Spatial scale of receptive fields in the visual sector of the cat thalamic reticular nucleus.
Inhibitory projections from the visual sector of the thalamic reticular nucleus to the lateral geniculate nucleus complete the earliest feedback loop in the mammalian visual pathway and regulate the flow of information from retina to cortex. There are two competing hypotheses about the function of the thalamic reticular nucleus. One regards the structure as a thermostat that uniformly regulates thalamic activity through negative feedback. Alternatively, the searchlight hypothesis argues for a role in focal attentional modulation through positive feedback, consistent with observations that behavioral state influences reticular activity. Here, we address the question of whether cells in the reticular nucleus have receptive fields small enough to provide localized feedback by devising methods to quantify the size of these fields across visual space. Our results show that reticular neurons in the cat operate over discrete spatial scales, at once supporting the searchlight hypothesis and a role in feature selective sensory processing.The searchlight hypothesis proposes that the thalamic reticular nucleus regulates thalamic relay activity through focal attentional modulation. Here the authors show that the receptive field sizes of reticular neurons are small enough to provide localized feedback onto thalamic neurons in the visual pathway.


Identity, activity, and the well-being of adolescents and youths: lessons from young people in a Micronesian society.
Comparative studies of the health, well-being, and social functioning of adolescents and youths have, in the past two decades, been focused on young people in developing countries where rapid social, cultural, and economic changes have been associated with dramatic increases in the rates of social problems indicative of poorer mental health. Young people in many Pacific Island societies suffer from some of the highest rates of social problems like suicide and substance abuse in the world. It is generally agreed that the increases in rates of social problems among youths in this region result from increases in psychosocial stress, anger, and frustration surrounding intergenerational conflict within the family. Much less is known about the aspects of everyday experiences of young people in the Pacific that can lead to psychosocial stress and the angry episodes of interpersonal conflict that often precede suicide attempts and binge drinking. This paper examines 40 cases of interpersonal conflict in young men's and women's experiences in the islands of Chuuk of the Federated States of Micronesia to better understand what can lead to elevated levels of psychosocial stress for youths in the Pacific. This study shows that the emotional crises of young people in Chuuk often emerge from the incongruence in their pursuit of valued personal and social identities within the family, the community, and the peer group. Thus youths who experience more incongruity in their engagements across the multiple activity settings of everyday life are at greater risk for stressful experiences.


Activity of DMBA, DMH and CP in triple- and single-dose rodent bone-marrow micronucleus assays.
1,2-Dimethylhydrazine, 7,12-dimethylbenzanthracene and cyclophosphamide were detected as positive using the triple-dose test protocol described by MacGregor (1989). Determination of the 3 day MLD may complicate the use of this test protocol.


Engineering AvidCARs for combinatorial antigen recognition and reversible control of CAR function.
T cells engineered to express chimeric antigen receptors (CAR-T cells) have shown impressive clinical efficacy in the treatment of B cell malignancies. However, the development of CAR-T cell therapies for solid tumors is hampered by the lack of truly tumor-specific antigens and poor control over T cell activity. Here we present an avidity-controlled CAR (AvidCAR) platform with inducible and logic control functions. The key is the combination of (i) an improved CAR design which enables controlled CAR dimerization and (ii) a significant reduction of antigen-binding affinities to introduce dependence on bivalent interaction, i.e. avidity. The potential and versatility of the AvidCAR platform is exemplified by designing ON-switch CARs, which can be regulated with a clinically applied drug, and AND-gate CARs specifically recognizing combinations of two antigens. Thus, we expect that AvidCARs will be a highly valuable platform for the development of controllable CAR therapies with improved tumor specificity.


Pharmacokinetic and Pharmacodynamic Comparison of Two Recombinant Human Erythropoietin Formulations, PDA10 and Eprex, in Healthy Korean Male Volunteers: A Randomized, Double-Blinded, Single-Dose, Two-Period Crossover Study.
A new biosimilar human recombinant epoetin alfa product (PDA10) has been developed by PanGen Biotech Inc., Korea. This study was planned to demonstrate the pharmacokinetic and pharmacodynamic comparability of PDA10 to an existing epoetin alfa (Eprex) after a single intravenous administration to healthy adult male volunteers. A randomized, double-blinded, single-dose, crossover study was conducted in 30 subjects. The subjects were assigned randomly to one of two sequence groups, and single doses of 100 IU/kg PDA10 or Eprex were administered intravenously on each of 2 treatment days separated by a 4-week washout period. Plasma erythropoietin concentrations were measured using an enzyme-linked immunosorbent assay and the pharmacokinetic parameters of the two treatments were compared. The time course and area under the effect curve (AUEC) of absolute reticulocyte counts were used as surrogate parameters for the pharmacodynamic evaluation. Adverse events (AEs) were recorded. A total of 30 subjects were enrolled, and 27 completed the study. The geometric mean ratios (PDA10/Eprex) of erythropoietin for maximum plasma concentration (C max) and area under the plasma concentration-time curve to the last measurable concentration (AUC0-last) after intravenous administration of 100 IU/kg were 1.00 (90% confidence interval [CI] 0.96-1.05) and 0.96 (90% CI 0.93-1.00). The absolute reticulocyte counts of PDA10 and Eprex were similar, as determined from the maximum reticulocyte count and AUEC0-last values. Treatment-emergent AEs were mild and occurred in seven subjects. PDA10 and Eprex met the regulatory criteria for bioequivalence with respect to their pharmacokinetic profiles and pharmacodynamic actions.


Treatment of nail psoriasis with a modified regimen of steroid injections.
To evaluate the efficacy of a modified regimen of intralesional steroid injection therapy for the treatment of nail psoriasis and assess the side effects of this regimen. Quasi-experimental study. Dermatology Department of Military Hospital, Rawalpindi, from February 1999 to January 2001. Patients having psoriatic nail dystrophy, reporting to the skin department of Military Hospital, Rawalpindi were registered. The features accounted for were pitting, onycholysis, subungual hyperkeratosis, ridging, thickening and color change. The affected digits were scored from 0 to 3 for the severity of each of these features. Similar number of control digits was also selected. Injection of triamcinolone acetonide (10 mg/ml) was given into the nail bed and matrix following ring block anesthesia. The features were re-scored after two months. A second injection was given after 02 months if warranted by poor response. The follow-up period ranged up to 06 months. A total of 100 nails were injected in 35 subjects. Pitting was the commonest presenting feature seen in 71 digits (71%) and improved in 41 digits (57.7%). Onycholysis was seen in 37 digits (37%) and improved in 15 digits (40.5%). Subungual hyperkeratosis was seen in 57 digits (57%) and improved in all the cases. Other features like longitudinal ridging, thickening and yellow oil drop-like discoloration showed marked improvement. The side effects of this regimen were minimal and included painless subungual hematoma. The modified regimen of steroid was found to be effective and safe for the treatment of psoriatic nail deformities in this series.


Prognostic relevance of regional lymph-node distribution in patients with N1-positive non-small cell lung cancer: A retrospective single-center analysis.
Lymph node (LN) metastases predict survival in patients with non-small cell lung cancer (NSCLC) treated with curative surgery. Nevertheless, prognostic differences within the same nodal (N) status have been reported. Consequently, the International Association for the Study of Lung Cancer (IASLC) proposed to stratify patients with limited nodal disease (pN1) from low (pN1a) to high (pN1b) nodal tumor burden. This study aimed to validate the IASLC proposal in a large single-center surgical cohort of patients with pN1 NSCLC. Data from 317 patients with pN1 NSCLC treated between January 2012 and December 2016, were retrospectively analyzed. Associations between distribution of LN metastases and survival were analyzed for different classification models-toward nodal extension (pN1a: one station involved; pN1b: multiple stations involved) and toward location (pN1 in the hilar [LN#10/11] or peripheral zone [LN#12-14]). Tumor-specific survival (TSS) in the entire pN1 cohort was 67.1% at five years. Five-year TSS rates for pN1a and pN1b patients were comparable (67.6% vs. 66.5%, p = 0.623). Significant survival differences from pN1a to pN1b were observed only in patients with adenocarcinoma histology and completed adjuvant chemotherapy (5-year TSS: pN1a, 80.4% vs. pN1b, 49.6%; p = 0.005). TSS for LN metastases in the hilar zone/peripheral zone or in both zones was 68.2% and 59.9%, respectively (p = 0.068). In multivariate analysis, adjuvant chemotherapy, squamous cell histology, and nodal disease limited to one zone nodal disease were identified as independent beneficial prognostic factors (p < 0.05). pN1 in only one region (hilar or lobar) was associated with better outcome than metastatic affection of both regions after surgery and adjuvant therapy. A stratification towards single (pN1a) and multiple (pN1b) N1-metastases was found of prognostic relevance only in adenocarcinoma. Prospective multicenter analysis of prognostic subgroups in N1 NSCLC is required to evaluate its clinical impact for consideration in future TNM classification.


Modeling cancelation of periodic inputs with burst-STDP and feedback.
Prediction and cancelation of redundant information is an important feature that many neural systems must display in order to efficiently code external signals. We develop an analytic framework for such cancelation in sensory neurons produced by a cerebellar-like structure in wave-type electric fish. Our biologically plausible mechanism is motivated by experimental evidence of cancelation of periodic input arising from the proximity of conspecifics as well as tail motion. This mechanism involves elements present in a wide range of systems: (1) stimulus-driven feedback to the neurons acting as detectors, (2) a large variety of temporal delays in the pathways transmitting such feedback, responsible for producing frequency channels, and (3) burst-induced long-term plasticity. The bursting arises from back-propagating action potentials. Bursting events drive the input frequency-dependent learning rule, which in turn affects the feedback input and thus the burst rate. We show how the mean firing rate and the rate of production of 2- and 4-spike bursts (the main learning events) can be estimated analytically for a leaky integrate-and-fire model driven by (slow) sinusoidal, back-propagating and feedback inputs as well as rectified filtered noise. The effect of bursts on the average synaptic strength is also derived. Our results shed light on why bursts rather than single spikes can drive learning in such networks "online", i.e. in the absence of a correlative discharge. Phase locked spiking in frequency specific channels together with a frequency-dependent STDP window size regulate burst probability and duration self-consistently to implement cancelation.


