Neostigmine interactions with non steroidal anti-inflammatory drugs.
1. The common mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) is the inhibition of the enzyme cyclo-oxygenase (COX), however, this inhibition is not enough to completely account for the efficacy of these agents in several models of acute pain. 2. It has been demonstrated that cholinergic agents can induce antinociception, but the nature of the interaction between these agents and NSAIDs drugs has not been studied. The present work evaluates, by isobolographic analysis, the interactions between the cholinergic indirect agonist neostigmine (NEO) and NSAIDs drugs, using a chemical algesiometric test. 3. Intraperitoneal (i.p.) or intrathecal (i.t.) administration of NEO and of the different NSAIDs produced dose-dependent antinociception in the acetic acid writhing test of the mouse. 4. The i.p. or i.t. co-administration of fixed ratios of ED(50) fractions of NSAIDs and NEO, resulted to be synergistic or supra-additive for the combinations ketoprofen (KETO) and NEO, paracetamol (PARA) and NEO) and diclofenac (DICLO) and NEO administered i.p. However, the same combinations administered i.t. were only additive. In addition, the combinations meloxicam (MELO) and NEO and piroxicam (PIRO) and NEO, administered either i.p. or i.t., were additive. 5. The results suggest that the co-administration of NEO with some NSAIDs (e.g. KETO, PARA or DICLO) resulted in a synergistic interaction, which may provide evidence of supraspinal antinociception modulation by the increased acetylcholine concentration in the synaptic cleft of cholinergic interneurons. The interaction obtained between neostigmine and the NSAIDs could carry important clinical implications.


THIRD TRIMESTER ULTRASOUND SCAN COMBINED WITH A CLINICAL METHOD FOR ACCURATE BIRTHWEIGHT PREDICTION AT TERM: A COHORT STUDY IN SPAIN.
To develop and assess an equation based on maternal clinical parameters and third trimester ultrasound biometry (combined method), and compare it with ultrasound-estimated foetal weight (EFW) calculated using the Hadlock 2 formula. Cohort study. A total of 1,224 women with singleton pregnancies who had undergone foetal ultrasound scanning (USS) at 34 weeks were recruited. The study was conducted at a reference center in Valencia (Spain) between January and December 2016. A gestation-adjusted projection (GAP) method was applied to estimated foetal-weight-for-gestational-age by foetal gender at delivery (EFWa). A multivariate regression was created to estimate foetal weight at term (EFWmr) using anthropometric, demographic, ultrasonographic and obstetric-neonatal variables. EFWa and EFWmr were calculated and compared with actual birthweight. The proportion for EFWmr within <10% of actual birthweight was greater than EFWa (82% vs. 65%, p<0.001). The mean relative error in foetal-weight predictions by using EFWmr was reduced from 6.7% to 0.9% (difference 5.7% 95% CI: 5.4 to 6.0) paired t-test p<0.001, significantly improving the accuracy attainable with USS. The EFWmr outperformed the GAP method in predicting birthweight, within 1% relative error. For new- borns <2,500 g, the proportion of estimates within <10% of the actual birthweight for the EFWmr was greater than that of the EFWa (20.4 vs. 16.3%, p=0.005). For babies with normal birthweight (2,500-3,999 g), EFWmr was a better predictor of birthweight than EFWa (84.5 vs. 65.7%, p<0.001). Mathematical modelling to predict birthweight improves third trimester routine ultrasound measurement to estimate neonatal weight at term.


Electrophysiological signatures of phonological and semantic maintenance in sentence repetition.
Verbal short-term memory comprises resources for phonological rehearsal, which have been characterized anatomically, and for maintenance of semantic information, which are less understood. Sentence repetition tasks tap both processes interactively. To distinguish brain activity involved in phonological vs. semantic maintenance, we recorded magnetoencephalography during a sentence repetition task, incorporating three manipulations emphasizing one mechanism over the other. Participants heard sentences or word lists and attempted to repeat them verbatim after a 5-second delay. After MEG, participants completed a cued recall task testing how much they remembered of each sentence. Greater semantic engagement relative to phonological rehearsal was hypothesized for 1) sentences vs. word lists, 2) concrete vs. abstract sentences, and 3) well recalled vs. poorly recalled sentences. During auditory perception and the memory delay period, we found highly left-lateralized activation in the form of 8-30 Hz event-related desynchronization. Compared to abstract sentences, concrete sentences recruited posterior temporal cortex bilaterally, demonstrating a neural signature for the engagement of visual imagery in sentence maintenance. Maintenance of arbitrary word lists recruited right hemisphere dorsal regions, reflecting increased demands on phonological rehearsal. Sentences that were ultimately poorly recalled in the post-test also elicited extra right hemisphere activation when they were held in short-term memory, suggesting increased demands on phonological resources. Frontal midline theta oscillations also reflected phonological rather than semantic demand, being increased for word lists and poorly recalled sentences. These findings highlight distinct neural resources for phonological and semantic maintenance, with phonological maintenance associated with stronger oscillatory modulations.


Early hospital readmission and survival in patients with cirrhosis: A population-based study.
Readmission in patients with cirrhosis is common. We aimed to determine the association between early hospital readmission and survival in the general population of patients with cirrhosis. This retrospective cohort study used routinely collected health care data from Ontario. We identified adults with cirrhosis using a validated case definition, and included those with at least one hospital admission between 1992 and 2016 resulting in discharge. Patients were classified into two groups based on timing of readmission after index admission: 1) ≤90 days, or 2) >90 days or no readmission. We described overall survival (OS) 90 days after the index hospitalization by readmission status using Kaplan-Meier curves and the log-rank test. The association between readmission and OS was evaluated using a multivariate Cox proportional hazards regression model. Our study included 115,081 patients. The median OS was shorter in patients readmitted in ≤90 days (4.1 years, IQR 0.9, 13.1) compared with those readmitted in >90 days or not readmitted during the study period (9.6 years, IQR 3.2, 21.9, p <0.001). Adjusting for potential confounders, those readmitted in ≤90 days had a higher hazard of death than those not readmitted (hazard ratio [HR] 1.56, 95% CI 1.53 to 1.59, p <0.001). Early readmission in patients with cirrhosis is a strong predictor of decreased OS. Our results suggest that patients with cirrhosis who have an early readmission should be further studied to determine whether this risk is modifiable. They can also be used to discuss long-term prognosis with patients and family members.


Severe hypercalcemia associated with Williams syndrome successfully treated with pamidronate infusion therapy.
Infantile hypercalcemia becomes manifest in 15% of patients with Williams syndrome (WS) and generally is not clinically severe. However, some patients with WS can have severe hypercalcemia and do not respond well to traditional therapies. Recently, pamidronate has been used in the treatment of childhood hypercalcemia associated with many disorders, but there is little experience with the treatment of hypercalcemia with bisphosphonates in patients with WS. We present a 17-month-old female patient, who had been diagnosed as WS by genetic analysis, admitted to our clinic for the investigation of severe hypercalcemia (4.02 mmol/L). Because the patient did not respond very well to fluid administration, furosemide infusion, and dietary calcium restriction, pamidronate infusion was performed and calcium levels returned to normal within 2 days. This case report is presented to point out that pamidronate therapy seems to be a safe and efficient way of treating life-threatening hypercalcemia in WS.


Efficacy of chromoendoscopy with indigocarmine for the detection of ascending colon and cecum lesions.
Previous data suggest that routine chromoendoscopy may increase detection rates of diminutive or flat lesions. The aim of this study was to evaluate the usefulness of chromoendoscopy in the ascending colon and cecum, where the incidence of diminutive or flat lesions is high. Between June 2006 and September 2006, a total of 316 consecutive patients were prospectively enrolled in this study. The patients were randomly divided into two groups (control group: 158 patients, chromoendoscopy group: 158 patients). If the quality of bowel preparation was poor or cecal intubation was not achieved, the patient was excluded from the study. In the control group, the ascending colon and cecum were observed twice without chromoendoscopy. In the chromoendoscopy group, the cecum and ascending colon were reinspected following staining with indigocarmine solution after conventional examination of the cecum and ascending colon. Finally, a total of 151 and 149 patients were enrolled in the control and chromoendoscopy groups, respectively. The chromoendoscopy group differed significantly from the control group in the number of additionally detected polyps (control: 14 versus chromoendoscopy: 62, p<0.001) and in the number of patients with additionally detected polyps (control: 12 versus chromoendoscopy: 50, p<0.001). Multivariate analysis revealed that detection of polyps after indigocarmine spraying was independently associated with a high body mass index and older age (p = 0.045 and p = 0.006, respectively). With chromoendoscopy using indigocarmine, more polyps can be detected in the ascending colon and cecum as compared with using conventional colonoscopy.


Varieties of learning automata: an overview.
Automata models of learning systems introduced in the 1960s were popularized as learning automata (LA) in a survey paper by Narendra and Thathachar (1974). Since then, there have been many fundamental advances in the theory as well as applications of these learning models. In the past few years, the structure of LA, has been modified in several directions to suit different applications. Concepts such as parameterized learning automata (PLA), generalized learning,automata (GLA), and continuous action-set learning automata (CALA) have been proposed, analyzed, and applied to solve many significant learning problems. Furthermore, groups of LA forming teams and feedforward networks have been shown to converge to desired solutions under appropriate learning algorithms. Modules of LA have been used for parallel operation with consequent increase in speed of convergence. All of these concepts and results are relatively new and are scattered in technical literature. An attempt has been made in this paper to bring together the main ideas involved in a unified framework and provide pointers to relevant references.


Influence of physical performance on elderly mortality, functionality and life satisfaction: FIBRA's study data.
To verify the influence of physical performance on elderly mortality, functionality and life satisfaction. A follow-up was performed on 900 Brazilian non-hospitalized elderly in the period 2008-2016, in which 154 deaths from natural causes were included in the survival analysis. the worst grip strength (RR = 1.60; CI 95% = 1.15-2.23, p = 0.005) and gait speed (RR = 1.82; CI 95% = 1.30-2.55, p < 0.001) performances were associated with increased mortality risk. Age was a confounding factor for strength (RR = 1.06; CI 95% = 1.03-1.09, p < 0.001) and rheumatoid arthritis was a confounding factor for speed (RR = 2.02; CI 95% = 1.36-3.01, p < 0.001). The elderly with good physical performance realized more instrumental and advanced activities of daily living, and good gait performance had a significant effect on life satisfaction (F = 6.87, p = 0.009). good physical performance seems to be fundamental for longevity and for accomplishing daily tasks. Furthermore, good mobility can affect life satisfaction-related mechanisms.


