to lecithin retinol acyltransferase and Ca2+-independent phosphatidylethanolamine (PE) N-acyltransferase led us to analyze H-Rev107 as an enzyme involved in phospholipid metabolism. Here, we show that recombinant H-Rev107s from rat, human, and mouse possess phospholipase (PL) A1 or A2 activity toward phosphatidylcholine (PC). Further examination with purified recombinant protein revealed that H-Rev107 functions as a cytosolic Ca2+-independent PLA(1/2) for PC and PE with higher PLA1 activity than PLA2 activity. Dithiothreitol and iodoacetic acid exhibited stimulatory and inhibitory effects, respectively. Histidine-21 and cysteine-111 of rat H-Rev107 were presumed to form a catalytic dyad based on database analysis, and their single mutants were totally inactive. These results suggested that H-Rev107 is a hydrolase of the thiol type. The N-terminal proline-rich and C-terminal hydrophobic domains of H-Rev107 were earlier reported to be responsible for the regulation of cell proliferation. Analysis of deletion mutants indicated that these domains are also catalytically essential, suggesting relevance of the catalytic activity to the anti-proliferative activity.


In vitro continuous amperometry with a diamond microelectrode coupled with video microscopy for simultaneously monitoring endogenous norepinephrine and its effect on the contractile response of a rat mesenteric artery.
Continuous amperometry with a diamond microelectrode and video microscopy were used to record (in vitro) endogenous norepinephrine release simultaneously with the evoked contractile response of a mesenteric artery from a healthy Sprague Dawley rat. Norepinephrine (NE) is a vasoconstricting neurotransmitter released from sympathetic nerves that innervate the smooth muscle cell layers surrounding arteries and veins. Using these two techniques along with several drugs, the NE released at sympathetic neuroeffector junctions nearby the microelectrode was measured as an oxidation current. Key to the amperometric measurement was the use of a diamond microelectrode because of the response sensitivity, reproducibility, and stability it provided. NE release was elicited by electrical stimulation at frequencies between 1 and 60 Hz, with a maximum response seen at 20 Hz. Confirmation that the oxidation current was, in fact, associated with endogenous NE came from the results of several drugs. Tetrodotoxin (TTX, 0.3 microM), a voltage-dependent sodium channel antagonist that blocks nerve conduction, abolished both the oxidation current and the arterial constriction. The alpha(2)-adrenergic autoreceptor antagonist, yohimbine (1.0 microM), caused an increase in the oxidation current and the corresponding constriction. The addition of cocaine (10 microM), an antagonist that inhibits neuronal NE reuptake, caused both the oxidation current and the contractile response to increase. These results, combined with the fact that the hydrodynamic voltammetric E(1/2) for endogenous NE was identical to that for a standard solution, confirmed that the oxidation current was due to NE and that this compound caused, at least in part, the contractile response. The results demonstrate that continuous amperometric monitoring of NE with a diamond microelectrode and video imaging of vascular tone allow real time local measurement of the temporal relationship between nerve-stimulated NE release and arterial constriction.


Citizen participation on regulatory boards.
This article examines the relationship between regulatory board function and citizen participation. The research indicates that public members generally prefer advisory boards, while provider members prefer quasi-judicial bodies. Implications of these findings for structuring citizen participation in the regulatory process are examined.