Genome-wide DNA methylation reveals potential epigenetic mechanism of age-dependent viral susceptibility in grass carp.
Grass carp are an important farmed fish in China that are infected by many pathogens, especially grass carp reovirus (GCRV). Notably, grass carp showed age-dependent susceptibility to GCRV; that is, grass carp not older than one year were sensitive to GCRV, while those over three years old were resistant to this virus. However, the underlying mechanism remains unclear. Herein, whole genome-wide DNA methylation and gene expression variations between susceptible five-month-old (FMO) and resistant three-year-old (TYO) grass carp were investigated aiming to uncover potential epigenetic mechanisms. Colorimetric quantification revealed that the global methylation level in TYO fish was higher than that in FMO fish. Whole-genome bisulfite sequencing (WGBS) of the two groups revealed 6214 differentially methylated regions (DMRs) and 4052 differentially methylated genes (DMGs), with most DMRs and DMGs showing hypermethylation patterns in TYO fish. Correlation analysis revealed that DNA hypomethylation in promoter regions and DNA hypermethylation in gene body regions were associated with gene expression. Enrichment analysis revealed that promoter hypo-DMGs in TYO fish were significantly enriched in typical immune response pathways, whereas gene body hyper-DMGs in TYO fish were significantly enriched in terms related to RNA transcription, biosynthesis, and energy production. RNA-seq analysis of the corresponding samples indicated that most of the genes in the above terms were upregulated in TYO fish. Moreover, gene function analysis revealed that the two genes involved in energy metabolism displayed antiviral effects. Collectively, these results revealed genome-wide variations in DNA methylation between grass carp of different ages. DNA methylation and gene expression variations in genes involved in immune response, biosynthesis, and energy production may contribute to age-dependent susceptibility to GCRV in grass carp. Our results provide important information for disease-resistant breeding programs for grass carp and may also benefit research on age-dependent diseases in humans.


Prospective longitudinal study of testosterone and incident depression in older men: The Health In Men Study.
Depression in older men has been associated with low circulating testosterone concentration but data from prospective studies are limited. We conducted a prospective longitudinal study in a community representative cohort of 3179 older men free of clinically significant depressive symptoms at baseline. The main objective of this study was to determine if low serum testosterone, dihydrotestosterone and estradiol concentrations are associated with the development of depressive symptoms. Incident depression was assessed with the Patient Health Questionnaire and via an electronic health record database (The West Australian Data Linkage System). The main exposures of interest were serum testosterone, dihydrotestosterone and estradiol measured by liquid chromatography-mass spectrometry and calculated free testosterone in baseline blood samples (collected between 2001 and 2004). One hundred and thirty five men (4.2%) developed depression over a median follow up time of 9.4 years (range 8.4-10.9). Men with incident depression were older (median age 77.7 vs 76.1 years, z=-3.82, p=0<0.001) and were more likely to have cardiovascular disease (43.0% vs 32.6%, χ(2)=6.32, p=0.012) and diabetes (22.2% vs 13.2%, χ(2)=8.95, p=0.003). Low serum total testosterone (<6.4 nmol/L) was associated with incident depression (HR 2.07, 95%CI 1.17-3.68) and this remained significant after adjustment for relevant potential confounding factors (HR 1.86, 95%CI 1.05-3.31). Low serum dihydrotestosterone, estradiol and calculated free testosterone were not associated with risk of depression. Low serum total testosterone, but not calculated free testosterone, was associated with incident depression in this sample of older men.


Evaluation of antioxidant, enzyme inhibition, nitric oxide production inhibitory activities and chemical profiles of the active extracts from the medicinal and edible plant: Althaea officinalis.
To develop the medicinal and edible plant resources of Althaea officinalis Linn in Europe and other places, this study concentrated on the bioactive ingredients of its different extracts. The phytochemical compositions of MeOH extracts were evaluated by UPLC-DAD-ESI-Q-TOF-MSn analysis. The in vitro antioxidant properties, enzymes inhibitory effects and nitric oxide (NO) production inhibitory activities of fractions obtained from the aerial parts of Althaea officinalis (APAO) were evaluated. The results identified 76 compounds, including 8 phenolic acids, 17 flavonoids, 6 coumarins, 9 triterpenes and 11 alkaloids. Fr. C-2 of APAO was found to have the highest TPC (175.8 ± 1.5 mg GAE/g) and TFC (466.9 ± 5.0 mg RE/g) with the highest antioxidant capacity in DPPH, ABTS, CUPRAC, FRAP and β-carotene bleaching assays. Fr. A showed noticeable inhibition of α-glucosidase with an IC50 value of 3.8 ± 0.1 μg/mL. However, Fr. B displayed stronger inhibitory activity on 5-lipoxygenase than quercetin, with the IC50 value of 8.4 ± 1.6 μg/mL. In addition, Fr. B also possessed potent inhibitory activities on NO production toward LPS-activated RAW 264.7 Cells with an IC50 value of 15.7 ± 1.6 μg/mL. Our findings suggest that different Althaea officinalis extracts may be considered sources of phenolic and flavonoid compounds with high potential as natural antioxidants, anti-inflammatory agents and blood sugar regulators. In addition, they can also be used in food and nutraceutical products with enhanced bioactivities.


Documented electronic medical record-based pain intensity scores at a tertiary pediatric medical center: a cohort analysis.
Previous surveys have suggested that pain in hospitalized patients remains undertreated. However, little is known about those with persistently high pain scores. To document the distribution of scores and analyze the clinical characteristics of outliers with persistently high pain scores. With institutional review board approval, a retrospective cohort analysis of more than 1.5 million documented scores was completed in a tertiary pediatric medical center during a three-year period. Patients with persistently high pain scores were identified for subgroup analysis. The median score was 0 (all years), and the means were 1.46, 1.34, and 1.3 in 2010, 2011, and 2012, respectively. Approximately 68% of admissions had at least one score of 4 or greater, although this level did not persist. Only 9% had mean scores of 4 or greater, and 1% (n = 492) had mean scores of 7 or greater. Scores remained high in patients within identifiable groups, that is, those with chronic pain (n = 311), sickle cell vaso-occlusive episodes (n = 52), and pain in children with developmental and neuromuscular disorders (n = 32). Few had persistently high scores with acute pain but without known comorbidities (n = 56). Detailed review of clinical characteristics of patients with persistently high scores led to the strong impression that, in most cases, persistently high pain was not simply because of inadequate administration of opioids. Instead, the first step in improving pain management of hospitalized children may be the identification of outliers with high pain scores to direct efforts on the development of interventions for patient groups with mechanistically similar pain.


Alterations of the in vivo torque-velocity relationship of human skeletal muscle following 30 days exposure to simulated microgravity.
The purpose of this study was to examine the effect of 30 d of 6 degrees headdown bedrest (BR) on the in vivo strength of skeletal muscle. Peak angle specific (0.78 rad below horizontal) torque of the knee extensor (KE) and flexor (KF) muscle groups of both limbs was assessed during unilateral efforts at four speeds (0.52, 1.74, 2.97 and 4.19 rad.s-1) during concentric and at three speeds (0.52, 1.74 and 2.97 rad.s-1) during eccentric actions. The average decrease (p less than 0.05) of peak angle specific torque directly post-BR for the KE across speeds of concentric and eccentric actions was about 19% (n = 7). Recovery for 30 d following BR markedly improved strength to about 92% (p greater than 0.05) of "normal." Strength of the KF was not altered (p greater than 0.05) by BR (about a 6% decrease independent of speed and type of muscle action). Changes of strength were not affected by the type or speed of muscle action. The results indicate that strength of extensor more than of flexor muscle groups of the lower limb is decreased by 30 d of bedrest and that this response does not alter the nature of the in vivo torque-velocity relation.


Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer.
As a natural alkaloid product isolated from Sophora alopecuroides. L, Sophoridine reshapes gastric cancer immune microenvironment via inhibiting chemotaxis and M2 polarization of tumor-associated macrophages (TAMs). However, the exact effects and underlying mechanism of Sophoridine on gastric cancer cells remains poorly known. The potential anti-tumor effects of Sophoridine on gastric cancer cell lines, including AGS and SGC7901 cells, were detected by CCK-8, EDU and colony forming assay, immunofluorescence, transwell assay, and flow cytometry. Molecular mechanisms of Sophoridine were investigated by siRNA transfection, nuclear/cytoplasmic extraction and western blot. The synergistic effects of Sophoridine with cisplatin on gastric cancer cells were further investigated in in vitro functional studies. Sophoridine exhibited potent tumor-suppressive activities in gastric cancer cells, including inhibition of proliferation, colony formulation, migration and invasion, as well as induction of apoptosis. In addition, we further showed that Sophoridine induced G2/M cell cycle arrest via inhibiting double-stranded DNA breaks repair and enhanced the efficacy of cisplatin in gastric cancer cells. Molecular studies further revealed that Sophoridine promoted β-catenin degradation by enhancing Estrogen-related receptor gamma (ESRRG) expression, but not depended on ubiquitination-proteasome pathway, either TRIM33-mediated (GSK3β-independent) or altered GSK3β activity, and thus exerted potent tumor-suppressive activities. Sophoridine depends on targeting ESRRG/β-catenin pathway to exert tumor-suppressive activities in gastric cancer cells and enhances the anti-tumor effect of cisplatin. Our study provided the promising preclinical anti-tumor evidence for the potential application of Sophoridine against gastric cancer.


Comparison of the effects of thymosin and other thymic factors on modulation of interleukin-2 production.
Thymosin fraction 5 (TF5) enhances interleukin-2 (IL-2) production by human peripheral blood mononuclear leukocytes (PBL) when cocultured in the presence of phytohemagglutinin (PHA). This important biological activity of TF5 is not due to the presence of two previously well-characterized component peptides, thymosin alpha 1 and thymosin beta 4, but rather to a new, still to be identified component of TF5. Comparison of TF5 with other well-defined thymic preparations and peptides indicates that this biological activity is unique to TF5 and a closely related extract prepared from porcine thymus tissue. Using a standard human PBL cell population obtained by leukopheresis and cryopreservation, it should now be possible to establish a reproducible bioassay for the isolation and characterization of one or more components of TF5 with the property of enhancing PHA-induced IL-2 production by human PBL.