Heat treatment of bovine colostrum: II. Effects on calf serum immunoglobulin, insulin, and IGF-I concentrations, and the serum proteome.
In-depth analysis of colostrum components has identified hundreds of proteins, but data are sparse regarding their systemic uptake in the newborn calf. Moreover, heat treatment may influence these colostral components and their absorption. Our objectives were to describe the serum proteome of newborn calves before and after colostrum feeding and the possible effects of colostral heat treatment. Newborn Holstein heifer calves (n = 22) were randomized within pair and fed heat-treated (n = 11; 60°C, 60 min) or raw (n = 11) colostrum at 8.5% of birth body weight by esophageal feeder within 1 h of birth. After the single colostrum feeding, calves were not fed until after the 8-h time point, when milk was offered free-choice. Blood samples were taken immediately before feeding (0 h), as well as 4, 8, and 24 h after feeding. Whole blood packed cell volume (%), serum Brix percentage, and plasma glucose concentrations were determined for all time points. Plasma insulin and insulin-like growth factor-I concentrations were determined by radioimmunoassay for selected time points. Serum IgA and IgG were measured by radial immunodiffusion at 24 h. The serum proteome was analyzed using nano-scale reverse-phase chromatography and tandem mass spectrometry (nano LC-MS/MS) in 0- and 8-h samples. For proteomics analysis, ratios of results for 8-h to 0-h samples were analyzed with false discovery rate adjustment. For all other outcomes, repeated-measures ANOVA was performed with the fixed effects of group, time, and their interaction, and random effect of pair. Serum Brix percentage and glucose concentrations increased over time and were independent of colostrum treatment. Serum IgG and IgA concentrations at 24 h did not differ between groups. Nano LC-MS/MS identified a total of 663 unique proteins in serum, of which 261 increased in abundance, whereas 67 decreased in abundance after feeding in both groups. Among serum proteins that increased in abundance and that were previously identified in colostrum, many belonged to those involved in immune response, coagulation, the classical complement pathway, or the antimicrobial peptide class of cathelicidins. Serum proteins that decreased in abundance and that were identified in colostrum belonged to the alternative complement pathway and the membrane attack complex. Thirty-eight proteins differed in calves that were fed heat-treated colostrum compared with those fed raw colostrum. Decreased abundances in calves fed heat-treated colostrum included several enzymes involved in glycolysis or glycogenolysis, whereas the incretin gastric inhibitory polypeptide and serum insulin were increased in this group. Our findings point to important innate immune defense pathways associated with colostrum ingestion in newborn calves. Furthermore, calves fed heat-treated colostrum showed differences in serum proteins and enzymes associated with carbohydrate metabolism.


Differences in the epidemiology of theileriosis on smallholder dairy farms in contrasting agro-ecological and grazing strata of highland Kenya.
A prospective cohort study was conducted in five purposively-sampled agro-ecological zone (AEZ)-grazing system strata in Murang'a District, Kenya, between March 1995 and June 1996. The study strata were selected based on a preliminary characterization study to represent the widest range of risks to East Coast fever (ECF) in the District and included zero-grazing and open-grazing farms. In total, 225 calves from 188 smallholder farms were examined from birth to 6 months of age and visited within the first 2 weeks of life and thereafter at bi-weekly intervals for up to 14 visits. The purpose of the study was to characterize the differences in epidemiology (risks of infection, morbidity and mortality) and potential control of ECF between the selected strata. Evidence of Theileria parva infection was assessed by increased antibody levels as measured in an indirect ELISA assay by the percent positivity (PP) of serum samples relative to a strong positive reference serum. Sero-conversion risks of T. parva were highest in the open-grazing strata. Antibody prevalence in adult cattle and ECF morbidity and mortality risks were also highest in open-grazing strata. While different, all five AEZ-grazing strata were considered to be endemically unstable for ECF. East Coast fever challenge was low in all zero-grazing strata and this challenge is likely to remain low due to continuing intensification of smallholder farming in the central highlands. In the open-grazing strata, there was higher challenge and a greater impact of ECF.


Key interactions in the trimolecular complex consisting of the rheumatoid arthritis-associated DRB1*04:01 molecule, the major glycosylated collagen II peptide and the T-cell receptor.
Rheumatoid arthritis (RA) is an autoimmune disease strongly associated with the major histocompatibility complex (MHC) class II allele DRB1*04:01, which encodes a protein that binds self-peptides for presentation to T cells. This study characterises the autoantigen-presenting function of DRB1*04:01 (HLA-DRA*01:01/HLA-DRB1*04:01) at a molecular level for prototypic T-cell determinants, focusing on a post-translationally modified collagen type II (Col2)-derived peptide. The crystal structures of DRB1*04:01 molecules in complex with the peptides HSP70289-306, citrullinated CILP982-996 and galactosylated Col2259-273 were determined on cocrystallisation. T cells specific for Col2259-273 were investigated in peripheral blood mononuclear cells from patients with DRB1*04:01-positive RA by cytofluorometric detection of the activation marker CD154 on peptide stimulation and binding of fluorescent DRB1*0401/Col2259-273 tetramer complexes. The cDNAs encoding the T-cell receptor (TCR) α-chains and β-chains were cloned from single-cell sorted tetramer-positive T cells and transferred via a lentiviral vector into TCR-deficient Jurkat 76 cells. The crystal structures identified peptide binding to DRB1*04:01 and potential side chain exposure to T cells. The main TCR recognition sites in Col2259-273 were lysine residues that can be galactosylated. RA T-cell responses to DRB1*04:01-presented Col2259-273 were dependent on peptide galactosylation at lysine 264. Dynamic molecular modelling of a functionally characterised Col2259-273-specific TCR complexed with DRB1*04:01/Col2259-273 provided evidence for differential allosteric T-cell recognition of glycosylated lysine 264. The MHC-peptide-TCR interactions elucidated in our study provide new molecular insights into recognition of a post-translationally modified RA T-cell determinant with a known dominant role in arthritogenic and tolerogenic responses in murine Col2-induced arthritis.


Tst-1, a member of the POU domain gene family, binds the promoter of the gene encoding the cell surface adhesion molecule P0.
Tst-1, a member of the POU domain gene family, is expressed in specific neurons and in myelinating glia in the mammalian nervous system. Bacterially expressed Tst-1 binds specifically to the promoter of the gene encoding myelin protein P0, a Schwann cell surface adhesion molecule. In cotransfection assays, Tst-1 can specifically repress the P0 promoter. The N-terminal part of Tst-1 protein is highly glycine- and alanine-rich, a structural feature shared by the helix-loop-helix protein TFEB.


Urogenital tuberculosis: patient classification in seven different groups according to clinical and radiological presentation.
To describe and classify 80 cases of urogenital tuberculosis in seven groups of similar clinical and radiological presentation. 80 patients (56 males, 70%; median age 34 years; age range 12 to 75) with urogenital tuberculosis were retrospectively reviewed. The patients were divided in seven groups: 1) Bilateral parenchymatous renal lesions; 2) No or minimal changes on radiographic examination; 3) Unilateral renal tuberculosis; 4) Contracted bladder; 5) Contracted bladder with renal failure; 6) Tuberculosis on a transplanted kidney; 7) Isolated genital tuberculosis. 1) Seven (8.8%) patients had multiple bilateral parenchymatous renal lesions with fever and malaise, characteristic of miliary tuberculosis. Three of these patients had AIDS. 2) Six (7.5%) cases had an early diagnosis, with minimal or no radiographic lesions. Two did not have any urologic symptoms. 3) Twelve (15%) patients had unilateral renal tuberculosis with partial (1 case) or total non-function kidney. 4) Thirty-seven (46.3%) patients had contracted bladder associated with unilateral partial (1 case) or total non-function kidney. 5) Ten (12.5%) patients had end stage renal disease due to tuberculosis with contracted bladder. 6) Four (5.0%) patients had tuberculosis on a transplanted kidney, with graft loss in half the cases. 7) Four (5.0%) patients had prostate or epididymis tuberculosis without associated renal lesion. Urogenital tuberculosis is a destructive disease of the urogenital tract with variable clinical and radiographic presentation. A classification according to similar patterns correlating with disease stage is feasible although early diagnosis is the only prevention of the most severe forms.


Identification of an immune gene expression signature associated with favorable clinical features in Treg-enriched patient tumor samples.
Immune heterogeneity within the tumor microenvironment undoubtedly adds several layers of complexity to our understanding of drug sensitivity and patient prognosis across various cancer types. Within the tumor microenvironment, immunogenicity is a favorable clinical feature in part driven by the antitumor activity of CD8+ T cells. However, tumors often inhibit this antitumor activity by exploiting the suppressive function of regulatory T cells (Tregs), thus suppressing the adaptive immune response. Despite the seemingly intuitive immunosuppressive biology of Tregs, prognostic studies have produced contradictory results regarding the relationship between Treg enrichment and survival. We therefore analyzed RNA-seq data of Treg-enriched tumor samples to derive a pan-cancer gene signature able to help reconcile the inconsistent results of Treg studies, by better understanding the variable clinical association of Tregs across alternative tumor contexts. We show that increased expression of a 32-gene signature in Treg-enriched tumor samples (n = 135) is able to distinguish a cohort of patients associated with chemosensitivity and overall survival. This cohort is also enriched for CD8+ T cell abundance, as well as the antitumor M1 macrophage subtype. With a subsequent validation in a larger TCGA pool of Treg-enriched patients (n = 626), our results reveal a gene signature able to produce unsupervised clusters of Treg-enriched patients, with one cluster of patients uniquely representative of an immunogenic tumor microenvironment. Ultimately, these results support the proposed gene signature as a putative biomarker to identify certain Treg-enriched patients with immunogenic tumors that are more likely to be associated with features of favorable clinical outcome.