Randomized comparison of postoperative short-term and mid-term complications between T-tube and primary closure after CBD exploration.
To compare the postoperative short-term and mid-term complications in patients who underwent CBD exploration and closure by using T-tube or primary closure. Prospective randomized clinical trial. Hepatobiliary Department of First Affiliated Hospital of Xinjiang Medical University, Urumqi, China, from August 2009 to March 2013. A total of 148 consecutive patients with Common Bile Duct Stones (CBDS) and CBD dilation were enrolled in this randomized study to undergo open cholecystectomy with CBD exploration. Pre-operative findings, postoperative short-term complications, postoperative follow-up (mid-term), and hospital stay were recorded and analyzed. A T-tube was inserted in 76 (51.35%) patients and the primary closure was done in 72 (48.64%) patients. There were no differences in the demographic characteristics and clinical presentations between the two groups. Compared with the T-tube group 8.97 ± 1.629 days, the postoperative stay in primary closure 5.34 ± 1.25 days was significantly shorter (p < 0.01). The incidence of overall postoperative short-term complications and mid-term complications were statistically but not significantly lower in the primary closure group (9.7%) than that in T-tube group (17.10%, p=0.189). Complications in the primary closure group were lower than that in T-tube group but there was no significant statistical difference. So during open surgery for CBD stones, primary closure of CBD appeared safe and effective with shorter hospital stays and less complications.


A redox-activated theranostic nanoagent: toward multi-mode imaging guided chemo-photothermal therapy.
Development of tumor microenvironment responsive and modulating theranostic nano-systems is of great importance for specific and efficient cancer therapy. Herein, we report a redox-sensitive nanoagent combining manganese dioxide (MnO2) and gold nanoshell coated silicon nanoparticles for synergistic chemo-photothermal therapy of hypoxia solid tumors. In highly reducing tumor tissues, the outer MnO2 nanosheet with the loaded drug would be dissociated by intracellular glutathione (GSH), resulting in on-demand drug release, as well as generating Mn2+ ions which provided high contrast magnetic resonance imaging (MRI), and fluorescence imaging (FI) in vitro and in vivo. While upon near-infrared (NIR) light irradiation, the gold nanoshell modulated the hypoxic tumor microenvironment via increasing blood flow, achieving enhanced photothermal therapy (PTT) and chemotherapy. After tail vein injection into tumor-bearing mice and monitoring in real time, the intelligent redox-activated nanoagent exhibited high tumor accumulation and powerful synergistic chemo-photothermal therapy efficiency. The proposed work developed a noninvasive strategy to modulate the tumor microenvironment and enhance the anticancer therapeutic effect. We believe that this single nano-platform exhibits promising potential as a comprehensive theranostic agent to enhance the efficacies of synergistic cancer therapy.


Treatment of reticulum cell sarcoma in SJL/J mice with Tween 80.
Tween 80 (polyoxyethylenesorbitan monooleate) was found to have anticancer activity in the SJL/J tumor system. Investigations to evaluate variables of importance in treatment revealed a loss of inhibitory influence when Tween 80 was administered by the subcutaneous rather than the intraperitoneal route of injection. Age at the onset of treatment was also a factor with significant reductions in incidences of reticulum cell sarcoma when treatment was initiated at 30 or at 40 weeks, but not at 20 weeks of age. Optimal inhibitory effects were achieved with concentrations of 5% Tween 80 (0.2 ml/mouse) or 10% Tween 80 (0.1 ml/mouse). No differences in inhibitory influence on SJL/J tumorigenesis were observed with variation in the frequency of treatment (biweekly, weekly or twice weekly injections).


