[New preparation method for barium enema: efficacy and administration of oral intestinal lavage solution with gastrointestinal prokinetic agent].
The modified Brown's method is commonly used in Japan as preparation for barium enema; however, in a few cases, its cleansing effect is not satisfactory even with the use of adequate diet. To develop a new method of preparation for barium enema, we examined the use of an oral intestinal lavage solution (PEG-ELS) with mosapride and compared it with the modified Brown's method. We administered mosapride and PEG-ELS by four different methods. These methods were assessed by the amount of remaining feces and the adequacy of barium coating. Methods in which mosapride was taken separately before and after the intake of PEG-ELS were more effective than the method using mosapride and the modified Brown's method. Lesion detection was almost the same as that with the modified Brown's method. In conclusion, preparation for barium enema using mosapride before and after PEG-ELS intake is more effective than the modified Brown's method.


On-line source-density computation with a minimum of electrodes.
An economical arrangement is described whereby the Laplacean of the scalp potential distribution delta2V/delta X2 + delta 2V/delta y2 can be approximately computed by analog methods, using a simple adaptation of the input stages of conventional EEG amplifiers. For maximum efficiency the method requires electrodes to be disposed in equilateral triangular arrays. This makes possible the computation of approximate source densities at 7 scalp locations for a total of only 13 electrodes.


Functional endothelin ETB receptors on renal papillary tubules.
Addition of endothelin-1 or endothelin-3 to rat renal papillary tubules produced a dose-dependent inhibition of the cAMP response to vasopressin stimulation. The average EC50 values were 1.1 +/- 0.6 and 2.6 +/- 1.1 nM, respectively, indicating mediation by an endothelin ETB receptor. Phorbol myristate acetate (1 microM) also inhibited the vasopressin-cAMP response and this inhibition was not additive with that to endothelin, indicating that the endothelin inhibition is mediated by activation of protein kinase C. These findings demonstrate functionally relevant endothelin ETB receptors on renal papillary tubules. Such receptors are a possible target for endothelin-3 produced within the kidney.


[The course of the adaptation processes in patients with neurocirculatory dystonia during health resort treatment].
Low activity of adaptation processes which impedes obtaining good results of heath resort treatment was observed in 16.7% of patients with neurocirculatory asthenia. Such patients need additional therapeutic measures to correct neurovegetative activity, heart performance. General conditioning should be more intensive.


Identification of potent anti-Candida metabolites produced by the soft coral associated Streptomyces sp. HC14 using chemoinformatics.
Candida albicans is the most common pathogen responsible for both spontaneous and recurrent candidiasis. The available treatment of Candida infections has several adverse effects, and the development of new drugs is critical. The current study looked at the synthesis of anti-Candida metabolites by Streptomyces sp. HC14 recovered from a soft coral. Using the Plackett Burman design, the medium composition was formulated to maximize production. Using GC-MS, the compounds have been identified, and a cheminformatics approach has been used to identify the potential source of activity. The compounds that showed high potential for activity were identified as pyrrolo[1,2-a]pyrazine-1,4-dione, hexahydro-3-(phenylmethyl)-3 and di-n-octyl based on their docking score against the cytochrome monooxygenase (CYP51) enzyme in Candida albicans. As a result of their discovery, fewer molecules need to be chemically synthesized, and fermentation optimization maximizes their synthesis, providing a strong foundation for the development of novel anti-Candida albicans agents.


Retraction: Amino acid derived highly luminescent, heteroatom-doped carbon dots for label-free detection of Cd2+/Fe3+, cell imaging and enhanced antibacterial activity.
[This retracts the article DOI: 10.1039/C5RA09525E.].