Twist2 promotes kidney cancer cell proliferation and invasion by regulating ITGA6 and CD44 expression in the ECM-receptor interaction pathway.
Twist2 is a member of the basic helix-loop-helix (bHLH) family and plays a critical role in tumorigenesis. Growing evidence has proven that Twist2 is involved in tumor progression; however, the role of Twist2 in human kidney cancer and its underlying mechanisms remain unclear. Real-time polymerase chain reaction and Western blot analysis were used to detect the expression of Twist2 in kidney cancer cells and tissues. Cell proliferation, cell cycle, apoptosis, migration, and invasion assay were analyzed using the Cell Count Kit-8, flow cytometry, wound healing, and Transwell analysis, respectively. In this study, we showed that Twist2 was upregulated in human kidney cancer tissues compared with normal kidney tissues. Twist2 promoted cell proliferation, inhibited cell apoptosis, and augmented cell migration and invasion in human kidney-cancer-derived cells in vitro. Twist2 also promoted tumor growth in vivo. Moreover, we found that the knockdown of Twist2 decreased the levels of ITGA6 and CD44 expression. This result indicates that Twist2 may promote migration and invasion of kidney cancer cells by regulating ITGA6 and CD44 expression. Therefore, our data demonstrated that Twist2 is involved in kidney cancer progression. The identification of the role of Twist2 in the migration and invasion of kidney cancer provides a potential appropriate treatment for human kidney cancer.


ZD7288 enhances long-term depression at early postnatal medial perforant path-granule cell synapses.
Hyperpolarization-activated, cyclic nucleotide-gated nonselective (HCN) channels modulate both membrane potential and resistance and play a significant role in synaptic plasticity. We compared the influence of HCN channels on long-term depression (LTD) at the medial perforant path-granule cell synapse in early postnatal (P9-15) and adult (P30-60) rats. LTD was elicited in P9-15 slices using low-frequency stimulation (LFS, 900 pulses, 1 Hz; 80 ± 4% of baseline). Application of the specific HCN channel blocker ZD7288 (10 μM) before LFS significantly enhanced LTD (62 ± 4%; P < 0.01), showing HCN channels restrain LTD induction. However, when ZD7288 was applied after LFS, LTD was similar to control values and significantly different from the values obtained with ZD7288 application before LFS (81 ± 5%; P < 0.01), indicating that HCN channels do not modulate LTD expression. LTD in slices from adult rats were only marginally lower compared to those in P9-15 slices (85 ± 6%), but bath application of ZD7288 prior to LFS resulted in the same amount of LTD (85 ± 5%). HCN channels in adult tissue hence lose their modulatory effect. In conclusion, we found that HCN channels at the medial perforant path-granule cell synapse compromise LFS-associated induction, but not expression of LTD in early postnatal, but not in adult, rats.


Effect of eicosapentaenoic acid and pitavastatin on electrophysiology and anticoagulant gene expression in mice with rapid atrial pacing.
Atrial remodeling is considered to be any persistent change in atrial structure or function, and is responsible for the development and perpetuation of atrial fibrillation (AF). Oxidative stress and intracellular pH regulation may also be linked to AF; however it remains unclear whether eicosapentaenoic acid (EPA) or statins have beneficial therapeutic effects. The aim of the present study was to investigate the effects of EPA and pitavastatin on the electrophysiology of and gene expressions in mice with rapidly-paced atria. Mice were treated with EPA (10 mg/g/day) or pitavastatin (30 ng/g/day) for 6 weeks, following which AF was simulated by 8-h atrial pacing at 1,800 bpm. The atrial electrophysiological properties and the expression of cardiac genes, potassium voltage-gated channel subfamily A member 5 (Kcna5), Kcn subfamily D member 2 (Kcnd2), Kv channel-interacting protein 2 (KChIP2), solute carrier family 9 member A1, thrombomodulin (TM) and tissue factor pathway inhibitor (TFPI) were examined using reverse transcription-quantitative polymerase chain reaction. In control mice, significant atrial electrical remodeling was observed (P<0.05); however, treatment with either EPA or pitavastatin ameliorated these electrophysiological changes (P>0.05). mRNA levels of Kcnd2, KChIP2 and Kcna5 were significantly upregulated in control mice (P<0.05), whereas treatment with EPA or pitavastatin attenuated this upregulation (P>0.05). Administration of pitavastatin significantly reduced the downregulation of both TFPI and TM (P<0.05). EPA treatment attenuated the TFPI downregulation compared with control mice (P>0.05), however no significant effect on TM expression was observed. In addition, both EPA (P>0.05) and pitavastatin (P<0.05) suppressed the overexpression of endothelial nitric oxide synthase. This was also exhibited in Ras-related C3 botulinum toxin substrate 1 genes (P<0.01 for both treatments). In conclusion, the results of the present study suggested that EPA and pitavastatin are able to prevent atrial electrical remodeling, thrombotic states and oxidative stress in rapidly-paced murine atria.


Neurology of musical performance.
Performing music at a professional level requires the integration of multimodal sensory and motor information and precise monitoring of the performance via auditory feedback. In the context of Western classical music, musicians are forced to reproduce highly controlled movements almost perfectly with a high reliability. These specialised sensorimotor skills are acquired during extensive training periods over many years. The superior skills of musicians are mirrored in functional and structural plastic adaptations of sensorimotor and auditory systems of the brain. Auditory-sensorimotor integration, for example, is accompanied by rapid modulations of neuronal connectivity in the time range of 20 minutes. Finally, dysfunctional plasticity in musicians, known as musician's dystonia, leads to deterioration of extensively trained fine motor skills. Musician's dystonia may be caused by training induced dysplasticity with pathological fusion of central nervous representations in sensorimotor cortical and subcortical brain regions.


Pulmonary carcinomas with a sarcomatoid element: an immunocytochemical and ultrastructural analysis.
Eight primary carcinomas of the lung with a prominent spindle-cell sarcomatoid component were studied by immunocytochemical staining and electron microscopy. The eight tumors were indistinguishable by conventional light microscopy, with the exception of one unusual neoplasm that followed multiple pathways of differentiation with elements of squamous cell carcinoma, rhabdomyosarcoma, chondrosarcoma, and an undifferentiated spindle-cell population. Reticulin fiber production by individual spindle cells and a sharp demarcation of the carcinomatous and sarcomatoid domains by light microscopy were not useful differentiating features. Three of the eight tumors exhibited keratin expression in both the carcinomatous and spindle-cell components. Both immunocytochemical and electron microscopic analyses were required to detect epithelial differentiation, as in one case keratin was identified only by immunocytochemical staining and in another only by ultrastructural examination. Epithelial differentiation was undetectable in the sarcomatoid component of five tumors, and in one case immunoreactive myoglobin was identified in spindle cells; skeletal muscle differentiation was confirmed ultrastructurally. We propose that pulmonary carcinomas exhibiting evidence of epithelial differentiation in a sarcomatoid component be termed spindle-cell carcinomas and that those biphasic tumors exhibiting mesenchymal differentiation into specific tissues, such as neoplastic bone, cartilage, or striated muscle, or lacking epithelial differentiation by light microscopy, immunocytochemistry, and electron microscopy be classified as carcinosarcomas. This distinction may ultimately be unnecessary, because these two tumors may represent different points along a morphologic and biologic continuum.


Emergency intravenous pyelography in the trauma patient. A reexamination of the indications.
Because of the high incidence of abnormal intravenous pyelograms (IVPs) in victims of blunt trauma undergoing resuscitation, a retrospective review of the Trauma Registry at the University of California, San Diego Medical Center, was undertaken to evaluate the indications for ordering this test. The charts of 216 patients were reviewed, all of whom had formal IVPs (four films) done as an emergency procedure at the time of admission. In this study, special attention was directed toward comparing both the degree of hematuria and the anatomic site of injury with the results of the IVP. A total of 20 renal injuries was detected by IVP. Of these injuries, all but one had hematuria that was greater than 50 red blood cells per high-power field. All but one of the abnormal IVPs were associated with obvious abdominal injuries. The results of the IVP influenced the clinical course of only one patient in the entire series. We conclude that the use of the formal IVP (four films) in the resuscitation phase of treating the multiply traumatized patient be reserved for those patients with penetrating abdominal injury or with hematuria consisting of greater than 50 red blood cells per high-power field. For any major blunt abdominal trauma without significant hematuria, a more simple and rapid study (one-shot IVP) to demonstrate bilateral nephrograms is probably adequate to rule out occult renal artery thrombosis.


[Primary disability from malignant neoplasms of the female population of Khmel'nik Province (1971-1973)].
The primary invalidism caused by malignant tumors has been studied statistically in the female population of the Khmel'nitsk Province, the Ukraine (1971-1973). The female population has been found to prevail over the male one among the mentioned category of invalids. Breast and genital cancer is the principal factor responsible for incapacity of young and mostly capable for work age group of women. At the same time, a high index of the population invalidism from malignant tumors in the Khmel'nitsk Province is reduced, whereas the incidence rate of this lesion is increased, to some extent it may be due to the well organized treatment and prophylactic measures with a wide application of antitumor therapy.


Early and extensive spinal white matter involvement in neuromyelitis optica.
Studies of longitudinally extensive spinal cord lesions (LESCLs) in neuromyelitis optica (NMO) have focused on gray matter, where the relevant antigen, aquaporin-4 (AQP4), is abundant. Because spinal white matter pathology in NMO is not well characterized, we aimed to clarify spinal white matter pathology of LESCLs in NMO. We analyzed 50 spinal cord lesions from eleven autopsied NMO/NMO spectrum disorder (NMOSD) cases. We also evaluated LESCLs with three or fewer spinal cord attacks by 3-tesla MRI in 15 AQP4 antibody-positive NMO/NMOSD patients and in 15 AQP4 antibody-negative multiple sclerosis (MS) patients. Pathological analysis revealed seven cases of AQP4 loss and four predominantly demyelinating cases. Forty-four lesions from AQP4 loss cases involved significantly more frequently posterior columns (PC) and lateral columns (LC) than anterior columns (AC) (59.1%, 63.6%, and 34.1%, respectively). The posterior horn (PH), central portion (CP), and anterior horn (AH) were similarly affected (38.6%, 36.4% and 31.8%, respectively). Isolated perivascular inflammatory lesions with selective loss of astrocyte endfoot proteins, AQP4 and connexin 43, were present only in white matter and were more frequent in PC and LC than in AC (22.7%, 29.5% and 2.3%, Pcorr = 0.020, and Pcorr = 0.004, respectively). MRI indicated LESCLs more frequently affected PC and LC than AC in anti-AQP4 antibody-seropositive NMO/NMOSD (86.7%, 60.0% and 20.0%, Pcorr = 0.005, and Pcorr = 0.043, respectively) and AQP4 antibody-seronegative MS patients (86.7%, 73.3% and 33.3%, Pcorr = 0.063, and Pcorr = 0.043, respectively). PH, CP and AH were involved in 93.3%, 86.7% and 73.3% of seropositive patients, respectively, and in 53.3%, 60.0% and 40.0% of seronegative patients, respectively. NMO frequently and extensively affects spinal white matter in addition to central gray matter, especially in PC and LC, where isolated perivascular lesions with astrocyte endfoot protein loss may emerge. Spinal white matter involvement may also appear in early NMO, similar to cerebral white matter lesions.