[Effect of ursodeoxycholic acid with traditional Chinese medicine on biochemical response in patients with primary biliary cholangitis: a real-world cohort study].
Objective: To examine the effects of ursodeoxycholic acid combined with Traditional Chinese Medicine on biochemical response in patients with primary biliary cholangitis. Methods: According to the method of receiving treatment, 197 patients with primary biliary cholangitis were divided into Traditional Chinese Medicine plus Western medicine group (93 cases, 47.2%) and Western medicine group (104 cases, 52.8%). From the baseline date, the combined group was treated with ursodeoxycholic acid plus traditional Chinese medicine decoction or Chinese patent medicine for at least one month and the Western medicine group simply took ursodeoxycholic acid . Additionally, Traditional Chinese medicine decoction prescriptions were mainly Xiaoyaosan and Yinchenhao. Chinese patent medicine were restricted to Biejia Ruangan tablets, Fuzheng Huayu capsules, Jiuweigantai capsules and Yinzhihuang capsules, which were used to treat liver fibrosis and cholestasis. The primary efficacy endpoint was defined as ALP level < 1.67 × ULN and ≥ 15% decrease in ALP with baseline level and TBIL≤ULN after 12 months of treatment. Results: The overall biochemical response rate of patients was 35.0% (69/197). The response rate of TCM+ Western medicine group was 43.0% (40/93), and that of Western medicine group was 27.9% (29/104). The difference between the two groups was statistically significant (χ(2) = 4.936, P < 0.05). Further analysis showed that the Chinese and Western medicine group was superior to the Western medicine group alone in reducing γ-glutamyltransferase (GGT) and TBiL [the median decline were GGT: 160.1 U/L and 111.3 U/L (Z = -2.474, P < 0.05), TBiL: 5.2 umol/l and 3.1 umol/l (Z = -2.125, P < 0.05)]. Conclusion: UDCA combined with TCM therapy can remarkably improve the biochemical response rate in patients with PBC and distinctly decrease the TBIL and GGT levels than UDCA monotherapy.


Oscillatory EEG dynamics underlying automatic chunking during sentence processing.
Sentences are easier to remember than random word sequences, likely because linguistic regularities facilitate chunking of words into meaningful groups. The present electroencephalography study investigated the neural oscillations modulated by this so-called sentence superiority effect during the encoding and maintenance of sentence fragments versus word lists. We hypothesized a chunking-related modulation of neural processing during the encoding and retention of sentences (i.e., sentence fragments) as compared to word lists. Time-frequency analysis revealed a two-fold oscillatory pattern for the memorization of sentences: Sentence encoding was accompanied by higher delta amplitude (4Hz), originating both from regions processing syntax as well as semantics (bilateral superior/middle temporal regions and fusiform gyrus). Subsequent sentence retention was reflected in decreased theta (6Hz) and beta/gamma (27-32Hz) amplitude instead. Notably, whether participants simply read or properly memorized the sentences did not impact chunking-related activity during encoding. Therefore, we argue that the sentence superiority effect is grounded in highly automatized language processing mechanisms, which generate meaningful memory chunks irrespective of task demands.


Internalization of the human CRF receptor 1 is independent of classical phosphorylation sites and of beta-arrestin 1 recruitment.
The corticotropin releasing factor receptor 1 (CRFR1) belongs to the superfamily of G-protein coupled receptors. Though CRF is involved in the aetiology of several stress-related disorders, including depression and anxiety, details of CRFR1 regulation such as internalization remain uncharacterized. In the present study, agonist-induced internalization of CRFR1 in HEK293 cells was visualized by confocal microscopy and quantified using the radioligand 125I-labelled sauvagine. Recruitment of beta-arrestin 1 in response to receptor activation was demonstrated by confocal microscopy. The extent of 125I-labelled sauvagine stimulated internalization was significantly impaired by sucrose, indicating the involvement of clathrin-coated pits. No effect on the extent of internalization was observed in the presence of the second messenger dependent kinase inhibitors H-89 and staurosporine, indicating that cAMP-dependent protein kinase and protein kinase C are not prerequisites for CRFR1 internalization. Surprisingly, deletion of all putative phosphorylation sites in the C-terminal tail, as well as a cluster of putative phosphorylation sites in the third intracellular loop, did not affect receptor internalization. However, these mutations almost abolished the recruitment of beta-arrestin 1 following receptor activation. In conclusion, we demonstrate that CRFR1 internalization is independent of phosphorylation sites in the C-terminal tail and third intracellular loop, and the degree of beta-arrestin 1 recruitment.