Impaired cortico-striatal functional connectivity is related to trait impulsivity in unmedicated patients with obsessive-compulsive disorder.
Convergent evidence has demonstrated that trait impulsivity, a key feature in obsessive-compulsive disorder (OCD), involves dysregulated frontal-striatal circuits. The present study aims to explore relationships between frontal-striatal circuits, trait impulsivity, and obsessive-compulsive symptoms. Thirty-six unmedicated patients with OCD and 50 healthy controls (HCs) matched for age, sex, and years of education underwent a magnetic resonance imaging (MRI) procedure. Voxel-wise statistical parametric analysis was used to investigate the differences in resting-state functional connectivity between brain regions functionally connected to six pairs of a-priori defined striatal seed regions, between patients with OCD and HCs. Associations between frontal-striatal connectivity and both trait impulsivity and symptom severity of OCD were analyzed. The results showed altered striatal functional connectivity in OCD group compared to HCs, including increased connectivity of dorsal caudate (DC)-orbitofrontal cortex (OFC), ventral striatum (VS)-OFC, VS-medial prefrontal cortex, and putamen-sensorimotor area, and decreased functional connectivity of DC-anterior cingulate cortex (ACC), putamen-ACC, and putamen-dorsolateral prefrontal cortex (DLPFC). Furthermore, the putamen-DLPFC connectivity was negatively correlated with attentional impulsivity in the OCD group, but showed a positive correlation in HCs. The present findings suggested that dorsal cognitive circuits could reflect the level of inhibitory control, which is balanced with the impulsive drive in healthy controls, but breakdown in OCD. Our findings supported that DLPFC-putamen connectivity underlying trait impulsivity, which were involved in the pathophysiology of OCD. The findings have provided new insights into the neurobiological mechanisms of OCD.


An examination of ethnic identity as a mediator of the effects of community participation and neighborhood sense of community on psychological empowerment among urban youth of color.
Empowerment research has made important contributions toward understanding youth development, well-being, and activism; however, it has failed to consider the impact that ethnic identity has on psychological empowerment (PE) and among related empowerment predictors (e.g., community participation and neighborhood sense of community [SOC]). The present study focuses on examining the mediating role of ethnic identity between community participation, neighborhood SOC, and PE. Using structural equation modeling path analysis techniques among a sample of Hispanic and Black youth (N = 1,480) from an underresourced community, this study examines the mediating role of ethnic identity between community participation, neighborhood SOC, and PE. Community participation and neighborhood SOC had a positive direct effect on both ethnic identity and PE. Both community participation and neighborhood SOC also indirectly affected PE through ethnic identity. This study supports the mediating role of ethnic identity and the direct effect of ethnic identity on PE. Results point toward the importance of ethnic identity with PE and in the empowerment process. Implications and directions for future research are discussed.


A Sandwich Metal-Insulation-Metal Composite for Magnetoelectric Memory: Experiment and Modeling.
Driven by the development of internet technology, higher requirements on information materials and data storage devices were demanded. To improve the work efficiency and performance of the new generation of information materials and data storage devices, the magnetoelectric (ME) coupling and storage mechanism of magnetoelectric composites deserve more attention. Here, we explored the influence of applied magnetic fields on the output voltage on a metal-insulation-metal (MIM) sandwich composite for realizing the magnetoelectric memory by experiments and modeling. It is found that the DC magnetic field (H dc) and the output voltage of the polyvinylidene fluoride film are linearly correlated. At a frequency of 1 kHz, the magnetoelectric voltage coefficient is 60.71 mV cm-1 Oe-1, which is evidently larger than that of other film materials. From this work, we can conclude that the MIM sandwich composite could generate higher magnetoelectric voltage under the AC magnetic field (H ac) with higher frequency, which could be used as the magnetoelectric memory device, and provides significant support for improving the performance of magnetoelectric memory devices and the whole internet system.


[(11)C]flumazenil positron emission tomography analyses of brain gamma-aminobutyric acid type A receptors in Angelman syndrome.
To evaluate the role of the gamma-aminobutyric acid type A (GABA(A)) receptor in Angelman syndrome (AS). We performed [(11)C]flumazenil positron emission tomography (PET) and examined GABA(A) receptor expression in 7 patients with AS of various genotypes (5 with the deletion, 1 with an imprinting defect [ID], and 1 with a UBE3A mutation) and 4 normal control healthy volunteers. Relative to the control subjects, the [(11)C]flumazenil binding potentials (BPs) were significantly higher in the cerebral cortex and cerebellum in the 5 patients with the deletion and in the 1 patient with a UBE3A mutation, and were less frequently or barely increased in adult patients with the deletion and in the patient with IDs. Total GABA(A) receptor expression was increased in patients with AS with various genotypes. We suggest that a developmental dysregulation of the GABA(A) receptor subunits occurs in patients with AS.