Impact of a spiritual care program on the sleep quality and spiritual health of Muslim stroke patients: A randomized controlled trial.
Stroke patients often experience poor sleep quality and spiritual health due to complications and limitations. In this situation, implementing spiritual care may reduce these problems. Therefore, this study aimed to examine the effect of a spiritual care program on sleep quality and spiritual health of Muslim stroke patients. This was a two-group randomized clinical trial conducted in Hamadan, Iran, in 2021, with 117 stroke patients. The samples were selected by convenience sampling and assigned to experimental (N = 59) and control (N = 58) groups based on random permutation blocks. The data were collected using the demographic information form, the Pittsburgh Sleep Quality Index, the Paloutzian and Ellison Spiritual Well-Being Scale, and the Modified Rankin Scale before and one month after the intervention. The experimental group received five daily sessions of spiritual care for 45-60 min based on standard and local methods, including patient orientation and identification of spiritual needs, religious care, supportive spiritual care, and beneficial evaluations. Data were analyzed by chi-square test, Fisher's exact test, independent t-test, and paired t-test at 0.05 significance level in SPSS 21. The socio-demographic characteristics were similar between the groups (p > 0.05). At baseline, there was no significant difference in sleep quality and spiritual health between the experimental and control groups (p > 0.05). However, after the intervention, the sleep quality and spiritual health of patients in the experimental group improved significantly compared with the control group (p < 0.05). The spiritual care program improved sleep quality and spiritual health of stroke patients; therefore, nurses should consider these aspects to provide holistic care.


Sodium loading and renal prostaglandins in old rats.
1. Previous studies have shown that altered synthesis of prostaglandins (PGs) in the kidney of ageing rats contributes to impaired Na conservation during sodium deprivation. In the present study, we wished to assess whether the disturbance of prostaglandin synthesis also affects the response to sodium loading in old rats. 2. We measured the urinary excretion of thromboxane B2 (TXB2), 6-keto PGF1 alpha (6KPGF1 alpha) and PGE2 in young (3-4 months) and old (20-21 months) rats after 24, 48 and 72 h of Na loading. In a separate protocol, we measured prostanoid synthesis by isolated glomeruli, cortical homogenates, medullary and papillary slices from young and old rats in basal conditions and after 15 days of dietary Na loading. 3. Young and old rats excreted similarly the Na load. The urinary excretion (U) of TXB2 and 6KPGF1 alpha were unchanged during Na load in young rats. U6KPGF1 alpha, which was significantly higher in old rats and UTXB2 which also tended to be elevated, decreased in old rats with Na loading. Sodium loading was associated with a transient increase of UPGE2 in young, but not in old rats. 4. TXB2 synthesis was increased in all portions of the kidneys of old rats. 6KPGF1 alpha production was elevated in glomeruli and cortex and that of PGE2 in cortex. In medulla and papilla only TXB2 synthesis was enhanced. 5. Sodium loading did not significantly change prostanoid synthesis in the kidneys of young rats. In old rats, glomerular and cortical TXB2 decreased whereas medullary and papillary 6KPGF1 alpha increased.(ABSTRACT TRUNCATED AT 250 WORDS)


Magnesium supplementation in pregnancy. A double-blind study.
The effect of magnesium supplementation in pregnancy was studied in 568 women who were treated with 15 mmol magnesium-aspartate-hydrochloride per day or aspartic acid as placebo given orally during pregnancy from less than or equal to 16 weeks. Allocation to the two groups was performed according to the women's birthdates. Magnesium supplementation during pregnancy was associated with significantly fewer maternal hospitalizations, a reduction in preterm delivery, and less frequent referral of the newborn to the neonatal intensive care unit. The results suggest that magnesium supplementation during pregnancy has a significant influence on fetal and maternal morbidity both before and after delivery.


Comparison of OMERACT-RAMRIS scores and computer-aided dynamic magnetic resonance imaging findings of hand and wrist as a measure of activity in rheumatoid arthritis.
The purpose of this study was to compare the value of conventional magnetic resonance imaging (MRI) finding of rheumatoid arthritis (RA) and computer-aided dynamic MRI measurements in predicting the activity of disease. The activity of the disease in 40 RA patients was evaluated by the disease activity score in 28 joints (DAS28). The conventional MRI of the wrists of all patients were scored for bone edema, synovitis and erosions, according to the criteria of RA-MRI scoring system (RAMRIS) developed by Outcome measures in rheumatology clinical trials (OMERACT) MR Imaging Group. Synovitis was also quantified by dynamic postcontrast MRI imaging using color coded maximum slope of increase maps and measurements of early enhancement rate (EER) and relative enhancement (RE). Twenty-two (55 %) patients with a score higher than 5.1 constituted the high disease activity group, 18 (45 %) patients with a score of 5.1 or less constituted moderate disease activity group. The dynamic MRI-EER score was the most significant parameter to differentiate between the groups (p = 0.001). Among OMERACT scores, only bone edema [p = 0.020 for wrist and p = 0.037 for metacarpophalangeal joints (MCP)] had a significant difference between the two groups. Dynamic MRI RE score and OMERACT scores for erosions and synovitis for both the wrist and MCP joints did not differ significantly between the two groups. Computer-aided dynamic MRI is a reliable, noninvasive method of evaluating the RA patients, which correlates with the DAS28 scores, at a higher significance than the OMERACT-RAMRIS scores.


Protamine sulphate coated poly (lactide-co-glycolide) nanoparticles of MUC-1 peptide improved cellular uptake and cytokine release in mouse antigen presenting cells.
MUC-1-peptide (M-1-pep) loaded poly (lactide-co-glycolide) nanoparticles were coated with protamine sulphate (PS), M-1-pep-PS-P-NPs for targeting antigen presenting cells (APCs) to evoke cytokine release. M-1-pep-PS-P-NPs were tailored by emulsion-diffusion evaporation method and characterised in vitro under a set of rigorous parameters. The average particle size and zeta potential of optimised M-1-pep-PS-P-B-NPs was measured to be 132.21 ± 30.71 nm and 6.29 ± 0.71 mV, significantly (p < 0.01) higher than 71.24 ± 17.76-nm and -43.41 ± 3.37 mV of M-1-pep-P-NPs. Further, 50-μg/ml concentration of M-1-pep-PS-P-B-NPs displayed 82.4% cellular uptake in RAW 264.7 cells calculated in setting of fluorescence intensity significantly (p < 0.05) elevated than 63.1% of M-1-pep-P-NPs. Consistent to quantitative results, M-1-pep-PS-P-B-NPs also confirmed advanced cellular uptake (CU) in RAW 264.7 cells in contrast to M-1-pep-P-NPs suppose to be through multiple mechanisms including phagocytosis and clathrin mediated endocytosis. M-1-pep-PS-P-B-NPs must be evaluated in vivo through inhalation route of administration for antitumor prospective in lung cancer xenograft model.


Organization of the smallest eukaryotic spindle.
In metazoans, plants, and fungi, the spindle checkpoint delays mitosis until each chromosome is attached to one or more of its own kinetochore microtubules (kMTs). Some unicellular eukaryotes, however, have been reported to have fewer kMTs than chromosomes [1-5]. If this is the case, it is unclear how the spindle checkpoint could be satisfied. In the vast majority of the previous studies, mitotic cells were chemically fixed at room temperature, but this does not always preserve dynamic and/or small structures like spindle MTs and kinetochores [6]. Indeed, later higher-resolution studies have reversed some earlier claims [7-11]. Here we show that in Ostreococcus tauri (the smallest eukaryote known), mitosis does involve fewer spindle microtubules than chromosomes. O. tauri cultures were enriched for mitotic cells, high-pressure frozen, and then imaged in 3D both in plastic and in a near-native ("frozen-hydrated") state through electron tomography. Mitotic cells have a distinctive intranuclear heterochromatin-free "spindle tunnel" with approximately four short and occasionally one long, incomplete (unclosed) microtubule at each end of the spindle tunnel. Because other aspects of O. tauri's spindle checkpoint seem typical, these data suggest that O. tauri's 20 chromosomes are physically linked and segregated as just one or a small number of groups.


Cognitive functions in preschool children with specific language impairment.
A growing body of research has focused on executive functions in children with specific language impairment (SLI). However, results show limited convergence, particularly in preschool age. The current neuropsychological study compared performance of cognitive functions focused on executive components and working memory in preschool children with SLI to typically developing controls. Performance on the measures cognitive flexibility, inhibition, processing speed and phonological short-term memory was assessed. The monolingual, Caucasian study sample consisted of 30 children with SLI (Mage = 63.3 months, SD = 4.3 months) and 30 healthy controls (Mage = 62.2 months, SD = 3.7 months). Groups were matched for age and nonverbal IQ. Socioeconomic status of the participating families was included. Children with SLI had significantly poorer abilities of phonological short-term memory than matched controls. A tendency of poorer abilities in the SLI group was found for inhibition and processing speed. We confirmed phonological short-term memory to be a reliable marker of SLI in preschoolers. Our results do not give definite support for impaired executive function in SLI, possibly owing to limited sensitivity of test instruments in this age group. We argue for a standardization of executive function tests for research use.


[Not Available].
Investigation into virulence and mycotoxin formation of the dry rot causing pathogen Fusarium sambucinum on potatos 11 strains ofFusarium sambucinum were isolated from tubers with dry rot symptoms from three different depots in the Land Brandenburg and Saxony-Anhalt. All isolates produced diacetoxyscripenol in artificially infected potato tubers. Additionally, two isolates produced T-2 and HT-2 toxins as well. The virulence and mycotoxin formation of the isolates was dependent on the potato varieties 'Sieglinde' and 'Berber' used in the experiment. The amount of diacetoxyscripenol in diseased tissue was positively correlated with the virulence of theF. sambucinum isolate and the susceptibility of the potato variety as well.


The wettability of electron spun membranes by synovial fluid.
Aseptic loosening due to periprosthetic osteolysis has been accepted as one of the leading causes of revision procedures in patients with previous joint arthroplasty. Recently, several strategies for suppression of osteolysis were proposed, mostly based on biological treatment such as mitigation of chronic inflammatory reactions. However, these biological treatments do not stop the debris migration but only reduce the inflammatory reaction. To address this shortcoming, we propose the concept of ultrahigh molecular weighted polyethylene particles filtration storage by electrospun membranes. Firstly, the surface tension of synovial fluid (SF) is obtained by use of a pendant droplet. Secondly, the contact angle of the electrospun membranes wetted by two different liquids is measured to obtain the free surface energy using of the Owens-Wendt model. Additionally, the wettability of electrospun membranes by SF as a function of technology parameters is studied.