Dental implant success-failure analysis: a concept of implant vulnerability.
This article shows the factors of importance in the long-term success and failure of oral implants based on literature review. Many factors are attributed to the failure of dental implants. The critical components leading to early and late implant failures are evaluated. The behavior of natural teeth and implants is compared in healthy and unfavorable local and systemic conditions. Similarities and differences among dental implants, healthy natural teeth, and ankylosed teeth are examined. Based on this comparison, the author attempts to draw a conclusion on the vulnerability of dental implants and their prognosis. The importance of ongoing clinical supervision of a patient's implant condition with a good recall program and the necessity to accumulate clinical data concerning implant failures over an extended period of time in a standardized manner are emphasized. It is also suggested that implant practitioners avoid giving guarantees of long-term implant success to their patients.


Fiber-optic liquid level sensor based on coupling optical path length variation.
The concept for a new and simple fiber-optic liquid level sensor is presented and experimental results are shown to demonstrate the principle. The sensing principle is based on light intensity modulation when rising and falling mode of liquid level causes coupling optical path distance variation between two optical fibers. Near continuous mode of liquid level variation could be monitored with resolution as low as 1 mm can be measured in the length scale of 25 cm.


Family Functioning and High Risk Adolescents' Aggressive Behavior: Examining Effects by Ethnicity.
The relationship between family functioning and adolescents' physical aggression has been well established, but whether these relationships might differ by ethnicity has received less attention. Ethnic variations may be important for targeting prevention programs to specific youth and families. This study examined the longitudinal relationship between family cohesion, parental monitoring, and physical aggression using data from the Multisite Violence Prevention Project sample of high-risk youth (elevated aggression). Participants were 1,232 high-risk middle school students (65% male; 70% African American; 15% Hispanic). Meaningful demographic variations were identified. After controlling for intervention condition and study site, family cohesion was significantly negatively related to physical aggression, more so for Hispanic youth. Parental monitoring was negatively associated with physical aggression for African American youth only. Our findings point to the importance of developing culturally sensitive family interventions to prevent physical aggression in middle school.


The use of a neck brace does not influence visual vertical perception.
Subjective visual vertical (SVV) evaluates the individual's capacity to determine the vertical orientation. Using a neck brace (NB) allow volunteers' heads fixation to reduce cephalic tilt during the exam, preventing compensatory ocular torsion and erroneous influence on SVV result. To analyze the influence of somatosensory inputs caused by a NB on the SVV. Thirty healthy volunteers performed static and dynamic SVV: six measures with and six without the NB. The mean values for static SVV were -0.075º±1.15º without NB and -0.372º±1.21º with NB. For dynamic SVV in clockwise direction were 1.73º±2.31º without NB and 1.53º±1.80º with NB. For dynamic SVV in counterclockwise direction was -1.50º±2.44º without NB and -1.11º±2.46º with NB. Differences between measurements with and without the NB were not statistically significant. Although the neck has many sensory receptors, the use of a NB does not provide sufficient afferent input to change healthy subjects' perception of visual verticality.


Comparison of incisional bursting strength of a bidirectional absorbable knotless suture material versus a standard continuous absorbable suture material for closure of the equine linea alba.
To evaluate the use of bidirectional knotless barbed suture material for closure of the equine linea alba. Laboratory study. Adult light horse cadavers (n = 24). A 25 cm incision was made through the linea alba, and a 200 L polyurethane bladder was positioned within the abdomen. The linea alba was closed either using USP2/EP5 bidirectional polydioxanone barbed suture or USP2/EP5 standard polydioxanone suture in a simple continuous pattern. Closure time was recorded for each suture type. The bladder was air-insufflated at 40 L/min, and the pressure at body wall failure recorded. The length of suture used for wound closure and wound failure modes were recorded. Suture length, closure time, bursting pressure, and failure modes were compared using Welch-Aspin t-tests. The incisional bursting pressure was comparable between the two groups (p > .05). Less suture material (p < .01) was required with the barbed suture than the standard suture. Closure time was less for the barbed suture than the standard suture (p < .01). Suture failure was the main failure mode in both groups (83% cases). Closure of the equine linea alba using bidirectional barbed suture material reduced the amount of foreign material in the wound and decreased closure time without compromising incisional strength. Bidirectional barbed suture material could be considered as an alternative to standard suture materials for closure of the equine line alba.