Hospitals worry about new FDA proposal for medical devices: technical complexities of labels could compromise utility.
A proposed FDA rule on unique device identification could complicate billing and bar-coding procedures for hospitals.


Accounting for reciprocal host-microbiome interactions in experimental science.
Mammals are defined by their metagenome, a combination of host and microbiome genes. This knowledge presents opportunities to further basic biology with translation to human diseases. However, the now-documented influence of the metagenome on experimental results and the reproducibility of in vivo mammalian models present new challenges. Here we provide the scientific basis for calling on all investigators, editors and funding agencies to embrace changes that will enhance reproducible and interpretable experiments by accounting for metagenomic effects. Implementation of new reporting and experimental design principles will improve experimental work, speed discovery and translation, and properly use substantial investments in biomedical research.


Circumdatin H, a new inhibitor of mitochondrial NADH oxidase, from Aspergillus ochraceus.
Circumdatin H (1), a new alkaloid from the culture broth of Aspergillus ochraceus, has been isolated, together with a known circumdatin, circumdatin E (2) and other known compounds: flavacol (3) and stephacidin A (4). The structure of 1 was established on the basis of chemical and spectral evidence. All of these alkaloids showed biological activity as inhibitors of the mammalian mitochondrial respiratory chain.


Evaluation of a fully automated centrifugal analyzer for performance of hemostasis tests.
We have evaluated the performance of a centrifugal analyzer, specifically designed for hemostasis tests, for methods based on clotting time as measured by light scattering, or based on splitting of chromogenic substrates. The results were compared with those obtained with a semiautomated coagulometer (clotting tests) or with a manually operated photometer (chromogenic tests). In general, the results with the centrifugal analyzer were at least as precise as those of the comparative methods, with greater output and ease of operation. Disadvantages of the instrument are its partial incompatibility with some commercial reagents and the relative rigidity of the operational parameters, which hinder its use for research.


Taste sensitivity in the embryo of the domestic fowl.
Two experiments were carried out to investigate the sense of taste in embryos of the domestic fowl. In the first, four taste substances; NaCl, HCl, glucose and SOA were diluted with distilled water and the response was compared with that to distilled water alone. No significant effects of taste were found. In the second experiment five taste substances: HCl, fructose, NaCl, KCl and quinine were diluted with fluids normally imbibed by the embryo: amniotic and/or allantoic fluid taken from other eggs. These solutions and also distilled water were compared with egg-fluid alone. A highly significant effect of the five solutions was found showing that the taste system becomes functional before the time of hatching. Distilled water produced on an unexpectedly large response in the embryo; possible reasons for this are discussed.


Functional connectivity between prefrontal cortex and striatum estimated by phase locking value.
The interplay between the prefrontal cortex (PFC) and striatum has an important role in cognitive processes. To investigate interactive functions between the two areas in reward processing, we recorded local field potentials (LFPs) simultaneously from the two areas of two monkeys performing a reward prediction task (large reward vs small reward). The power of the LFPs was calculated in three frequency bands: the beta band (15-29 Hz), the low gamma band (30-49 Hz), and the high gamma band (50-100 Hz). We found that both the PFC and striatum encoded the reward information in the beta band. The reward information was also found in the high gamma band in the PFC, not in the striatum. We further calculated the phase-locking value (PLV) between two LFP signals to measure the phase synchrony between the PFC and striatum. It was found that significant differences occurred between PLVs in different task periods and in different frequency bands. The PLVs in small reward condition were significant higher than that in large reward condition in the beta band. In contrast, the PLVs in the high gamma band were stronger in large reward trials than in small trials. These results suggested that the functional connectivity between the PFC and striatum depended on the task periods and reward conditions. The beta synchrony between the PFC and striatum may regulate behavioral outputs of the monkeys in the small reward condition.