Antimicrobial stewardship: Improving antibiotic prescribing practice in a respiratory ward.
International efforts have mandated guidelines on antibiotic use and prescribing, therefore the focus is now on encouraging positive behavioral changes in antibiotic prescribing practice. Documentation of indication and intended duration of antibiotic use in drug charts is an evidence-based method of reducing inappropriate antibiotic prescribing. It is also a standard detailed in our local antimicrobial guidelines. We collected baseline data on compliance with documentation of indication and duration in drug charts in a respiratory ward which revealed compliance rates of 24% and 39% respectively. We introduced interventions to improve accessibility to the guideline and to increase awareness by distributing antibiotic guardian pocket cards with a three-point checklist and strategically-placed mini-posters. We also aim to increase team motivation by obtaining their feedback in multidisciplinary team meetings and by introducing certificates for their involvement in the quality improvement process. The results of the second cycle post-intervention showed an increase in compliance rates for documentation of indication and duration of 97% and 69% respectively. After a further awareness and discussion session at the multidisciplinary team meeting with the local antimicrobial management team audit nurses, a third cycle showed compliance rates of 94% and 71% for indication and duration respectively. This project has highlighted the importance of improving accessibility and of encouraging interventions that would bring about a change in personal value and subsequently in behavior and individual practice.


Venous thromboembolism in the outpatient setting.
There has been great interest in optimizing prophylaxis against venous thromboembolism (VTE) in the hospital setting. However, data from earlier studies suggest that most VTEs occur in the outpatient setting. The purposes of this observational study were to describe the frequency of VTEs occurring in the outpatient setting, characterize the prevalence of previously identified risk factors for VTE, and identify previous use of VTE prophylaxis. The medical records of residents from the Worcester metropolitan area diagnosed as having International Classification of Diseases, Ninth Revision codes consistent with possible VTE during 1999, 2001, and 2003 were independently validated and reviewed by trained abstractors. A total of 1897 subjects had a confirmed episode of VTE. In all, 73.7% of patients developed VTE in the outpatient setting; a substantial proportion of these patients had undergone surgery (23.1%) or hospitalization (36.8%) in the preceding 3 months. Among these patients, 67.0% experienced VTE within 1 month of the preceding hospital encounter. Other major risk factors for VTE in the outpatient setting included active malignant neoplasm (29.0%) or previous VTE (19.9%). Among 516 patients with a recent hospitalization who subsequently developed VTE, less than half (42.8%) had received anticoagulant prophylaxis for VTE during that visit. More VTEs were diagnosed in the 3 months following hospitalization than during hospitalization. Efforts to improve in-hospital use of VTE prophylaxis may help decrease the incidence of outpatient VTE. However, given the shortening of hospital stays, studies of extended VTE prophylaxis following hospital discharge are warranted.


The morpho-functional organization of secretory traffic. Here today, where tomorrow?
The morpho-functional principles of secretory traffic are still unclear, in stark contrast with our advanced knowledge of the underlying molecular machineries. Recently, the conceptual and technological hindrances that have delayed progress in this area have been disappearing, and new glimpses of the organization of traffic in intact cells are being revealed by a cluster of powerful morphological techniques. Here, we discuss the new advances in the light of the three main possible traffic principles: by anterograde vesicles, progression/maturation, and flow via continuities.


A magnetic liquid deformable mirror for high stroke and low order axially symmetrical aberrations.
We present a new class of magnetically shaped deformable liquid mirrors made of a magnetic liquid (ferrofluid). Deformable liquid mirrors offer advantages with respect to deformable solid mirrors: large deformations, low costs and the possibility of very large mirrors with added aberration control. They have some disadvantages (e.g. slower response time). We made and tested a deformable mirror, producing axially symmetrical wavefront aberrations by applying electric currents to 5 concentric coils made of copper wire wound on aluminum cylinders. Each of these coils generates a magnetic field which combines to deform the surface of a ferrofluid to the desired shape. We have carried out laboratory tests on a 5 cm diameter prototype mirror and demonstrated defocus as well as Seidel and Zernike spherical aberrations having amplitudes up to 20 microm, which was the limiting measurable amplitude of our equipment.


Maspin regulates hypoxia-mediated stimulation of uPA/uPAR complex in invasive breast cancer cells.
Maspin, a unique serine proteinase inhibitor (serpin), plays a key role in mammary gland development and is silenced during breast cancer progression. Maspin has been shown to inhibit tumor cell motility and invasion in cell culture, as well as growth and metastasis in animal models. In this study, we investigated the effect of maspin on the regulation of hypoxia-induced expression of urokinase-type plasminogen activator (uPA) and its receptor (uPAR), with respect to invasive potential in metastatic breast cells MDA-MB-231. We hypothesized that maspin can neutralize or mitigate hypoxia-induced expression of uPA/uPAR in metastatic breast cancer cells, resulting in suppression of their invasive potential. To test our hypothesis, we employed the highly invasive MDA-MB-231 breast cancer cells that are devoid of maspin, and transfected them with the maspin gene, and then determined the effect of hypoxia on uPA/uPAR expression. Normal mammary epithelial cells 1436N1 were used as a control. Our findings demonstrate that maspin downregulated the basal and hypoxia-induced uPA/uPAR expression and reduced the stimulatory effect of hypoxia on the in vitro invasive ability of MDA-MB-231-cells. In addition, maspin also inhibited the enzymatic activity of secreted and cell associated uPA in MDA-MB-231 cells. These results indicate that maspin inhibits hypoxia-induced invasion of metastatic breast cancer cells by blocking the uPA system, thus illuminating an important molecular pathway for therapeutic consideration.


Sweepstake evolution revealed by population-genetic analysis of copy-number alterations in single genomes of breast cancer.
Single-cell sequencing is a promising technology that can address cancer cell evolution by identifying genetic alterations in individual cells. In a recent study, genome-wide DNA copy numbers of single cells were accurately quantified by single-cell sequencing in breast cancers. Phylogenetic-tree analysis revealed genetically distinct populations, each consisting of homogeneous cells. Bioinformatics methods based on population genetics should be further developed to quantitatively analyse the single-cell sequencing data. We developed a bioinformatics framework that was combined with molecular-evolution theories to analyse copy-number losses. This analysis revealed that most deletions in the breast cancers at the single-cell level were generated by simple stochastic processes. A non-standard type of coalescent theory, the multiple-merger coalescent model, aided by approximate Bayesian computation fit well with the data, allowing us to estimate the population-genetic parameters in addition to false-positive and false-negative rates. The estimated parameters suggest that the cancer cells underwent sweepstake evolution, where only one or very few parental cells produced a descendent cell population. We conclude that breast cancer cells successively substitute in a tumour mass, and the high reproduction of only a portion of cancer cells may confer high adaptability to this cancer.


Elongated styloid processes and calcified stylohyoid ligaments in a patient with neck pain: implications for manual therapy practice.
The purpose of this paper is to present a case of a patient with neck pain, tinnitus, and headache in the setting of bilateral elongated styloid processes (ESP) and calcified stylohyoid ligaments (CSL), how knowledge of this anatomical variation and symptomatic presentation affected the rehabilitation management plan for this patient, and to discuss the potential relevance of ESPs and CSLs to carotid artery dissection. A 29-year-old male military helicopter mechanic presented for chiropractic care for chronic pain in the right side of his neck and upper back, tinnitus, and dizziness with a past history of right side parietal headaches and tonsillitis. Conventional radiographs showed C6 and C7 spinous process fractures, degenerative disc disease at C6/7, and an elongated right styloid process with associated calcification of the left stylohyoid ligament. Volumetric computerized tomography demonstrated calcification of the stylohyoid ligaments bilaterally. Given the proximity of the calcified stylohyoid apparatus to the carotid arteries, spinal manipulation techniques were modified to minimize rotation of the neck. Rehabilitation also included soft tissue mobilization and stretching, corrective postural exercises, and acupuncture. An otolaryngologist felt that the symptoms were not consistent with Eagle syndrome and the tinnitus was associated with symmetric high frequency hearing loss, likely due to occupational noise exposure. Initially, the patient's symptoms improved but plateaued by the fifth visit. Neck pain in the presence of ESPs and CSLs can be associated with Eagle syndrome, which can include ipsilateral head and neck pain, odynophagia, dysphagia, and cerebrovascular symptoms. This case, initially thought to be Eagle syndrome, highlights proper diagnostic workup for this condition and presents potential contraindications to consider with regard to cervical spine manipulation in such patients. Manual therapy precautions pertaining to cervical spine manipulation may be appropriate in cases involving ESPs and calcified stylohyoid ligaments.


Protective effects of rhubarb on experimental severe acute pancreatitis.
To investigate the effects of rhubarb on severe acute pancreatitis (SAP) in rats. Severe acute pancreatitis was induced by two intraperitoneal injections of cerulein (40 microg/kg body weight) plus 5-h restraint water-immersion stress. Rhubarb (75-150 mg/kg) was orally fed before the first cerulein injection. The degree of pancreatic edema, serum amylase level, local pancreatic blood flow (PBF), and histological alterations were investigated. The effects of rhubarb on pancreatic exocrine secretion in this model were evaluated by comparing with those of somatostatin. In the Cerulein+Stress group, severe edema and diffuse hemorrhage in the pancreas were observed, the pancreatic wet weight (11.60+/-0.61 g/Kg) and serum amylase (458 490+/-43 100 U/L) were markedly increased (P<0.01 vs control). In the rhubarb (150 mg/kg) treated rats, necrosis and polymorphonuclear neutrophil (PMN) infiltration in the pancreas were significantly reduced (P<0.01), and a marked decrease (50%) in serum amylase levels was also observed (P<0.01). PBF dropped to 38% (93+/-5 mL/min per 100 g) of the control in the Cerulein+Stress group and partly recovered in the Cerulein+Stress+Rhubarb 150 mg group (135+/-12 mL/min per 100 g) (P<0.01). The pancreatic exocrine function was impaired in the SAP rats. The amylase levels of pancreatic juice were reduced in the rats treated with rhubarb or somatostatin, comparing with that of untreated SAP group. The bicarbonate concentration of pancreatic juice was markedly elevated only in the rhubarb-treated group (P<0.01). Rhubarb can exert protective effects on SAP, probably by inhibiting the inflammation of pancreas, improving pancreatic microcirculation, and altering exocrine secretion.