Systemic inflammation and cortical neurochemistry in never-medicated first episode-psychosis individuals.
Studies of cellular and cytokine profiles have contributed to the inflammation hypothesis of schizophrenia; however, precise markers of inflammatory dysfunction remain elusive. A number of proton magnetic resonance spectroscopy (1H-MRS) studies in patients with first-episode psychosis (FEP) have shown higher brain levels of metabolites such as glutamate, myo-inositol (mI) and choline-containing compounds (tCho), suggesting neuroinflammation. Here, we present peripheral inflammatory profiles in antipsychotic-naive FEP patients and age-and-sex matched healthy controls, as well as cortical glutamate, mI and tCho levels using 1H-MRS. Inflammatory profiles were analyzed using cytokine production by peripheral blood mononuclear cells, that were either spontaneous or stimulated, in 48 FEP patients and 23 controls. 1H-MRS of the medial prefrontal cortex was obtained in 29 FEP patients and 18 controls. Finally, 16 FEP patients were rescanned after 4 weeks of treatment (open-label) with Risperidone. FEP patients showed a higher proportion of proinflammatory Th1/Th17 subset, and an increased spontaneous production of Interleukin (IL)-6, IL-2 and IL-4 compared with the control group. Results obtained from 1H-MRS showed no significant difference in either glutamate, mI or tCho between FEP and control groups. At baseline, CD8% showed a negative correlation with glutamate in FEP patients; after 4 weeks of risperidone treatment, the FEP group exhibited a decrease in glutamate levels which positively correlated with CD4 + T cells. Nevertheless, these correlations did not survive correction for multiple comparisons. FEP patients show evidence of immune dysregulation, affecting both the innate and adaptive immune response, with a predominantly Th2 signature. These findings, along with the changes produced by antipsychotic treatment, could be associated with both systemic and central inflammatory processes in schizophrenia.


The identification of serum tuftsin by reverse-phase high-performance liquid chromatography and mass spectrometry.
We describe for the first time a method for unambiguously identifying the phagocytic stimulating tetrapeptide tuftsin from trypsinized human serum. The method consists of separating serum tuftsin by reverse-phase (RP)-HPLC, collecting HPLC fractions corresponding to the synthetic tuftsin retention time, and then subjecting those fractions to mass spectrometry/mass spectrometry (MS/MS) analysis, which provides optimal molecular specificity to the measurement. Although quantification was not the goal, it was estimated that the amount of tuftsin found by RP-HPLC and MS/MS was in the hundreds of nanograms per milliliter.


A corpus of potentially contradictory research claims from cardiovascular research abstracts.
Research literature in biomedicine and related fields contains a huge number of claims, such as the effectiveness of treatments. These claims are not always consistent and may even contradict each other. Being able to identify contradictory claims is important for those who rely on the biomedical literature. Automated methods to identify and resolve them are required to cope with the amount of information available. However, research in this area has been hampered by a lack of suitable resources. We describe a methodology to develop a corpus which addresses this gap by providing examples of potentially contradictory claims and demonstrate how it can be applied to identify these claims from Medline abstracts related to the topic of cardiovascular disease. A set of systematic reviews concerned with four topics in cardiovascular disease were identified from Medline and analysed to determine whether the abstracts they reviewed contained contradictory research claims. For each review, annotators were asked to analyse these abstracts to identify claims within them that answered the question addressed in the review. The annotators were also asked to indicate how the claim related to that question and the type of the claim. A total of 259 abstracts associated with 24 systematic reviews were used to form the corpus. Agreement between the annotators was high, suggesting that the information they provided is reliable. The paper describes a methodology for constructing a corpus containing contradictory research claims from the biomedical literature. The corpus is made available to enable further research into this area and support the development of automated approaches to contradiction identification.


Identification of differentially expressed long non-coding RNAs and mRNAs in orbital adipose/connective tissue of thyroid-associated ophthalmopathy.
Extracellular matrix remodeling and orbital adipose/connective tissue expansion are two key features of thyroid-associated ophthalmopathy (TAO). Recent studies have indicated the critical role of long non-coding RNAs (lncRNAs) in the pathogenesis of ocular disorders. However, little is known about the roles of lncRNAs in orbital adipose/connective tissue of TAO. In this study, the profiles of lncRNAs and mRNAs in the orbital adipose/connective tissue of TAO were identified by RNA sequencing. A total of 809 differential lncRNAs and 607 differential mRNAs were identified, among which 52 genes were found to be significantly related to the extracellular matrix. Co-expression network analysis suggested that lncRNAs might regulate extracellular matrix remodeling in orbital adipose/connective tissue of TAO. Additionally, the target genes of lncRNAs involved in the lipid metabolism and cytokine-cytokine receptor interaction were also identified. These results may provide potential regulatory mechanisms of lncRNAs in the orbital adipose/connective tissue of TAO.


Outcome of surgery for acromegaly performed by different surgeons: importance of surgical experience.
The aim of this study was to evaluate transsphenoidal surgery results in acromegalic patients which were performed not by a single surgeon but by different surgeons. The study included 30 (M/F: 13/17) patients whose follow-up data were available. Basal or nadir postglucose growth hormone levels of less than 2 ng/ml were accepted as cure criteria. Six of them underwent a further operation due to previous surgical failure. Cure was achieved in 33% of patients while hypopituitarism was observed in 10% (3/30) of patients after the first operation. The cure rates were 63% and 15% in patients with microadenomas (n = 11) and macroadenomas (n = 19) respectively (p = 0.042). Only one of the patients (16%) who underwent a second operation achieved remission, while hypopituitarism was observed in five of them (83%). There was no significant difference in the cure rates between the first and second operation, but the risk of hypopituitarism was significantly higher in patients who underwent further surgery (p = 0.008). The cure rate following surgery is significantly lower in acromegalic patients with macroadenomas than in patients with microadenomas. Cure probability decreases with a further operation, while complication risk increases significantly. Octreotide therapy, which could be used as an alternative therapy to the surgery, revealed high success rates in both microadenomas and macroadenomas. The low cure rates found in this study compared with published series could be attributed to the fact that operations were performed by inexperienced surgeons.


Measuring the quality of interprofessional collaboration in child mental health collaborative care.
This pilot study examines the potential utility of the Perception of Interprofessional Collaboration Model and the shared decision-making scales in evaluating the quality of partnership in child mental health collaborative care. Ninety-six primary care professionals working with children and youth responded to an internet survey which included the Perception of Interprofessional Collaboration Model scale (PINCOM-Q) and an adapted version of a shared decision-making scale (Échelle de confort décisionnel, partenaire-ECD-P). The perceptions of child mental health professionals were compared with those of other professionals working with children. The PINCOM-Q and the ECD-P scales had an excellent internal consistency and they were moderately correlated. Child mental health professionals' Individual Interprofessional Collaboration scores from the PINCOM-Q individual aspects subscale were better than that of other child professionals. These scales may be interesting instruments to measure the quality of partnership in child mental health collaborative care settings. Research needs to replicate these findings and to determine whether the quality of collaboration is a predictor of mental health outcome.


Four-year prostate-specific antigen progression in the non-cancer population of the European Randomized Study of Screening for Prostate Cancer.
To determine the rate of conversion of prostate-specific antigen (PSA) to values of > 4 ng/mL in a normal male population. In men with an initial PSA level of < 4 ng/mL the probability of having a PSA of > or = 4 ng/mL and its relationship with the age at first PSA test, baseline PSA level and time to the determination was evaluated. Statistical methods were used to correct for the within-subject variability across many PSA determinations. In all, 45433 PSA tests in 21169 men with an initial PSA of < 4 ng/mL were available. Overall, in 960 men (4.5%) the PSA level changed to > or = 4 ng/mL. The lowest chance was for men aged < 55 years with an initial PSA of < 1 ng/mL and a new PSA determination during the first 18 months (0.952 conversions per 1000 men) while the highest was for men aged < 55 years with an initial PSA level of > 2.5 ng/mL (395 conversions per 1000 men). There was a significant and independent relationship between conversion and the interval between determinations, with conversion being 3.33 times more frequent during 18-42 months than with the reference category (< 18 months) and 5.23 times more frequent during > 42 months. The probability of conversion independently increased by 3 lambda for every additional year of age. Every unit of basal PSA multiplied by 6.48 the probability of conversion. The risk for conversion to a PSA of > or = 4 ng/mL can be anticipated from the patient's age and initial PSA level. Re-screening before 4 years after the first round can be useless for men with an initial PSA of < 1 ng/mL. Four-year intervals could be inadequate for men with an initial PSA of > 2.5 ng/mL if conversion to > 4 ng/mL is to be avoided.


Slab thickness tuning approach for solid-state strong coupling between photonic crystal slab nanocavity and a quantum dot.
The quality factor and mode volume of a nanocavity play pivotal roles in realizing the strong coupling interaction between the nanocavity mode and a quantum dot. We present an extremely simple method to obtain the mode volume and investigate the effect of the slab thickness on the quality factor and mode volume of photonic crystal slab nanocavities. We reveal that the mode volume is approximatively proportional to the slab thickness. As compared with the previous structure finely optimized by introducing displacement of the air holes, via tuning the slab thickness, the quality factor can be enhanced by about 22%, and the ratio between the coupling coefficient and the nanocavity decay rate can be enhanced by about 13%. This can remarkably enhance the capability of the photonic crystal slab nanocavity for realizing the strong coupling interaction. The slab thickness tuning approach is feasible and significant for the experimental fabrication of the solid-state nanocavities.


Controlling Echinococcus multilocularis-ecological implications of field trials.
Two field trials to reduce the prevalence of Echinococcus multilocularis in foxes have been conducted in recent years. Although both trials reduced prevalence considerably, they failed to eradicate the parasite in the study region. Following the control trial in northern Germany, prevalence recovered unexpectedly and rapidly, reaching pre-control levels five quarters (15 months) after the end of control. To understand the internal dynamics of the parasite-host system's reaction to control, we developed a spatially explicit simulation model, Echi. The simulation model incorporates the information available concerning fox tapeworm population dynamics. Using epidemiological parameters to adjust pre-control prevalence, the model predicts the temporal evolution of the prevalence of E. multilocularis in controlled foxes without departing from the range of uncertainty of the field data. However, the model does not predict the rapid pre-control recovery observed in the field trial. The deviation of the model's prediction from field data indicates the involvement of processes not yet taken into account. We modified the model step by step to mimic processes with the potential to cause the rapid post-control recovery of the prevalence of E. multilocularis in foxes. Neither the longevity of tapeworm eggs nor the migratory behaviour of foxes showed any influence on the post-control reaction of the parasite-host system. However, landscape structures leading to a heterogeneous distribution of infected foxes have the potential to alter the system's reaction to control. If infected foxes are concentrated in multiple clusters in the landscape, the model prediction tallied with the range of uncertainty of the field data. Such spatial distribution of infected foxes may be caused by differential abiotic conditions influencing the survival of tapeworm eggs. The model was found to comply best with field data if the foxes acquire partial immunity by being exposed to the fox tapeworm. Both hypotheses explaining the rapid post-control recovery of the prevalence of E. multilocularis observed in the fox population were supported by field data. Both hypotheses have far-reaching consequences for future control trials. The spatial aggregation of infected foxes would enable control efforts to be concentrated on these highly infected areas. However, the acquisition of immunity acts as a buffer to control, necessitating intensified control measures.