Major depressive disorder is associated with abnormal interoceptive activity and functional connectivity in the insula.
Somatic complaints and altered interoceptive awareness are common features in the clinical presentation of major depressive disorder (MDD). Recently, neurobiological evidence has accumulated demonstrating that the insula is one of the primary cortical structures underlying interoceptive awareness. Abnormal interoceptive representation within the insula may thus contribute to the pathophysiology and symptomatology of MDD. We compared functional magnetic resonance imaging blood oxygenation level-dependent responses between 20 unmedicated adults with MDD and 20 healthy control participants during a task requiring attention to visceral interoceptive sensations and also assessed the relationship of this blood oxygenation level-dependent response to depression severity, as rated using the Hamilton Depression Rating Scale. Additionally, we examined between-group differences in insula resting-state functional connectivity and its relationship to Hamilton Depression Rating Scale ratings of depression severity. Relative to the healthy control subjects, unmedicated MDD subjects exhibited decreased activity bilaterally in the dorsal mid-insula cortex (dmIC) during interoception. Activity within the insula during the interoceptive attention task was negatively correlated with both depression severity and somatic symptom severity in depressed subjects. Major depressive disorder also was associated with greater resting-state functional connectivity between the dmIC and limbic brain regions implicated previously in MDD, including the amygdala, subgenual prefrontal cortex, and orbitofrontal cortex. Moreover, functional connectivity between these regions and the dmIC was positively correlated with depression severity. Major depressive disorder and the somatic symptoms of depression are associated with abnormal interoceptive representation within the insula.


[Inhibition of neovascularization of the eye by dietary factors exemplified by isoflavonoids].
Chronic malignant diseases with neovascularization sometimes seem to improve when an exclusively plant-based diet is followed. In order to identify antiangiogenic substances in such diets, inhibitory factors such as genistein were isolated. We investigated the antiangiogenic substance genistein with regard to the possibility of an inhibitory effect on corneal angiogenesis in vivo. Corneal neovascularization was experimentally induced in NZW rabbits by the use of methylcellulose discs loaded with 250 ng basic fibroblast growth factor (bFGF). Blood vessels grew from the limbus towards the pellet and were quantified under the microscope. Genistein was injected subconjunctivally (0.04 mg genistein/day). All eyes which received genistein subconjunctivally showed a statistically significant reduction of blood vessels at the limbus (from 63 +/- 40 vessels to 36 +/- 11 vessels; P = 0.001). Vascularized areas in the eyes treated with genistein also decreased, from 21.4 +/- 6.7 mm2 to 10.4 +/- 5.0 mm2 (P < 0.0001). Our results show that components of a plant-based diet, such as genistein, inhibit ocular neovascularization in vivo. The genistein level rises significantly in human urine following ingestion of soy products, for example. Therefore, certain vegetarian diets could have a positive effect on ocular diseases characterized by progressive neovascularization.


[Total arterial bypass operations with complete sternotomy in the awake patient].
In minimally invasive coronary artery bypass surgery beating heart procedures and operations via limited incisions became more popular and are routinely performed in many centers. An additional approach to minimize general trauma is avoidance of general anesthesia endotracheal intubation. Between March and June 2001, 14 spontaneously breathing patients underwent coronary artery bypass grafting on the beating heart without general anesthesia. Intra- and postoperative analgesia management was performed using continuous epidural infusion of local anesthetics at level Th2-Th3. Single (n = 8) as well as double (n = 5) and triple (n = 1) bypass grafting was performed with the off pump technique. Surgical access to the chest cavity was created via partial (n = 8) or complete sternotomy (n = 6). Twelve patients remained awake throughout the procedure; 2 patients required secondary intubation due to incomplete sensory block and pneumothorax. Operating time was 94 +/- 18 minutes. Intermediate care monitoring time amounted to 4.8 +/- 0.6 hours. No surgery-related complications or myocardial infarction occurred. Postoperative angiography reviewed good graft function in all patients. Our preliminary experience shows that complete surgical revascularization is safe and feasible without endotracheal intubation and general anesthesia. Thus, invasiveness in cardiac surgery is further reduced with less need for intensive care unit monitoring enabling faster mobilization and recovery.


RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist.
Increased synthesis of Apolipoprotein A-I (ApoA-I) and HDL is believed to provide a new approach to treating atherosclerosis through the stimulation of reverse cholesterol transport. RVX-208 increases the production of ApoA-I in hepatocytes in vitro, and in vivo in monkeys and humans, which results in increased HDL-C, but the molecular target was not previously reported. Using binding assays and X-ray crystallography, we now show that RVX-208 selectively binds to bromodomains of the BET (Bromodomain and Extra Terminal) family, competing for a site bound by the endogenous ligand, acetylated lysine, and that this accounts for its pharmacological activity. siRNA experiments further suggest that induction of ApoA-I mRNA is mediated by BET family member BRD4. These data indicate that RVX-208 increases ApoA-I production through an epigenetic mechanism and suggests that BET inhibition may be a promising new approach to the treatment of atherosclerosis.


Predictive Value of Carcinoembryonic and Carbohydrate Antigen 19-9 Related to Some Clinical, Endoscopic and Histological Colorectal Cancer Characteristics.
Colorectal cancer (CRC) is an important oncological and public health problem worldwide, including Serbia. Unfortunately, half of the patients are recognized in an advanced stage of the disease, therefore, early detection through specific tumor biomarkers, such as carcinoembryonic (CEA) and carbohydrate antigen 19-9 (CA 19-9), is the only way to cope with CRC expansion. Our cross-sectional study evaluated the influence of some clinical, endoscopic and histological characteristics of CRC on CEA and CA 19-9 serum levels, to determine whether these biomarkers could be related to CRC detection. The study included 372 participants: 181 suffered from CRC and 191 participants were controls. Endoscopic and histological examinations were used for CRC diagnosis, while additional ultrasound and abdominal computerised tomography imaging were used for staging the disease. Measurement of CEA and CA 19-9 was performed after CRC confirmation. Age, gender, tumor localization, macro-morphological and histological characteristics did not influence biomarkers serum levels. Both were significantly higher (p<0.01) in patients with Dukes D stage of CRC compared with controls. Sensitivity (76.8%) and specificity (76.6%) of CEA alone were higher than for CA 19-9, but with no statistical significance. Furthermore, sensitivity of CEA alone in the Dukes A/B group was similar to the entire CRC patient group. Although not recommended as a screening method for the general population, elevated values of each biomarker indicate further diagnostic procedures and their simultaneous testing can improve the diagnostic sensitivity in early detection of CRC, as shown by the united analysis (AUC 0.842).


THE EVOLUTION OF REPRODUCTIVE ISOLATION AS A CORRELATED CHARACTER UNDER SYMPATRIC CONDITIONS: EXPERIMENTAL EVIDENCE.
A set of experiments is described that tests the general hypothesis that sympatric speciation is genetically feasible whenever reproductive isolation evolves indirectly as a correlated character. We specifically test the hypothesis that disruptive selection on habitat preference can lead to sympatric speciation when individuals mate locally within their selected habitat. Drosophila melanogaster was used as a model system. A 35-generation experiment using a complex habitat maze led to complete reproductive isolation between subpopulations using different spatiotemporal habitats. The reproductive isolation that developed over the course of the experiment was a result of offspring returning to mate in the habitat type selected by their parents, i.e., a gradual breakdown in migration between habitats.