Structural heterogeneity of attC integron recombination sites revealed by optical tweezers.
A predominant tool for adaptation in Gram-negative bacteria is the functional genetic platform called integron. Integrons capture and rearrange promoterless gene cassettes in a unique recombination process involving the recognition of folded single-stranded DNA hairpins-so-called attC sites-with a strong preference for the attC bottom strand. While structural elements have been identified to promote this preference, their mechanistic action remains incomplete. Here, we used high-resolution single-molecule optical tweezers (OT) to characterize secondary structures formed by the attC bottom (${{att}}{{{C}}_{{\rm{bs}}}}$) and top (${{att}}{{{C}}_{{\rm{ts}}}}$) strands of the paradigmatic attCaadA7 site. We found for both sequences two structures-a straight, canonical hairpin and a kinked hairpin. Remarkably, the recombination-preferred ${{att}}{{{C}}_{{\rm{bs}}}}$ predominantly formed the straight hairpin, while the ${{att}}{{{C}}_{{\rm{ts}}}}$ preferentially adopted the kinked structure, which exposes only one complete recombinase binding box. By a mutational analysis, we identified three bases in the unpaired central spacer, which could invert the preferred conformations and increase the recombination frequency of the ${{att}}{{{C}}_{{\rm{ts}}}}$in vivo. A bioinformatics screen revealed structural bias toward a straight, canonical hairpin conformation in the bottom strand of many antibiotic resistance cassettes attC sites. Thus, we anticipate that structural fine tuning could be a mechanism in many biologically active DNA hairpins.


An analysis of electrical impedance measurements applied for plant N status estimation in lettuce (Lactuca sativa).
Nitrogen plays a key role in crop yields. Hence, farmers may apply excessive N fertilizers to crop fields, inducing environmental pollution. Crop N monitoring methods have been developed to improve N fertilizer management, most of them based on leaf or canopy optical-property measurements. However, sensitivity to environmental interference remains an important drawback. Electrical impedance has been applied to determine the physiological and nutritional status of plant tissue, but no studies related to plant-N contents are reported. The objective of this article is to analyze how the electrical impedance response of plants is affected by their N status. Four sets of lettuce (Lactuca sativa L.) with a different N-source concentrations per set were used. Total nitrogen and electrical impedance spectra (in a 1 to 100 kHz frequency range) were measured five times per set, three times every other day. Minimum phase angles of impedance spectra were detected and analyzed, together with the frequency value in which they occurred, and their magnitude at that frequency. High and positive correlation was observed between plant N content and frequency values at minimum phase angle with no significant variations detected between days of measurement. These results suggest that electrical impedance can be sensitive to plant N status.


Direct evidence for tumor necrosis factor-alpha signaling in arteriogenesis.
Arteriogenesis serves as an efficient mechanism for flow restoration after arterial occlusion. This process is associated with inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha), although their role in arteriogenesis remains unclear. We hypothesized that arteriogenesis is reduced in mice lacking functional TNF-alpha or p55 receptor. To test this hypothesis, we developed a novel microsphere-based murine model of hindlimb perfusion measurement. Unilateral femoral arteries of nude (n=9), TNF-alpha(-/-) (n=9), TNF-alpha receptor p55(-/-) (n=8), and p75(-/-) (n=8) mice as well as their appropriate genetic background controls were occluded. The nude mice underwent laser Doppler hindlimb flux measurements preoperatively, postoperatively, and after 7 days. Seven days after ligation, all animals underwent tissue perfusion determinations using fluorescent microspheres. Laser Doppler findings confirmed acute decrease in flux with falsely normal values after 1 week. Microsphere results from control mice showed perfusion restoration to values approximately 50% of normal within 7 days. TNF-alpha(-/-) mice demonstrated a significant reduction (45.1%) in collateral artery perfusion compared with controls (TNF-alpha(-/-) 22.4+/-5.1% versus B6x129 49.7+/-9.3%; P<0.01). p55(-/-) mice exhibited an almost identical 45.8% reduction in collateral artery formation (p55(-/-) 28.3+/-4.3% versus C57BL/6J 61.8+/-9.1%; P<0.01), whereas p75(-/-) mice were equivalent to controls (p75(-/-) 54.5+/-5.5%; P=0.13). Microsphere techniques in mice offer a tool for the molecular dissection of arteriogenesis mechanisms. These results suggest that TNF-alpha positively modulates arteriogenesis probably via signaling through its p55 receptor.


Hydroxamate Siderophores Secreted by Plant Endophytic Pseudomonas putida Elicit Defense against Blast Disease in Rice Incited by Magnaporthe oryzae.
Our study focuses on a hydroxamate-type siderophore from Pseudomonas putida BP25, known for chelating ferric iron and aiding microbial growth in iron-deficient environments. Confirmed through CAS-agar and tetrazolium tests, a purified siderophore extract was obtained via ion-exchange chromatography. Applying varying concentrations of this siderophore to rice seedlings demonstrated concentration-dependent effects on shoot and root phenotypes. Prophylactic application on rice leaves significantly reduced blast severity (68.7-97.0%), surpassing curative application (47.5-86.87%). Additionally, the siderophore treatment elevated peroxidase, polyphenol oxidase, and total phenols in rice plants. Defense-related genes linked to salicylic acid (OsPR1.1, OsNPR1, OsPDF2.2), and other pathways (Oshox24, OsCLE, OsGLP3-3, OsEIN2.4, OsCSE) promoting blast suppression showed upregulation. However, the OsACS6 gene associated with ethylene-induced internodal elongation was significantly downregulated. Overall, our findings propose that the siderophore from Pseudomonas putida BP25 induces defense gene transcription, offering potential for sustainable rice production via bio-formulation.


Diabetic Neuropathic Pain and Serotonin: What Is New in the Last 15 Years?
The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is involved in numerous physiological functions and plays a key role in pain modulation including neuropathic pain. Diabetic neuropathy is a common complication of diabetes mellitus often accompanied by chronic neuropathic pain. Animal models of diabetes offer relevant tools for studying the pathophysiological mechanisms and pharmacological sensitivity of diabetic neuropathic pain and for identifying new therapeutic targets. In this review, we report data from preclinical work published over the last 15 years on the analgesic activity of drugs acting on the serotonergic system, such as serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressants, and on the involvement of certain serotonin receptors-in particular 5-HT1A, 5-HT2A/2c and 5-HT6 receptors-in rodent models of painful diabetic neuropathy.


Relevance of Upper Limb Muscle Synergies to Dynamic Force Generation: Perspectives on Rehabilitation of Impaired Intermuscular Coordination in Stroke.
This study investigated the impact of stroke on the control of upper limb endpoint force during isokinetic exercise, a dynamic force-generating task, and its association with stroke-affected muscle synergies. Three-dimensional upper limb endpoint force and electromyography of shoulder and elbow muscles were collected from sixteen chronic stroke survivors and eight neurologically intact adults. Participants were instructed to control the endpoint force direction during three-dimensional isokinetic upper limb movements. The endpoint force control performance was quantitatively evaluated in terms of the coupling between forces in orthogonal directions and the complexity of the endpoint force. Upper limb muscle synergies were compared between participants with varying levels of endpoint force coupling. The stroke survivors generating greater force abnormality than the others exhibited interdependent activation profiles of shoulder- and elbow-related muscle synergies to a greater extent. Based on the relevance of synergy activation to endpoint force control, this study proposes isokinetic training to correct the abnormal synergy activation patterns post-stroke. Several ideas for implementing effective training for stroke-affected synergy activation are discussed.


Targeting Opsin4/Melanopsin with a Novel Small Molecule Suppresses PKC/RAF/MEK/ERK Signaling and Inhibits Lung Adenocarcinoma Progression.
The identification of oncogenic biomolecules as drug targets is an unmet need for the development of clinically effective novel anticancer therapies. In this study, we report for the first time that opsin 4/melanopsin (OPN4) plays a critical role in the pathogenesis of non-small cell lung cancer (NSCLC) and is a potential drug target. Our study has revealed that OPN4 is overexpressed in human lung cancer tissues and cells, and is inversely correlated with patient survival probability. Knocking down expression of OPN4 suppressed cells growth and induced apoptosis in lung cancer cells. We have also found that OPN4, a G protein-coupled receptor, interacted with Gα11 and triggered the PKC/BRAF/MEK/ERKs signaling pathway in lung adenocarcinoma cells. Genetic ablation of OPN4 attenuated the multiplicity and the volume of urethane-induced lung tumors in mice. Importantly, our study provides the first report of AE 51310 (1-[(2,5-dichloro-4-methoxyphenyl)sulfonyl]-3-methylpiperidine) as a small-molecule inhibitor of OPN4, suppressed the anchorage-independent growth of lung cancer cells and the growth of patient-derived xenograft tumors in mice. IMPLICATIONS: Overall, this study unveils the role of OPN4 in NSCLC and suggests that targeting OPN4 with small molecules, such as AE 51310 would be interesting to develop novel anticancer therapies for lung adenocarcinoma.


Phosphatidylcholine biosynthesis and choline transport in the anaerobic protozoon Entodinium caudatum.
Choline accumulation and phosphatidylcholine biosynthesis were investigated in the choline-requiring anaerobic protozoon Entodinium caudatum by incubating whole cells or subcellular fractions with [14C] choline, phosphoryl [14C] choline and CDP-[14C] choline. 2. All membrane fractions contained choline kinase (EC 18.104.22.168) and CDP-choline-1,2-diacylglycerol cholinephosphotransferase (EC 22.214.171.124), although the specific activities were less in the cell-envelope fraction. Choline phosphate cytidylyltransferase (EC 22.214.171.124) was limited to the supernatant, and this enzyme was rate-limiting for phosphatidylcholine synthesis in the whole cell. 3. Synthesis of phosphatidylcholine from free choline by membranes was only possible in the presence of supernatant. Such reconstituted systems required ATP (2.5 mM), CTP (1 mM) and Mg2+ (5 mM) for maximum synthesis of the phospholipid. CTP and Mg2+ were absolute requirements. 4. Hemicholinium-3 prevented choline uptake by the cells and was strongly inhibitory towards choline kinase; the other enzymes involved in phosphatidylcholine synthesis were minimally affected. 5. Ca2+ ions (0.5 mM) substantially inhibited CDP-choline-1,2-diacylglycerol cholinephosphotransferase in the presence of 15 mM-Mg2+, but choline phosphate cytidylyltransferase and choline kinase were less affected. 6. No free choline could be detected intact cells even after short (10-180s) incubations or at temperatures down to 10 degrees C. The [14C] choline entering was mainly present as phosphorylcholine and to a lesser extent as phosphatidylcholine. 7. It is suggested that choline kinase effectively traps any choline within the cell, thus ensuring a supply of the base for future growth. At low choline concentrations the activity of choline kinase is rate-limiting for choline uptake, and the enzyme might possibly play an active role in the transport phenomenon. Thus the choline uptake by intact cells and choline kinase have similar Km values and show similar responses to temperature and hemicholinium-3.