Neuroprotection of Fasting Mimicking Diet on MPTP-Induced Parkinson's Disease Mice via Gut Microbiota and Metabolites.
Parkinson's disease (PD) is strongly associated with life style, especially dietary habits, which have gained attention as disease modifiers. Here, we report a fasting mimicking diet (FMD), fasting 3 days followed by 4 days of refeeding for three 1-week cycles, which accelerated the retention of motor function and attenuated the loss of dopaminergic neurons in the substantia nigra in 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced PD mice. Levels of brain-derived neurotrophic factor (BDNF), known to promote the survival of dopaminergic neurons, were increased in PD mice after FMD, suggesting an involvement of BDNF in FMD-mediated neuroprotection. Furthermore, FMD decreased the number of glial cells as well as the release of TNF-α and IL-1β in PD mice, showing that FMD also inhibited neuro-inflammation. 16S and 18S rRNA sequencing of fecal microbiota showed that FMD treatment modulated the shifts in gut microbiota composition, including higher abundance of Firmicutes, Tenericutes, and Opisthokonta and lower abundance of Proteobacteria at the phylum level in PD mice. Gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry revealed that FMD modulated the MPTP-induced lower propionic acid and isobutyric acid, and higher butyric acid and valeric acid and other metabolites. Transplantation of fecal microbiota, from normal mice with FMD treatment to antibiotic-pretreated PD mice increased dopamine levels in the recipient PD mice, suggesting that gut microbiota contributed to the neuroprotection of FMD for PD. These findings demonstrate that FMD can be a new means of preventing and treating PD through promoting a favorable gut microbiota composition and metabolites.


Nuances in transcanal endoscopic surgical technique for glomus tympanicum tumors.
To describe the utility and nuances of transcanal endoscopic surgery (TCES) on glomus tympanicum tumors from a single surgeon's experience. Twelve patients, eight female and four males, diagnosed pre-operatively with glomus tympanicum tumors. They all underwent endoscopic resection by a single surgeon. Feasibility of endoscopic resection of glomus tympanicum tumors without conversion to a microscopic approach. Secondary outcomes include tumor stage, pre and post-operative audiometry, vertigo, sensorineural hearing loss (SNHL) and integrity of the facial nerve, ossicles, chorda tympani and tympanic membrane. Twelve patients underwent TCES, eight patient's pathology results were glomus tympanicum, ranging from Glasscock-Jackson grade I-III. Due to loss in follow up, 6/8 patients had complete audiometric data, which were analyzed. Average pre-operative air-bone-gap (ABG) was 5.41 compared to post-operative ABG of 5.08 (p > 0.89). No patients resulted in any, post-operative vertigo, tinnitus, SNHL, facial nerve injury or chorda tympani nerve injury. Two patients had intentional tympanic membrane perforations secondary to tumor adherence to the membrane. They were repaired with tragal perichondrium graft. No patients have had any recurrences. Endoscopic resection of glomus tympanicum tumors is a feasible and effective, alternative visualization modality for the neurotologist. Surgical pearls are described herein.


Levels and profiles of brominated and chlorinated contaminants in human breast milk from Thessaloniki, Greece.
Human breast milk samples (n=87) collected between July 2004 and July 2005 from primipara and multipara mothers from Thessaloniki, Greece were analysed for six groups of persistent organic pollutants (POPs): polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane and its metabolites (DDTs), chlordane compounds (CHLs), hexachlorocyclohexane isomers (HCHs) and hexachlorobenzene (HCB). DDTs [median: 410ng/g lipid weight (lw)], PCBs (median: 90ng/g lw) and HCHs (median: 40ng/g lw) were the predominantly identified compounds in all the breast milk samples. Levels of PBDEs (median: 1.5ng/g lw) in human breast milk samples from Thessaloniki, Greece were lower compared to other countries. Maternal age had a positive correlation with most compounds, but not with PBDEs. Women with a higher occupational exposure to PBDEs (i.e., working in office environments) had higher PBDE concentrations than all others and showed strong correlations, especially for BDE 47 and BDE 153. None of the analysed compounds showed any correlation with parity. Based on these levels, the daily intake of each group of POPs via human milk was calculated and compared with the tolerable daily intakes (TDI) or the reference doses (RfD). For the majority of samples (85 out of 87) a higher daily intake of PCBs than the TDI was calculated, while 11 out of 87 samples had a higher HCB intake than the TDI. The TDI and the RfD were not exceeded for DDTs and PBDEs, respectively. This is the first report of brominated flame retardants in human breast milk from Greece.


Human exposure to mycotoxins in Egypt.
This investigation examined the exposure of Egyptian infants to Aflatoxin M1 (AfM1) and of lactating mothers to Aflatoxin B1, using AfM1 in human milk as a biomarker for exposure to AfB1. The presence of ochratoxin A (OA) in human milk was also investigated to determine the levels of infants exposure to OA from human milk. The results indicated that AfM1 was found in 66 (55 %) of 120 human milk samples with a mean of 0.3 ± 0.53 ng/mL (range 0.02 to 2.09 ng/mL). OA was found in 43 (35.8 %) of 120 human milk samples with a mean of 21.1 ± 13.7 ng/mL (range 5.07 to 45.01 ng/mL), which will cause a daily intake of OA from human milk exceeding the suggested tolerable dose of 5 ng/kg-1 of OA body weight. On the other side AfM1 was found in 25 % of blood samples (5 out of 20 samples), at a mean of 1.18 ng/mL, but it was detected only in one urine sample (1 out of 20 samples). OA was detected only in 2 out of 13 blood samples (15.4 %) with an average 3.67 ng/mL. Whereas OA was not detected in all analyzed urine samples.


Comparative Study of Bipolar Electrocautery Versus Silk Ligation for Hemostasis During Tonsillectomy.
Tonsillectomy is a commonly performed surgery in otolaryngological practice. Owing to the possibility of postoperative bleeding, it is considered as one of the major surgical procedures. Various techniques have been advocated, however dissection and electrocautery are the most commonly used techniques in tonsillectomy. The objective was to study and compare the relative efficacy using two methods of tonsillectomy- bipolar electrocautery versus silk ligation. This prospective study included 50 patients who underwent tonsillectomy. Patients were randomly divided into two groups. In Group A, left tonsillar fossa haemorrhage was controlled by ligation, while in Group B, bipolar diathermy was used to control bleeding of right tonsillar fossa. Comparison was done in terms of time taken for hemostasis, amount of intra-operative blood loss and post-operative pain. 130 (72.22%) male and 50 (27.77%) females were included. Group A included 20 cases while Group B included 30 cases. The mean time taken for hemostasis in Group A patients was 40.5 ± 4.4 min as compared to 25.3 ± 6.2 min in Group B patients. The mean blood loss on cautery side was 49.5 ± 4.5 ml and that on the ligation side was 68.6 ± 5.3 ml. Post-operative pain was significantly more in Group B patients as compared to Group A patients. Bipolar diathermy is a quicker and faster method to achieve hemostasis with little intraoperative blood loss as compated to silk ligation.


Analysis of the impact of digital watermarking on computer-aided diagnosis in medical imaging.
Medical images (MI) are relevant sources of information for detecting and diagnosing a large number of illnesses and abnormalities. Due to their importance, this study is focused on breast ultrasound (BUS), which is the main adjunct for mammography to detect common breast lesions among women worldwide. On the other hand, aiming to enhance data security, image fidelity, authenticity, and content verification in e-health environments, MI watermarking has been widely used, whose main goal is to embed patient meta-data into MI so that the resulting image keeps its original quality. In this sense, this paper deals with the comparison of two watermarking approaches, namely spread spectrum based on the discrete cosine transform (SS-DCT) and the high-capacity data-hiding (HCDH) algorithm, so that the watermarked BUS images are guaranteed to be adequate for a computer-aided diagnosis (CADx) system, whose two principal outcomes are lesion segmentation and classification. Experimental results show that HCDH algorithm is highly recommended for watermarking medical images, maintaining the image quality and without introducing distortion into the output of CADx.


Use of physical processes to maximize goat milk cream hydrolysis: Impact on structure and enzymatic hydrolysis.
This study evaluated the use of ultrasound (US), high-shear dispersion (HSD), stirring (ST), and low or high pressure homogenization (LPH or HPH) technologies to modify the goat milk cream (GMC) structure, focusing on improving the enzymatic hydrolysis of its lipids. The GMC structure was evaluated, as well as its creaming and emulsion stability index (ESI). The processed GMC was hydrolyzed by lipase at 50 °C for 300 min, and the fatty acids concentration (FAC) was evaluated over the reaction. ST, HPH, and HSD showed ∼ 90% lower emulsion destabilization, 10 times higher ESI, and smaller fat globule size than unprocessed GMC. The pretreatments increased the hydrolysis rate up to 2.4 times and the final FAC up to 8.7 times. ST (4 min), HPH (40 MPa) and HSD (5 min/ 25,000 rpm) showed the best results, which were correlated with the changes in the GMC structure. The results suggest that the physical treatments impacted the substrate structure, favoring enzyme activity and accelerating the hydrolysis degree. Therefore, the application of physical processes can be an interesting strategy to enhance the hydrolysis of GMC, aiming to produce compounds of industrial interest.


Animal-free production of ccc-supercoiled plasmids for research and clinical applications.
The topological structure of plasmid DNA can be characterized by capillary gel electrophoresis (CGE analysis)-an important tool for quality control and stability assessments in DNA storage or application. Hence, a large-scale manufacturing process was developed that allows the removal of undesired open circular (oc) or linear plasmid topologies, bacterial genomic DNA, RNA, proteins as well as lipopolysaccharides (endotoxins) and results in obtaining supercoiled (covalently closed circular, ccc) plasmid DNA in a pure form without using any animal-derived substances. Using CGE, the development and in-line monitoring for pharmaceutical plasmid production starting from fermentation control throughout the whole manufacturing process including the formulated and filled product can be performed the first time in a way conforming to good manufacturing practices (GMP). Plasmid stability data were obtained from analysis of shear effects influencing the plasmid quality in DNA drug delivery formulation and application (e.g. gene gun or jet injection). The physical stability of plasmid DNA is for the first time evaluated in DNA storage experiments on the level of different plasmid forms.


Retinotopic organization within the lateral posterior complex of the cat.
Electrophysiological mapping methods were employed to systematically study the retinotopic organization within the cat's lateral posterior complex (LP). Visual responses were recorded in all the major subdivisions of the LP as well as in several adjoining cell groups. Specifically, separate representations of the visual field were identified for pulvinar, zones LP1-c, LP1-r, LPi, and LPm. Partial representations of the visual field were also evident in the geniculate wing, subdivisions of the lateral posterior shell, the inferior division of the posterior nuclear group, the suprageniculate nucleus, and the central lateral nucleus. Sufficient mapping observations were made to define the internal organization of major visual representations. Additionally, there was a very close correspondence between the mapping observations when they were compared with the cytoarchitectural criteria for recognizing functional cell groups (Updyke: J. Comp. Neurol. 219:143-181, '83).


Anticipatory Manoeuvres in Bird Flight.
It is essential for birds to be agile and aware of their immediate environment, especially when flying through dense foliage. To investigate the type of visual signals and strategies used by birds while negotiating cluttered environments, we presented budgerigars with vertically oriented apertures of different widths. We find that, when flying through narrow apertures, birds execute their maneuvers in an anticipatory fashion, with wing closures, if necessary, occurring well in advance of the aperture. When passing through an aperture that is narrower than the wingspan, the birds close their wings at a specific, constant distance before the aperture, which is independent of aperture width. In these cases, the birds also fly significantly higher, possibly pre-compensating for the drop in altitude. The speed of approach is largely constant, and independent of the width of the aperture. The constancy of the approach speed suggests a simple means by which optic flow can be used to gauge the distance and width of the aperture, and guide wing closure.


Temporal analysis of transcription and replication during acute infection with lymphocytic choriomeningitis virus.
We have analyzed the accumulation of viral genomic and messenger RNAs in tissue culture cells during the first 24 hr of acute infection with lymphocytic choriomeningitis virus (LCMV). This has allowed comparison of the relative amounts of the genomic L and S RNAs (both genomic sense and genomic complementary sense) and of nucleoprotein (NP) and glycoprotein precursor (GP-C) mRNAs. Using these techniques NP mRNA was detected simultaneously with genomic S RNA, but the amount of NP mRNA accumulating during this period of infection was higher than that of GP-C mRNA. This is consistent with a model for ambisense RNA transcription and replication proposed by D.D. Auperin, V. Romanowski, M. Galinski and D. H. L. Bishop (J. Virol. 52: 897-904, 1984). The accumulation of S RNA exceeded that of L RNA and, for both L and S RNAs, the amount of genomic sense RNA was higher than that of genomic complementary RNA.


European trial of cyclosporine in chronic active Crohn's disease: a 12-month study. The European Study Group.
The role of cyclosporine in Crohn's disease is controversial. This study aimed to delineate the long-term effect of cyclosporine in chronic active Crohn's disease. One hundred eighty-two patients from 33 European centers were included. The patient cohort was stratified at entry into a stratum with low Crohn's Disease Activity Index (CDAI) ( < 200) and high CDAI ( > 200). The low-activity group continued to receive the pretrial steroid dose for 2 months, and the high-activity group received 1 mg.kg-1.day-1 prednisone initially. During months 3 and 4, the dose of steroids was reduced stepwise to 5 mg/day in all patients. Placebo and cyclosporine (5 mg.kg-1.day-1) were administered throughout the 12-month study period. The main parameter of efficacy was the CDAI, and the main end point was the number of patients in remission at month 12. During cyclosporine therapy, 35% (95% confidence interval [95% Cl], 25%-46%) of the patients achieved a full remission (CDAI, < 150) after 4 months compared with 27% (95% Cl, 18%-38%) in the placebo group (P > 0.05). At month 12, only 20% (95% Cl, 12%-31%) vs. 20% (95% Cl, 12%-31%) of the patients had maintained a continuous remission. No major differences between treatment groups were found within each of the two strata. The long-term treatment of chronic active Crohn's disease with cyclosporine plus low-dose steroids does not offer an advantage compared with low-dose steroids alone.


De Novo Carborane-Containing Macrocyclic Peptides Targeting Human Epidermal Growth Factor Receptor.
l-Carboranylalanine (LCba) is a unique artificial amino acid containing a cluster of 10 boron atoms. Since the three-dimensional aromaticity and charge distributions of the carborane side chain are quite different from any side chains of proteinogenic amino acids, there is no report whether LCba can be a substrate for the translation machinery. Here, we report studies on the ribosomal incorporation of LCba into peptide via initiation and elongation using the flexizyme-assisted translation system. Our results indicate that only the initiation step could tolerate LCba incorporation, but the elongation steps could not, very likely due to its steric bulkiness of the side chain. Based on this knowledge, we have designed a library of macrocyclic peptides initiated by α-N-(2-choloroacetyl)-l-carboranylalanine (ClAc-LCba) and selected molecules capable of binding to human epidermal growth factor receptor (hEGFR). Two peptides that were forwarded to deeper studies exhibited affinities with KD values at 16 and 20 nM against hEGFR. Computational modeling of one of the peptides suggested that the carborane side chain might be directly involved in the interaction with the hydrophobic β-sheet core in the EGF binding site of hEGFR, which is consistent with the mutational data where replacing LCba residue with LPhe completely eliminated the binding activity. Cell lines that stably express hEGFR could be stained by incubation with the C-terminal fluorescein-labeled peptides, whereas hEGFR-negative cells could not be stained. This study provides a general strategy for the de novo discovery of carborane-containing macrocyclic peptides targeting various tumor biomarker proteins, potentially applicable to boron neutron capture therapy.


Effects of agricultural tillage and sediment accumulation on emergent plant communities in playa wetlands of the U.S. High Plains.
Identifying community assembly filters is a primary ecological aim. The High Plains, a 30 million ha short-grass eco-region, is intensely cultivated. Cultivation disturbance, including plowing and eroded soil deposition down-slope of plowing, influences plant composition in depressional wetlands, such as playas, within croplands. We evaluated influences of wetland cultivation and sediment deposition on plant composition in playas embedded within croplands (46 plowed and 32 unplowed) and native grasslands (79) across 6 High Plains' states. Sediment accumulation ranged from 7 to 78 cm in cropland and 1 to 35 cm in grassland playas. Deeper sediments and plowing each decreased wetland plant richness, 28% and 70% respectively in cropland wetlands. Sediment depth reduced richness 37% in small grasslands playas while it increased richness 22% in larger ones, suggesting moderate disturbance increased richness when there were nearby propagule sources. Sediment depth was unrelated to species richness in plowed wetlands, probably because plowing was a strong disturbance. Plowing removed perennial plants from vegetation communities. Sediment accumulation also influenced species composition in cropland playas, e.g., probability of Eleocharis atropurpurea increased with sediment depth, while probability of Panicum capillare decreased. In grassland playas, observed lighter sediment depths did not influence species composition after accounting for wetland area. Sediment accumulation and plowing shift wetland plant communities toward annual species and decrease habitat connectivity for wetland-dependent organisms in cropland playas over 39,000 and 23,400 ha respectively. Conservation practices lessening sediment accumulation include short-grass buffer strips surrounding wetlands. Further, wetland tillage, allowed under federal agricultural conservation programs, should be eliminated.


Advances in HIV therapeutics and cure strategies: findings obtained through non-human primate studies.
Human immunodeficiency virus (HIV), the main contributor of the ongoing AIDS epidemic, remains one of the most challenging and complex viruses to target and eradicate due to frequent genome mutation and immune evasion. Despite the development of potent antiretroviral therapies, HIV remains an incurable infection as the virus persists in latent reservoirs throughout the body. To innovate a safe and effective cure strategy for HIV in humans, animal models are needed to better understand viral proliferation, disease progression, and therapeutic response. Nonhuman primates infected with simian immunodeficiency virus (SIV) provide an ideal model to study HIV infection and pathogenesis as they are closely related to humans genetically and express phenotypically similar immune systems. Examining the clinical outcomes of novel treatment strategies within nonhuman primates facilitates our understanding of HIV latency and advances the development of a true cure to HIV.


Proposed actions are no actions: re-modeling an ontology design pattern with a realist top-level ontology.
Ontology Design Patterns (ODPs) are representational artifacts devised to offer solutions for recurring ontology design problems. They promise to enhance the ontology building process in terms of flexibility, re-usability and expansion, and to make the result of ontology engineering more predictable. In this paper, we analyze ODP repositories and investigate their relation with upper-level ontologies. In particular, we compare the BioTop upper ontology to the Action ODP from the NeOn an ODP repository. In view of the differences in the respective approaches, we investigate whether the Action ODP can be embedded into BioTop. We demonstrate that this requires re-interpreting the meaning of classes of the NeOn Action ODP in the light of the precepts of realist ontologies. As a result, the re-design required clarifying the ontological commitment of the ODP classes by assigning them to top-level categories. Thus, ambiguous definitions are avoided. Classes of real entities are clearly distinguished from classes of information artifacts. The proposed approach avoids the commitment to the existence of unclear future entities which underlies the NeOn Action ODP. Our re-design is parsimonious in the sense that existing BioTop content proved to be largely sufficient to define the different types of actions and plans. The proposed model demonstrates that an expressive upper-level ontology provides enough resources and expressivity to represent even complex ODPs, here shown with the different flavors of Action as proposed in the NeOn ODP. The advantage of ODP inclusion into a top-level ontology is the given predetermined dependency of each class, an existing backbone structure and well-defined relations. Our comparison shows that the use of some ODPs is more likely to cause problems for ontology developers, rather than to guide them. Besides the structural properties, the explanation of classification results were particularly hard to grasp for 'self-sufficient' ODPs as compared with implemented and 'embedded' upper-level structures which, for example in the case of BioTop, offer a detailed description of classes and relations in an axiomatic network. This ensures unambiguous interpretation and provides more concise constraints to leverage on in the ontology engineering process.