In-bore MRI interventions: current status and future applications.
This review discusses the feasibility, recent advances and current status of in-bore MRI-guided interventional techniques for diagnosis and treatment of focal prostate cancer (PCa) and also explores the future applications, highlighting the emerging strategies for the treatment of PCa. Multiparametric MRI has opened up opportunities for diagnosis and targeted therapeutics to the site of disease within the organ wherein minimizing the incidence of treatment-related toxicity of whole gland therapy. MRI-guided targeted biopsy has a higher detection rate for significant cancer and lower rate of detection of insignificant cancer. In comparison to ultrasound-guided focal therapy, in-bore treatment provides the advantage of real time thermal monitoring during treatment and assessment of treatment coverage by an enhanced scan immediately post-treatment. Preliminary results of ongoing phase I and II in-bore focal PCa treatment trials via transperineal, transrectal and transurethral routes, using different energy modalities for the ablation, have shown promising results. Advances in multiparametric-MRI has opened up opportunities for in-bore targeted focal treatment of PCa in the correctly selected patient.


miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1.
We examined the microRNAs (miRNAs) expressed in chronic lymphocytic leukemia (CLL) and identified miR-150 as the most abundant, but with leukemia cell expression levels that varied among patients. CLL cells that expressed ζ-chain-associated protein of 70 kDa (ZAP-70) or that used unmutated immunoglobulin heavy chain variable (IGHV) genes, each had a median expression level of miR-150 that was significantly lower than that of ZAP-70-negative CLL cells or those that used mutated IGHV genes. In samples stratified for expression of miR-150, CLL cells with low-level miR-150 expressed relatively higher levels of forkhead box P1 (FOXP1) and GRB2-associated binding protein 1 (GAB1), genes with 3' untranslated regions having evolutionary-conserved binding sites for miR-150. High-level expression of miR-150 could repress expression of these genes, which encode proteins that enhance B-cell receptor signaling, a putative CLL-growth/survival signal. Also, high-level expression of miR-150 was a significant independent predictor of longer treatment-free survival or overall survival, whereas an inverse association was observed for high-level expression of GAB1 or FOXP1 for overall survival. This study demonstrates that expression of miR-150 can influence the relative expression of GAB1 and FOXP1 and the signaling potential of the B-cell receptor, thereby possibly accounting for the noted association of expression of miR-150 and disease outcome.


Frequency modulation time delay thermal lens effect spectrometry: a new technique of transient photothermal calorimetry.
A new type of laser-induced thermal lens effect measurement is demonstrated in which the thermooptic impulse response of a weakly absorbing sample is recovered in the time delay domain through excitation with a fast linear frequency sweep. The autocorrelation function of the excitation sweep approximates to a Dirac delta function to a time resolution limited by the modulation bandwidth of the sweep, thereby permitting the fast recovery of high quality frequency and impulse response information. Impulse response data recovered in the time delay domain showed good agreement with the results predicted from Fresnel diffraction theory, indicating an equivalence to the response recovered in a typical pulsed measurement. The FM time delay technique, however provides enhanced measurement dynamic range and an overall reduced peak excitation power when compared with the pulsed measurement.


Studies on the formation of N-methylperfluoroalkylnitrile cations from perfluoroacylphenethylamines in electron ionisation mass spectrometry: unique marker ion fragments in methamphetamine analysis.
The mass spectra of the perfluoroacyl derivatives of methamphetamine show a unique and characteristic fragment ion identified as the N-methylperfluoroalkylnitrile cation (C(n)F(2n+1)CNCH(3))(+). This ion appears at various m/z values depending on the nature of the perfluoroacyl species and is generated via rearrangement of the perfluoroacyl immonium fragment formed by loss of the benzyl-radical from the molecular ion. Analogous ions have been described in the mass spectra of other methamphetamine-like side chain substances regardless of the aromatic ring substitution pattern. The scope and limitation of this rearrangement pathway were evaluated in this study by preparing a set of substituted phenethylamines and related compounds of varying structure. The perfluoroacyl moiety leads to the formation of the highest abundance of the N-methyl nitrile cation fragment while hydrocarbon acyl groups do not show the N-methylnitrile cation as a significant peak. The N-methyl group is required for the formation of the N-methyl nitrile cation and higher N-alkyl homologues eliminate the corresponding alkene species from the acyl immonium fragment. The loss of benzaldehyde and acetone from the perfluoroacylimmonium species produces the highest relative abundance of the unique N- methylperfluoroalkylnitrile cation.


[Timing of elective term caesarean sections; trends in the Netherlands].
To analyse if from 2000-2010 the rate of elective caesarean sections (CS) before 39 0/7 weeks of gestation declined when compared with all elective CS, and to evaluate the possible associated factors. Retrospective cohort study. Using data from The Netherlands Perinatal Registry, all term elective CS (n = 59,653) from 2000-2010 were selected. Trends in patient characteristics and in performing an elective CS before 39 0/7 weeks were analysed using regression analysis, and differences between hospitals using the χ2 test. Using multiple logistic regression analysis it was analysed which factors were associated with performing an elective CS before 39 0/7 weeks. The percentage of elective CS before 39 0/7 weeks decreased from 56% in 2000 to 43% in 2010 (p < 0.0001). In peripheral hospitals an elective SC was performed more often before 39+0 weeks than in academic hospitals; 53% in peripheral teaching hospitals, 57% in peripheral non-teaching hospitals, and 46% in academic hospitals. Adjusted odds ratios and 95% confidence intervals were 1.38 (1.30-1.47) in peripheral teaching hospitals, and 1.55 (1.46-1.65) in peripheral non-teaching hospitals. In hospitals where the number of deliveries per year was situated in the lower quartile, elective CS before 39 0/7 weeks was carried out more often than in hospitals where deliveries per year were in the upper quartile, 60% versus 52% (p < 0.0001). In the period 2000-2009 the timing of elective CS improved marginally. In 2010 the trend began to decline, even though 43% of elective caesarean sections were still carried out before 39 0/7 weeks. This results in a higher risk of neonatal morbidity and health problems in long-term.


Effect of whole soy and purified isoflavone daidzein on renal function--a 6-month randomized controlled trial in equol-producing postmenopausal women with prehypertension.
The aim of the study was to examine the long-term effect of commonly used whole soy foods (soy flour) and purified daidzein (one major isoflavone and the precursor of equol) on renal function among prehypertensive postmenopausal women who are also equol producers, a population most likely to benefit from soy intervention. This was a 6-month double-blind, randomized, placebo-controlled trial. Two hundred seventy eligible Chinese women were randomized to either one of the three treatments: 40 g soy flour (whole soy group), 40 g low-fat milk powder + 63 mg daidzein (daidzein group) or 40 g low-fat milk powder (placebo group) daily each for 6 months. Fasting blood and 24-h urine samples were collected at the beginning and end of trial. Serum creatinine, cystatin C, urea, angiotensin-converting enzyme, minerals and 24-h urinary creatinine and minerals were analyzed. Estimated glomerular filtration rate (eGFR) was calculated with the Cockcroft-Gault and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. Two hundred fifty-three subjects completed the study according to the protocol. Urinary isoflavones indicated good compliance of participants. No significant changes were observed in most of renal parameters, however, there was a less decrease in eGFRcockcroft in 6-month change (p=0.044) and %change (p=0.031) with whole soy intake relative to milk placebo. Subgroup analysis among women with lowered renal function suggested whole soy consumption tended to improve markers of renal function relative to control. Six-month consumption of whole soy tended to have a modest improvement of renal function in prehypertensive postmenopausal women with lowered renal function. Future trials in subjects with more declined renal function are necessary. The trial was registered in ClinicalTrials.gov with identifier of NCT01270737. (URL: http://clinicaltrials.gov/ct2/show/NCT01270737).


Iodine-125-fibrinogen kinetics in the rabbit arterial wall.
Elevated fibrinogen has been claimed as an independent risk factor for the development of atherosclerosis. Incorporation of fibrinogen into human atherosclerotic lesions has been demonstrated. We assessed in a rabbit model of experimental atherosclerosis, biodistribution as well as kinetics and vascular uptake of (125)I-fibrinogen. Rabbits aged 6 months were fed a 1% cholesterol supplemented diet. After experimental de-endothelialization of rabbit aorta using a Fogarthy catheter, (125)I-fibrinogen uptake was enhanced by more than one order of magnitude as compared to intact segments covered by endothelium. Six rabbits per group were examined. Even re-endothelialized segments showed a significantly higher uptake of the radiolabeled protein. Maximum arterial uptake varied between 12 (de- and re-endothelialized segments) and 24h (intact areas) after injection of (125)I-fibrinogen. In conclusion, these experiments for the first time suggest the increased uptake of radiolabeled fibrinogen in the aortic de-endothelized wall in rabbits.


Burden of potentially avoidable anticoagulant-associated hemorrhagic and thromboembolic events in the elderly.
On average, patients receiving therapy with oral anticoagulants (OACs) in the community are in the therapeutic range only 55% of the time. Anticoagulation control strongly influences the risk of hemorrhagic and thromboembolic events in such patients. However, not all anticoagulation-associated events are attributable to poor anticoagulation control, nor do all hemorrhagic or thromboembolic events occur in anticoagulated patients. Measure the proportion of serious hemorrhagic and thromboembolic events that would be avoided if anticoagulation control was perfect. A retrospective cohort study of eastern Ontario using population-based administrative databases. Anticoagulation control was determined for each day of OAC exposure using linear interpolation. Incident hemorrhagic or thromboembolic hospitalizations for control and OAC patients were identified. Hemorrhages and thromboemboli in OAC patients were deemed to be avoidable if they occurred at international normalized ratios of > 3 and < 2, respectively. The study included > 183,000 patient-years of observation with 6,400 patient-years of OAC exposure. Anticoagulation control could be determined for 51.5% of OAC exposure time. Control patients had hemorrhagic and thromboembolic event rates of 1.8% and 1.5% per year, respectively. A total of 10,020 people were exposed to OACs, and spent 14.2% and 26.7% of the time, respectively, with excessively high and low anticoagulation intensity. Excessively high anticoagulation intensity explained 25.6% (95% confidence interval [CI], 19.4 to 31.7) and 2.0% (95% CI, 1.5 to 2.5) , respectively, of all serious hemorrhages in the anticoagulated and entire population. Excessively low anticoagulation intensity explained 11.1% (95% CI, 4.4 to 17.7) and 1.1% (95% CI, 0.7 to 1.6) of all thromboemboli, respectively. Our study showed that extreme anticoagulation intensity significantly impacted the health of the population. Improving anticoagulation control will have significant effects on the incidence of serious hemorrhagic and thromboembolic events in the both the anticoagulated and entire populations.