Pain Intensity and Fear Avoidance Explain Disability Related to Chronic Low Back Pain in a Saudi Arabian Population.
A cross-sectional study. The aim of this study was to describe multi-dimensional profiles for people with chronic low back pain (CLBP) and to examine the associations between CLBP-related disability and individual, psychosocial and physical factors in a Saudi population. CLBP-related disability is a multidimensional phenomenon. There is growing interest in exploring factors associated with CLBP-related disability in Saudi Arabia but research is limited in comparison to other countries. Participants completed questionnaires covering demographics, pain intensity, back beliefs, fear avoidance, psychological distress, and physical activity. Oswestry Disability Index (ODI) was used to measure disability. Participants also performed a standardized sequence of physical performance tests and a Pain Behavior Scale was used to evaluate pain behaviors during performance of these tests. The relationships between disability and all variables were explored using univariate and multivariate regression analyses. One hundred and fifteen participants were included, 63% of whom were female. Participants demonstrated moderate disability (mean [SD]: 26.6 [13.5]). The mean (SD) back beliefs score was 28.6 (7.3). Mean depression, anxiety, and stress (DASS 21) scores indicated mild distress; however, 26% to 39% scored in the moderate to severe range for at least one subscale. In univariate analyses, pain intensity and fear avoidance beliefs (physical activity and work) were moderately associated with disability (r = 0.56, 0.49, 0.52, respectively, P < 0.001), with all other factors demonstrating weak association. Multivariate regression revealed that pain intensity, fear avoidance beliefs, psychological distress, and participants' age were all found to be associated with disability, accounting for 52.9% (adjusted R = 0.529) of variability. This study provides a unique insight into the clinical profile of people with CLBP in a Saudi Arabian population. Pain and psychosocial factors were significantly associated with disability. This study supports the contention that CLBP-related disability is a multifactorial biopsychosocial condition across different cultures. 3.


Dyslipidemia treatment strategies in primary and secondary prevention. Dyslipemia Registry of the Spanish Arteriosclerosis Society.
Clinical studies show that patients with high cardiovascular risk are still far from reaching the therapeutic objectives, especially of the levels of LDL cholesterol. If the management of these patients in specialized units differs from other scenarios is known. 61 certified Lipid Units were selected in the Registry of Dyslipemias of the Spanish Arteriosclerosis Society for the collection of study data. The study included 3958 subjects >18 years of age who met the criteria for hypercholesterolemia (LDL cholesterol ≥160 mg/dL or non-HDL cholesterol ≥190 mg/dL) without familial hypercholesterolemia. A total 1,665 subjects were studied with a mean follow-up time of 4.2 years. A total of 42 subjects had a cardiovascular event since their inclusion in the Registry, which represents 0.6%. There were no differences in the treatment used at follow-up, but 50% of the patients did not reach the therapeutic goals at the visit end of follow-up. An increase in the potency of the lipid-lowering treatment was observed, including PCSK9 inhibitors use in 16.7% of subjects with recurrences.


Hepatocellular Carcinoma: New Developments.
This is a review of current practices and upcoming developments regarding hepatocellular carcinoma (HCC). This includes a contemporary review of the diagnosis, staging, and treatment of HCC. Furthermore, the authors provide a review of certain ongoing trials and future directions of various treatment modalities for HCC.


Health care in the shadow of Old Faithful.
Yellowstone National Park is served by a unique hospital and clinic system that includes primary care, inpatient stabilization, and professional education for health care professionals.


Novel combination immunotherapy for pancreatic cancer: potent anti-tumor effects with CD40 agonist and interleukin-15 treatment.
With the poorest 5-year survival of all cancers, improving treatment for pancreatic cancer is one of the biggest challenges in cancer research. We sought to explore the potential of combining both priming and activation of the immune system. To achieve this, we combined a CD40 agonist with interleukin-15 and tested its potential in pancreatic cancer. Response to this combination regimen was assessed in pancreatic ductal adenocarcinoma mouse models, and a thorough analysis of the tumor microenvironment was performed. We demonstrated profound reduction in tumor growth and increased survival of mice with the majority of mice being cured when both agents were combined, including an unprecedented 8-fold dose reduction of CD40 agonist without losing any efficacy. RNAseq analysis showed involvement of natural killer (NK) cell- and T-cell-mediated anti-tumor responses and the importance of antigen-presenting cell pathways. This combination resulted in enhanced infiltration of tumors by both T cells and NK cells, as well as a striking increase in the ratio of CD8+ T cells over Tregs. We also observed a significant increase in numbers of dendritic cells (DCs) in tumor-draining lymph nodes, particularly CD103+ DCs with cross-presentation potential. A critical role for CD8+ T cells and involvement of NK cells in the anti-tumor effect was highlighted. Importantly, strong immune memory was established, with an increase in memory CD8+ T cells only when both interleukin-15 and the CD40 agonist were combined. These novel preclinical data support initiation of a first-in-human clinical trial with this combination immunotherapy strategy in pancreatic cancer.


Clinical scales in autoimmune encephalitis-A retrospective monocentric cohort study.
Assessing severity of antibody-mediated encephalitis (AE) or paraneoplastic encephalitis (PE) requires valid and reliable scores to guide treatment decisions and predict outcome both in clinical routine and studies. We aimed to validate the prognostic value of the clinical assessment scale in autoimmune encephalitis (CASE) and the anti-NMDAR-encephalitis one-year functional status (NEOS) score in patients suffering from AE and PE in a large monocentric cohort. We retrospectively applied the CASE and NEOS score to patients with definite AE and PE treated at a tertiary hospital. Correlations were established between the CASE and NEOS score and the modified Rankin scale (mRs). Multivariable analyses were calculated to identify predictors of outcome. Thirty-four patients (27 AE, 7 PE) were included. Correlations between mRS and CASE score were strongest in patients with AE compared to PE at all intervals, but in the subgroups (LGI1, NMDAR, GAD, miscellaneous surface antibodies, PE) the correlation was strongest in the interval after baseline. Patients with AE seemed to display better outcomes compared to PE, which was underlined by multivariable analysis. Improvement was mostly observed within 6-12 months after disease onset, after which little or no further improvement was noted with some exception for two patients with anti-NMDARE who recovered substantially even after 12 months of treatment. The NEOS score significantly predicted the outcome at last follow-up in patients with AE with a sensitivity of 79% at a cut-off value of 2 points (AUC 0.79, 95% CI 0.58-0.99, p = 0.04). The CASE and NEOS score are suitable supplementary tools in addition to the mRS for capturing diverse symptoms, for grading and monitoring symptom severity.


New Zealand experience of I125 brachytherapy for choroidal melanoma.
To examine patient survival, visual function and complications in all patients with choroidal melanoma treated with I125 brachytherapy between 1995 and 2003 at the authors' institution. To compare the results from their institution with those from international series. Data were collected on 92 consecutive patients. Dosimetry was calculated for the lens, fovea, optic nerve and tumour apex. Follow-up status of each patient domiciled outside the treatment centre was analysed from a postal questionnaire. Average pretreatment tumour dimensions were 3.9 mm (thickness) and 15.2 mm (diameter). Complete follow-up data were available on 92% of patients. Regression of tumour occurred in 88% of cases. Five enucleations were performed. There were five melanoma-related deaths. Visual acuity remained >6/12 in 35% of patients and >6/60 in 51% of patients. The most frequently observed complication was radiation retinopathy (maculopathy 23%, peripheral retinopathy 17%). Radiation cataract was seen in 11% and optic neuropathy in 10%. Dose of more than 90 Gy to the macula gave a 63% chance of developing maculopathy (P < 0.01). A tumour larger than 4 mm significantly increased the risk of developing radiation maculopathy (P = 0.003). Development of radiation cataract was dose-related; >25 Gy to the lens gave a 44% risk of cataract development (P < 0.001). For tumours less than 4 mm from the disc margin there was a 50% risk of optic neuropathy (P < 0.001). Patient outcomes following brachytherapy were excellent with a high percentage of patients retaining mobility vision. Development of complications was related to the tumour location and dose to non-tumour structures.


[Feedback strategies in assistive technology to promote social participation in children with cerebral palsy: Systematic review].
Living with cerebral palsy has consequences such as social interaction. Assistive technologies used for improving independence only focuses on biological and physiological variables. The main objective in this review is to synthesize the evidence on interventions with assistive technologies, including feedback systems, with the aim of discovering outcomes of social participation in children with cerebral palsy. There were 5 databases from rehabilitation which showed 683 articles in which only 9 were included. The studies assessed social participation with several instruments. The majority suggested positive effects in activities such as: walking, writing, playing, and social interaction. There were tools such as electronic pencils, switches, and exoskeletons present. Due to the poor quality of the methodologies of these studies, the search does not establish solid conclusions. However, the evidence suggests that assistive technologies with feedback have a positive impact on aspects of social participation.


Rapid Categorization of Human and Ape Faces in 9-Month-Old Infants Revealed by Fast Periodic Visual Stimulation.
This study investigates categorization of human and ape faces in 9-month-olds using a Fast Periodic Visual Stimulation (FPVS) paradigm while measuring EEG. Categorization responses are elicited only if infants discriminate between different categories and generalize across exemplars within each category. In study 1, human or ape faces were presented as standard and deviant stimuli in upright and inverted trials. Upright ape faces presented among humans elicited strong categorization responses, whereas responses for upright human faces and for inverted ape faces were smaller. Deviant inverted human faces did not elicit categorization. Data were best explained by a model with main effects of species and orientation. However, variance of low-level image characteristics was higher for the ape than the human category. Variance was matched to replicate this finding in an independent sample (study 2). Both human and ape faces elicited categorization in upright and inverted conditions, but upright ape faces elicited the strongest responses. Again, data were best explained by a model of two main effects. These experiments demonstrate that 9-month-olds rapidly categorize faces, and unfamiliar faces presented among human faces elicit increased categorization responses. This likely reflects habituation for the familiar standard category, and stronger release for the unfamiliar category deviants.


Visual function correlates with foveal slope, retinal and choroidal thickness on optical coherence tomography in type 2 Macular Telangiectasia.
To correlate the foveal slope angle (FSA), retinal (RT) and choroidal (CT) thickness measured using optical coherence tomography (OCT) across different stages of type 2 macular telangiectasia (MacTel) with best-corrected visual acuity (BCVA). A cross-sectional study of 182 gradable quality macular OCT images of 49 patients with type 2 MacTel was carried out. RT was measured on the Spectralis OCT machine from ETDRS (Early Treatment Diabetic Retinopathy Study) retinal thickness map and later used for calculating FSA. RT and CT were measured at 500-µm intervals up to 1500 µm from foveal centre manually. The change in RT, CT and FSA across five stages of type 2 MacTel was assessed. The measurements were correlated with BCVA. The FSA, RT and CT were calculated quadrantwise and stagewise. The FSA and RT showed a significant negative correlation with disease stage and BCVA (p < .05) in all four quadrants. No significant correlation was noted between CT and BCVA. Multivariate linear regression analysis identified the temporal FSA to correlate best with BCVA. BCVA correlates best with temporal FSA. Smaller the temporal FSA, poorer the vision.


Effect of microaerobic conditions on the degradation kinetics of cellulose.
Limited oxygen supply to sludge digesters has shown to be an effective method to eliminate hydrogen sulfide from the biogas produced during anaerobic digestion but uneven results have been found in terms of the effect on the degradation of complex organic matter. In this study, the effect that the limited oxygen supply provoked on the "anaerobic" degradation of cellulose was evaluated in batch-tests. The microaerobic assays showed to reach a similar maximum production of methane than the anaerobic ones after 19 d and a similar hydrolytic activity (considering a first order rate constant); however, the microaerobic assays presented a shorter lag-phase time than the anaerobic test resulting in faster production of methane during the first steps of the degradation; specifically, the maximum methane production found in the anaerobic test in 19 d was found in the microaerobic test before the day 15.


Follow-up of patients with early breast cancer: is it time to rewrite the story?
The guidelines for follow-up in breast cancer survivors support only performance of periodic physical examination and annual mammography. However, medical oncologists and primary care physicians routinely recommend both blood tests and non-mammographic imaging tests in asymptomatic patients, leading to an increased anxiety related to false-positive results and higher medical expenses. Recently, advanced imaging technologies have improved sensitivity/specificity to detect metastatic lesions before symptoms arise. Considering the progress made in the treatment of metastatic disease and the rapid evolution of targeted therapy, that requires customization of the strategy according to molecular characteristics of the disease, patients could derive real benefit to early detection of disease recurrence. This hypothesis must be tested in a prospective clinical trial.


An RFX transcription factor regulates ciliogenesis in the closest living relatives of animals.
Cilia allowed our protistan ancestors to sense and explore their environment, avoid predation, and capture bacterial prey.1,2,3 Regulated ciliogenesis was likely critical for early animal evolution,2,4,5,6 and in modern animals, deploying cilia in the right cells at the right time is crucial for development and physiology. Two transcription factors, RFX and FoxJ1, coordinate ciliogenesis in animals7,8,9 but are absent from the genomes of many other ciliated eukaryotes, raising the question of how the regulation of ciliogenesis in animals evolved.10,11 By comparing the genomes of animals with those of their closest living relatives, the choanoflagellates, we found that the genome of their last common ancestor encoded at least three RFX paralogs and a FoxJ1 homolog. Disruption of the RFX homolog cRFXa in the model choanoflagellate Salpingoeca rosetta resulted in delayed cell proliferation and aberrant ciliogenesis, marked by the collapse and resorption of nascent cilia. In cRFXa mutants, ciliogenesis genes and foxJ1 were significantly downregulated. Moreover, the promoters of S. rosetta ciliary genes are enriched for DNA motifs matching those bound by the cRFXa protein in vitro. These findings suggest that an ancestral cRFXa homolog coordinated ciliogenesis in the progenitors of animals and choanoflagellates and that the selective deployment of the RFX regulatory module may have been necessary to differentiate ciliated from non-ciliated cell types during early animal evolution.


Rapid Quantitative Determination of Squalene in Shark Liver Oils by Raman and IR Spectroscopy.
Squalene is sourced predominantly from shark liver oils and to a lesser extent from plants such as olives. It is used for the production of surfactants, dyes, sunscreen, and cosmetics. The economic value of shark liver oil is directly related to the squalene content, which in turn is highly variable and species-dependent. Presented here is a validated gas chromatography-mass spectrometry analysis method for the quantitation of squalene in shark liver oils, with an accuracy of 99.0 %, precision of 0.23 % (standard deviation), and linearity of >0.999. The method has been used to measure the squalene concentration of 16 commercial shark liver oils. These reference squalene concentrations were related to infrared (IR) and Raman spectra of the same oils using partial least squares regression. The resultant models were suitable for the rapid quantitation of squalene in shark liver oils, with cross-validation r (2) values of >0.98 and root mean square errors of validation of ≤4.3 % w/w. Independent test set validation of these models found mean absolute deviations of the 4.9 and 1.0 % w/w for the IR and Raman models, respectively. Both techniques were more accurate than results obtained by an industrial refractive index analysis method, which is used for rapid, cheap quantitation of squalene in shark liver oils. In particular, the Raman partial least squares regression was suited to quantitative squalene analysis. The intense and highly characteristic Raman bands of squalene made quantitative analysis possible irrespective of the lipid matrix.


Distribution of diuretics and hypoglycemic sulfonylureas in rabbit erythrocytes.
The distribution of three sulfonylureas and six diuretics in rabbit erythrocytes was studied in vitro at 37 degrees C. The drugs were taken up by the erythrocyte compartment, and distribution equilibrium was reached within 60 min of incubation. A distribution percentage in erythrocyte compartment was maintained at roughly constant value over the whole concentration range of drugs. Therefore, a linear relationship was established between total concentrations of drug in whole blood or erythrocyte suspension and in the erythrocyte compartment. Bovine serum albumin combined with the erythrocyte suspension appeared to reduce drug distribution in the erythrocyte compartment. Whole blood obtained from renal failure rabbits showed greater distribution of drug in the erythrocyte compartment compared with the whole blood of a normal rabbit. This might be due to a change in plasma protein binding ability related to the progress of renal failure.


Ethanol and tolerated doses of Amanita phalloides protect against lethal doses of the mushroom.
Single tolerated doses of a lyophilizate from Amanita phalloides (ADL) failed to increase the survival rate of mice after the LD90 of the mushroom. Also, pretreatment with large doses of ethanol did not protect against lethal doses of APL. However, with combined administration of single tolerated doses of APL and of ethanol, the survival rate of mice after a lethal challenge with APL was increased from 13% to up to 100%. Both ethanol and APL potentiated the effect of barbiturate narcosis, but the combined pretreatment was not more effective. The protection against APL afforded by the combined regimen may be due to inhibition of activating hepatic microsomal enzymes, but biochemical studies are needed to support this hypothesis.


Phyto-synthesized Gold Nanoparticles as Antitumor Agents.
Phyto, or plant-derived metal nanoparticles, are an interesting and intensive studied group of green synthesized nanoparticles. In the last decade, numerous medicinal plant extracts were used for the synthesis of stable gold or silver nanoparticles with diverse biological effects, such as antioxidant activity, antimicrobial activity, anti-inflammatory activity, hypoglycemic effect, antitumor activity and catalytic activity. This review has systematized and discussed information from the last 5 years about the research regarding antitumor/anticancer potential of gold nanoparticles obtained via medicinal plant extracts, with special attention on their selective cytotoxicity on tumor cells and on their mechanism of action, in vitro and in vivo assessments. Much more in vivo and clinical studies are needed before considering phyto-synthesized gold nanoparticles as significant for future medicine.


Comparison of the effects of 7.2% hypertonic saline and 20% mannitol on electrolyte and acid-base variables in dogs with suspected intracranial hypertension.
Hyperosmolar agents frequently are used to decrease intracranial pressure but their effects on electrolyte and acid-base variables have not been prospectively investigated. Compare duration and magnitude of changes in electrolyte and acid-base variables after hyperosmolar treatment. Twenty-eight client-owned dogs with intracranial hypertension caused by various pathologies. Prospective, randomized, nonblinded, experimental cohort study. Fifteen dogs received a single dose (4 mL/kg) of 7.2% hypertonic saline (HTS), 13 dogs received 20% mannitol (MAN) 1 g/kg IV. Electrolyte and acid-base variables were measured before (T0 ), and 5 (T5 ), 60 (T60 ), and 120 (T120 ) minutes after administration. Variables were compared between treatments and among time points within treatment groups. Mean plasma sodium and chloride concentrations were higher after HTS than MAN at T5 (158 vs 141 mEq/L; 126 vs 109 mEq/L) and significant differences were maintained at all time points. After HTS, plasma sodium and chloride concentrations remained increased from T0 at all time points. After MAN, plasma sodium and chloride concentrations decreased at T5 , but these changes were not maintained at T60 and T120 . Plasma potassium concentration was lower at T5 after HTS compared with T0 (3.6 vs 3.9 mEq/L) and compared to MAN (3.6 vs 4.1 mEq/L). At T60 and T120 , plasma ionized calcium concentration was lower after HTS than MAN (1.2 vs 1.3 mmol/L). No significant differences were found in acid-base variables between treatments. At the administered dose, dogs receiving HTS showed sustained increases in plasma sodium and chloride concentrations, whereas dogs receiving MAN showed transient decreases. Future studies should assess the effects of multiple doses of hyperosmolar agents on electrolyte and acid-base variables.


Neurological Gait Abnormalities Moderate the Functional Brain Signature of the Posture First Hypothesis.
The posture first hypothesis suggests that under dual-task walking conditions older adults prioritize gait over cognitive task performance. Functional neural confirmation of this hypothesis, however, is lacking. Herein, we determined the functional neural correlates of the posture first hypothesis and hypothesized that the presence of neurological gait abnormalities (NGA) would moderate associations between brain activations, gait and cognitive performance. Using functional near-infrared spectroscopy we assessed changes in oxygenated hemoglobin levels in the pre-frontal cortex (PFC) during normal walk and walk while talk (WWT) conditions in a large cohort of non-demented older adults (n = 236; age = 75.5 ± 6.49 years; female = 51.7 %). NGA were defined as central (due to brain diseases) or peripheral (neuropathic gait) following a standardized neurological examination protocol. Double dissociations between brain activations and behavior emerged as a function of NGA. Higher oxygenation levels during WWT were related to better cognitive performance (estimate = 0.145; p < 0.001) but slower gait velocity (estimate = -6.336, p < 0.05) among normals. In contrast, higher oxygenation levels during WWT among individuals with peripheral NGA were associated with worse cognitive performance (estimate = -0.355; p < 0.001) but faster gait velocity (estimate = 14.855; p < 0.05). Increased activation in the PFC during locomotion may have a compensatory function that is designed to support gait among individuals with peripheral NGA.