Depletion of florfenicol and florfenicol amine residues in chicken eggs.
1. The aim of this study was to develop a suitable method for the analysis of florfenicol (FF) and its metabolite florfenicol amine (FFA) in chicken eggs and to determine FF and FFA residue depletion in eggs of laying hens. 2. The analytes were extracted from yolk, albumen and whole egg by phosphate buffer and ethyl acetate. Following purification, samples were analysed by high-performance liquid chromatography. 3. Fifty laying hens were divided into 5 groups, and each hen received doses of 20 mg/kg FF: Group 1 (received a single oral dose by gavage); Group 2 (a single intramuscular dose); Group 3 (a single subcutaneous dose); Group 4 (multiple oral doses for 3 d) and Group 5 (multiple oral doses for 5 d). 4. Limits of detection and of quantitation values were 1.94 and 6.45 g/10(9) g (ppb) for FF, respectively, and 0.48 and 1.58 ppb for FFA, respectively. Relative standard deviation values of intra-day and inter-day variation below 11% also confirmed the usefulness of the method for analysing FF and FFA in eggs. 5. From the first day of both oral and parenteral administration, FF and FFA were detected at 0.1% and 0.08% of dosage, respectively, and 57% of the drugs were eliminated from the egg yolk. Elimination time of FF was 8 d in Groups 1, 2 and 3; 9 d in Group 4 and 10 d in Group 5.


Bioactive Peptides in Preventative Healthcare: An Overview of Bioactivities and Suggested Methods to Assess Potential Applications.
Food derived bioactive peptides can be generated from various protein sources and usually consist of between 2-30 amino acids with bulky, side-chain aromatic amino acids preferred in the ultimate and penultimate positions at the C-terminal end of the amino acid chain. They are reported to impart a myriad of preventative health beneficial effects to the consumer once ingested and these include heart health benefits through inhibition of enzymes including renin (EC 220.127.116.11) and angiotensin- I-converting enzyme (ACE-1; EC 184.108.40.206) within the renin angiotensin aldosterone system (RAAS) anti-inflammatory (due to inhibition of ACE-I and other enzymes) and anti-cancer benefits, prevention of type-2 diabetes through inhibition of dipeptidyl peptidase IV (DPP-IV), bone and dental strength, antimicrobial and immunomodulatory effects and several others. Peptides have also reported health benefits in the treatment of asthma, neuropathic pain, HIV and wound healing. However, the structure, amino acid composition and length of these peptides, along with the quantity of peptide that can pass through the gastrointestinal tract and often the blood-brain barrier (BBB), intact and reach the target organ, are important for the realisation of these health effects in an in vivo setting. This paper aims to collate recent important research concerning the generation and detection of peptides in the laboratory. It discusses products currently available as preventative healthcare peptide options and relevant legislation barriers to place a food peptide product on the market. The review also highlights useful in silico computer- based methods and analysis that may be used to generate specific peptide sequences from proteins whose amino acid sequences are known and also to determine if the peptides generated are unique and bioactive. The topic of food-derived bioactive peptides for health is of great interest to scientific research and industry due to evolving drivers in food product innovation, including health and wellness for the elderly, infant nutrition and optimum nutrition for sports athletes and the humanisation of pets. This paper provides an overview of what is required to generate bioactive peptide containing hydrolysates, what methods should be used in order to characterise the beneficial health effects of these hydrolysates and the active peptide sequences, potential applications of bioactive peptides and legislative requirements in Europe and the United States. It also highlights success stories and barriers to the development of peptide-containing food products that currently exist.


Do antipsychotics limit disability in schizophrenia? A naturalistic comparative study in the community.
Though antipsychotics are effective against symptoms of schizophrenia and prevent relapses, their effect on disability has not been studied in a comparative design. To compare disability of schizophrenia patients receiving continuous antipsychotic treatment with that of those not receiving or receiving irregular treatment in a rural community setting using a naturalistic comparative study design. Disability was assessed in 182 schizophrenia patients living in Thirthahalli Taluk of Shimoga District, Karnataka, using Indian Disability Evaluation and Assessment Scale (IDEAS). Fifty patients (27.5%) were receiving regular treatment in the previous 2 years and their disability was assessed for the period when they were on antipsychotics. The remaining 132 patients (72.5%) had off-antipsychotics periods in the previous 2 years and their disability was assessed for the period when they were off-antipsychotics. Patients on antipsychotics had significantly less disability across all domains of disability and in total IDEAS scores. Multivariate regression analysis showed that treatment status predicted disability scores after controlling for the effects of the confounding factors. Different levels of exposure to antipsychotic treatment were associated with different levels of disability. Treatment with antipsychotics is associated with significantly less disability. There is an urgent need to bring schizophrenia patients under the umbrella of treatment.


KNS-760704 [(6R)-4,5,6,7-tetrahydro-N6-propyl-2, 6-benzothiazole-diamine dihydrochloride monohydrate] for the treatment of amyotrophic lateral sclerosis.
Developing effective treatments for chronic neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) has proven extremely difficult. ALS is universally fatal, characterized by progressive weakness due to the degeneration of upper and lower motor neurons, and leads eventually to respiratory failure which is the usual cause of death. Only a single treatment has been approved, the modestly effective nonspecific neuroprotectant Rilutek (riluzole; 2-amino-6-(trifluoromethoxy)benzothiazole). KNS-760704 [(6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride, RPPX], a synthetic amino-benzothiazole with demonstrated activity in maintaining mitochondrial function, is being developed as a treatment for ALS. It has proven to be effective in multiple in vitro and in vivo assays of neuroprotection, including the G93A-SOD1 mutant mouse model; however, its specific mechanism of action remains unknown. The potential of KNS-760604 as a treatment for ALS was first suggested by studies showing that its optical enantiomer, Mirapex[(6S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine; pramipexole dihydrochloride; PPX], a high-affinity agonist at dopamine D2, D3, and D4 receptors, exhibits important neuroprotective properties independent of its dopamine receptor agonism. In cell-based assays, both RPPX and PPX reduce the production of reactive oxygen species (ROS), attenuate the activation of apoptotic pathways, and increase cell survival in response to a variety of neurotoxins. However, PPX has limited utility as a clinical neuroprotective agent because the drug concentrations required for neuroprotection would likely produce unacceptable dopaminergic side effects. RPPX, on the other hand, while possessing the same neuroprotective potential as PPX, is a much lower-affinity dopamine receptor agonist and may therefore be more useful in the treatment of ALS. This review will examine the data supporting the hypothesis that the RPPX may have therapeutic potential for the treatment of neurodegenerative disorders including ALS. In addition, we will briefly review recent preclinical data in support of RPPX, and discuss the current status of its clinical development.


[A comparative analysis of antireflux and direct methods of ureteral implantation in intestinal continent urinary derivation].
Intestinal continent urinary derivation was made from 1997 to 2006 in three groups of patients. The following kinds of derivation were performed: ureterosygmostomy according to Maintz-Pouch and Abol-Enein modification (group 1, n=32); heterotopic replacement of the urinary bladder in various modifications (group 2, 50 patients); orthotopic replacement according to Hautmann, Studer, Abol-Enein, sygmocystoplasty, n=51). In group 1 ureterosygmoanastomosis was created only by antireflux methods: Goodwin and Hohenfellner submucous technique and Abol-Enein extramural implantation. In groups 2 and 3 uretero-intestinal anastomosis was created by Wallace direct implantation and antireflux--Abol-Enein extramural implantation. The patients were followed up from 6 months to 9 years. The results show that both methods are effective. The antireflux methods are preferable in detubulizing ureterosygmostomy, in extended atonic ureters in case of creation of continent heterotopic and orthotopic reservoirs. The problem of antireflux mechanisms in creation of neobladder needs further investigation.


Impact of community-based presumptive chloroquine treatment of fever cases on malaria morbidity and mortality in a tribal area in Orissa State, India.
In the Global Strategy for Malaria Control, one of the basic elements is early detection and prompt treatment of malaria cases, especially in areas where health care facilities are inadequate. Establishing or reviving the existing drug distribution centers (DDC) at the peripheral levels of health care can achieve this. The DDCs should be operationally feasible, acceptable by community and technical efficient, particularly in remote hard-core malaria endemic areas. Volunteers from villages were selected for distribution of chloroquine and the selection was made either by villagers or head of the village. The services of the volunteers were absolutely free and voluntary in nature. Chloroquine was provided free of charge to all fever cases. The impact was evaluated based on the changes observed in fever days, fever incidence, parasite incidence and parasite prevalence (proportion of persons harbouring malaria parasite) in the community. Comparisons were made between 1st, 2nd and 3rd year of operation in the experimental villages and between the experimental and check areas. A total of 411 village volunteers in 378 villages in the experimental community health center with a population of 125,439 treated 88,575 fever cases with a mean annual incidence of 331.8 cases per 1,000 population during the three-year study period. The average morbid days due to fever (AFD) was reduced to 1.6 +/- 0.1 from 5.9 +/- 2.1 in the experimental villages while it remained at 5.0 +/- 1.0 in the check villages. There was a significant reduction, (p < 0.05) in Annual Fever Incidence (AFI) in the experimental hilltop and foothill villages in comparison to check villages. The change in Annual Parasite Incidence (API) was, however, not statistically significant (p > 0.05). In plain villages that were low endemic, the reductions in AFI and API in experimental villages were statistically significant (p < 0.05). There was significant reduction in the parasite prevalence in high endemic villages of the experimental area both during 2nd and 3rd year when compared with the check area (p < 0.05) but no such reduction was observed in low endemic areas (p > 0.0.5). Mortality due to malaria declined by 75% in the experimental villages in the adult age group whereas there was an increasing trend in check villages. The study demonstrated that a passive chloroquine distribution system operated by village volunteers in tribal areas is feasible and effective in reducing malaria-related morbidity and mortality.


Maintenance rituximab or observation after frontline treatment with bendamustine-rituximab for follicular lymphoma.
Bendamustine (B) with rituximab (R) is a standard frontline treatment for medically fit follicular lymphoma (FL) patients. The safety and efficacy of maintenance rituximab (MR) after BR induction has not been formally compared to observation for FL, resulting in disparate practice patterns. Prospective trials have shown benefit of MR after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or R-CVP (rituximab, cyclophosphamide, vincristine, prednisone), yet recent data from the GALLIUM study comparing outcomes of patients treated with chemotherapy with R or obinutuzumab (G) showed higher than anticipated fatal adverse events with BR/BG. In order to assess the efficacy and tolerability of MR after BR, we retrospectively collected data on 640 newly diagnosed patients treated with FL. We found that patients who achieved partial remission (PR) after ≥4 cycles of BR had improved duration of response (DOR) with MR vs. no maintenance, whereas those in complete remission did not. These findings were confirmed in a validation cohort. In the entire study population, the known fatal adverse event rate after BR was 2·5% and did not significantly differ in those receiving MR versus no maintenance. [Correction added on 14 January 2019, after online publication: The preceding sentence has been corrected in this current version.] Within the limitations inherent to retrospective analysis, these data suggest that FL patients with a PR to BR experience prolongation of remission with MR with an acceptable safety profile.


Misremembering Brexit: partisan bias and individual predictors of false memories for fake news stories among Brexit voters.
Exposure to fake news stories can result in false memories for the events portrayed, and this effect can be enhanced if the stories conform to the reader's ideological position. We exposed 1299 UK residents to fabricated news stories about Brexit. 44% of participants reported a false memory for at least one fabricated story, with a higher rate of false memories for stories that reflected poorly on the opposing side. This effect of ideological congruency was somewhat greater among participants who were exposed to a threat to their social identity as a Leave or Remain supporter; however, this moderating effect was only statistically significant in exploratory analyses using a more conservative definition of false memory. Participants with higher cognitive ability and analytical reasoning scores were less susceptible to false memories. Individuals with better knowledge about Brexit showed better discrimination between true and false stories, while self-reported engagement with the Brexit debate was associated with an increased tendency to "remember" any story, regardless of its truth. These results implicate a combination of social and individual factors in the development of false memories from fake news, and suggest that exposure to social identity threats may enhance the polarising effects of fake news.


Long-lived quantum coherence of two-level spontaneous emission models within structured environments.
We investigate the long-lived quantum coherence of two-level spontaneous emission models within structured environments. The population of the system under the asymptotic non-Markovian dynamics is linked to the spectral density of the reservoir through a general functional relation between them. We figure out explicitly the preservation of quantum coherence, via notions of entanglement and quantum discord, in connection with the spectral parameters of Ohmic class reservoirs, and then show how to achieve them optimally. We expect these results to contribute to reservoir engineering with the aim of enhancing stationary quantum coherence in noisy environments.


Negative regulation in correct tissue-specific expression of mouse mammary tumor virus in transgenic mice.
Mouse mammary tumor virus (MMTV) is an endogenous murine retrovirus that is expressed in the epithelial cells of the mammary and salivary glands, lungs, kidneys, and seminal vesicles and in the lymphoid cells of the spleen and thymus. Several studies have shown that the long terminal repeat (LTR) of this virus can direct the expression of reporter genes to the same tissues in transgenic mice. To determine whether multiple regulatory elements within the LTR are involved in this tissue-specific expression, we have established lines of transgenic mice containing transgenes that have deletions in the MMTV LTR. Deletions of all LTR sequences upstream of -364 or of LTR sequences from -165 to -665 both result in the expression of linked reporter genes such as the simian virus 40 early region or the bacterial enzyme chloramphenicol acetyltransferase in novel sites, such as the heart, brain, and skeletal muscle; expression of endogenous MMTV and transgenes containing the full-length LTR is not detected in these organs. Negative regulation appears to involve more than one region, since deletion of sequences between either -201 and -471 or -201 and -344, as well as sequences upstream of -364, results in inappropriate expression in heart, brain, and skeletal muscle. Therefore, a negative regulatory element(s) in the MMTV LTR can suppress transcription from the viral promoter in several different organs. This represents the first example of generalized negative regulatory elements that act in many different tissues in transgenic mice to prevent inappropriate expression of a gene.


Resolving the structure of inner ear ribbon synapses with STED microscopy.
Synapses are diverse in form and function; however, the mechanisms underlying this diversity are poorly understood. To illuminate structure/function relationships, robust analysis of molecular composition and morphology is needed. The molecular-anatomical components of synapses-vesicles, clusters of voltage-gated ion channels in presynaptic densities, arrays of transmitter receptors in postsynaptic densities-are only tens to hundreds of nanometers in size. Measuring the topographies of synaptic proteins requires nanoscale resolution of their molecularly specific labels. Super-resolution light microscopy has emerged to meet this need. Achieving 50 nm resolution in thick tissue, we employed stimulated emission depletion (STED) microscopy to image the functionally and molecularly unique ribbon-type synapses in the inner ear that connect mechano-sensory inner hair cells to cochlear nerve fibers. Synaptic ribbons, bassoon protein, voltage-gated Ca(2+) channels, and glutamate receptors are inhomogeneous in their spatial distributions within synapses; the protein clusters assume variations of shapes typical for each protein specifically at cochlear afferent synapses. Heterogeneity of substructure among these synapses may contribute to functional differences among auditory nerve fibers. The morphology of synaptic voltage-gated Ca(2+) channels matures over development in a way that depends upon bassoon protein, which aggregates in similar form. Functional properties of synaptic transmission appear to depend on voltage-gated Ca(2+) channel cluster morphology and position relative to synaptic vesicles. Super-resolution light microscopy is a group of techniques that complement electron microscopy and conventional light microscopy. Although technical hurdles remain, we are beginning to resolve the details of molecular nanoanatomy that relate mechanistically to synaptic function.


Configural Gestalts remain nothing more than the sum of their parts in visual agnosia.
We report converging evidence that higher stages of the visual system are critically required for the whole to become more than the sum of its parts by studying patient DF with visual agnosia using a configural superiority paradigm. We demonstrate a clear dissociation between this patient and normal controls such that she could more easily report information about parts, demonstrating a striking reversal of the normal configural superiority effect. Furthermore, by comparing DF's performance to earlier neuroimaging and novel modeling work, we found a compelling consistency between her performance and representations in the early visual areas, which are spared in this patient. The reversed pattern of performance in this patient highlights that in some cases visual Gestalts do not emerge early on without processing in higher visual areas. More broadly, this study demonstrates how neuropsychological patients can be used to unmask representations maintained at early stages of processing.


Organ perfusion with Hemopump device assistance with and without intraaortic balloon pumping.
Our objective was to analyze the potential advantage of combining an intraaortic balloon pump with a transthoracic Hemopump device (Medtronic, Inc., Minneapolis, Minn.) (Nimbus Medical, Inc., Rancho Cordova, Calif.). Twelve sheep underwent implantation of a transthoracic Hemopump device and an intraaortic balloon pump. In the first series (n = 6), we analyzed the influence of the counterpulsation on the performance of the Hemopump device. In the second group (n = 6), hemodynamic changes, myocardial wall thickening, organ perfusion, and myocardial perfusion (determined with colored microspheres) were analyzed under the following conditions: (1) control situation, (2) during application of coronary stenosis, (3) during support with the Hemopump device, and (4) during support with the Hemopump device combined with intraaortic balloon pump support. In the first series, we found that addition of counterpulsation reduced output with the Hemopump device by 11.1% +/- 6%. In the second series, it was shown that coronary stenosis significantly reduced contractility (rate of pressure change and wall thickening) but did not cause hemodynamic collapse. Myocardial blood flow was significantly reduced in the poststenotic subendocardial regions (mean subendocardial blood flow dropped from 78 +/- 33 to 24 +/- 17 ml/min/100 gm; p = 0.0486). Support with the Hemopump device alone improved the ratio of subendocardial to subepicardial blood flow, but endocardial underperfusion remained (analysis of variance, p < 0.001). The Hemopump device with an intraaortic balloon pump completely restored perfusion in poststenotic regions. Peripheral organ perfusion did not change during ischemia or mechanical support. The association of balloon counterpulsation with the Hemopump device reduces the Hemopump output by 11% and increases myocardial blood flow to ischemic regions. Perfusion to peripheral organs remains unaltered. The transthoracic Hemopump device combined with an intraaortic balloon pump is an ideal support system for the ischemic, failing heart.


CircRNA (circ_0008057) promotes uremic serum-mediated proliferation and migration of vascular smooth muscle cells via miR-370/PLk1 signaling pathway.
In order to explore the mechanism of gefitinib-acquired resistance in lung cancer, a new biomarker has been developed for early clinical diagnosis and intervention; human NSCLC (Non-Small Cell Lung Cancer) cell lines H292 (denoted as H292S) and PC9 (denoted as PC9S) were used to establish gefitinibresistant NSCLC cell lines H292 and PC9 models. CCK-8 (Cell Counting Kit-8) method was used to test the drug resistance of the cells. circRNAs (circular RNAs) that were differentially expressed before and after resistance were screened by RNA sequencing technology. The effects of circSETD3 overexpression and interference on the sensitivity of gefitinib was observed to analyze the nuclear localization of circSETD3 and verify the interaction between circSETD3-miR-520h-ABCG2. The results showed that the most significant change in differential expression of human NSCLC cell lines before and after drug resistance was hsa_circ_0000567, that is, circSETD3, which is mainly present in the cytoplasm. In H292S and PC9S, compared with the negative control group, the cell proliferation ability of the overexpression group was significantly increased, and the apoptosis ability was significantly decreased. In H292R and PC9R, compared with the negative control group, the proliferation ability of the interference group was significantly decreased, and the apoptosis ability was significantly increased. Overexpression of circSETD3 to H292S and PC9S, the expression of ABCG2 increased significantly. Also, the expression of ABCG2 decreased significantly after transfection with miR-520h mimics. H292R and PC9R interfered with circSETD3, the expression of ABCG2 decreased significantly. Moreover, the expression of ABCG2 increased significantly after transfection with miR-520h inhibitor. In conclusion, circSETD3 can be used as a novel biomarker for lung cancer. It relieves miR-520h degradation of the transporter ABCG2 by down-regulating the miR-520h expression, causing gefitinib to be pumped out of the cell.