Sexual Dysfunction and Distress Among Childhood Sexual Abuse Survivors: The Role of Post-Traumatic Stress Disorder.
Research has revealed that survivors of childhood sexual abuse (CSA) have elevated sexual dysfunction and distress. Nevertheless, a vast majority of studies examining sexual dysfunction and distress among CSA survivors were conducted among women only, and the moderating role of post-traumatic stress disorder (PTSD) symptoms between a history of CSA and sexual dysfunction and distress is yet to be investigated. To fill this gap, the present study aimed to investigate the following: (i) are there sex differences in the relations between CSA and sexual dysfunction and distress and (ii) whether PTSD symptoms mediate the relations between CSA and sexual dysfunction and distress. This study was conducted online among 792 Israeli men and women aged 18-70 years; among whom, 367 reported a history of CSA. The findings of the present study suggest that PTSD symptoms mediate the relations between CSA and sexual dysfunction and distress. Results indicated that those who had a history of CSA reported elevated sexual dysfunction and sexual distress, as compared with non-abused participants, regardless of their sex. Furthermore, PTSD symptoms were related to sexual dysfunction and sexual distress and mediated the relations between a history of CSA and sexual dysfunction and distress. A history of CSA predicted elevated PTSD symptoms, which in turn, were related to elevated sexual dysfunction and distress. Clinical interventions for CSA survivors should incorporate various treatment approaches to alleviate both PTSD symptoms and sexual dysfunction and distress. The present findings indicate the need for clinicians to identify PTSD symptoms and to conjoin distinctive treatment approaches to relieve survivors' PTSD symptoms, as well as their sexual dysfunction and distress. The study included a non-clinical, convenience sample and used self-report measures, which are highly subjective and increase the possibility of social desirability biases. However, on the plus side, it provides important information on CSA survivor's sexual functioning and can assist in establishing intervention goals, and to evaluate treatment. PTSD symptoms were found to mediate the relations between a history of CSA and sexual dysfunction and distress, implying that PTSD symptoms serve as a mechanism underlying sexual dysfunction and distress among CSA survivors. Gewirtz-Meydan A, Lahav Y. Sexual Dysfunction and Distress Among Childhood Sexual Abuse Survivors: The Role of Post-Traumatic Stress Disorder. J Sex Med 2020;17:2267-2278.


Development of equilibrium domain shapes in phospholipid monolayers.
Fluorescence micrographs of monolayers of L-alpha-dipalmitoylphosphatidylcholine (DPPC) at the air water interface are analyzed. Ordered phase domains in coexistence with the fluid lipid phase change their shapes with time and with lateral pressure. With domains fixed under an electrode and well separated from their neighbours a peculiar instability of the boundary lines is observed. It is ascribed to the onset of an electrostatically induced shape transition. Elaborating the boundary regions where domain fusion and fission, respectively, are observed leads to a model on in-plane dipole orientation.


Transcranial Direct Current Stimulation (tDCS) Promotes state-dependent Effects on Neuroinflammatory and Behavioral Parameters in rats Chronically Exposed to Stress and a Hyper-Palatable Diet.
Chronic stress is a common condition affecting health, often associated with unhealthy eating habits. Transcranial direct current stimulation (tDCS) has been proposed to address these issues. Thus, this research investigated the effects of tDCS on biometric, behavioral, and neurochemical parameters in chronically stressed rats fed a hyper-palatable cafeteria diet (CAFD). The study lasted 8 weeks, with CAFD exposure and/or chronic restraint stress model (CRS - 1 h/day, 5 days/week, for 7 weeks) started concurrently. tDCS or sham sessions were applied between days 42 and 49 (0.5 mA, 20 min/day). CAFD increased body weight, caloric consumption, adiposity, and liver weight. It also altered central parameters, reducing anxiety and cortical levels of IL-10 and BDNF. In turn, the CRS resulted in increased adrenals in rats with standard diet (SD), and anxiety-like and anhedonic behaviors in rats with CAFD. tDCS provided neurochemical shifts in CAFD-fed stressed rats increasing central levels of TNF-α and IL-10, while in stressed rats SD-fed induced a decrease in the adrenals weight, relative visceral adiposity, and serum NPY levels. These data demonstrated the anxiolytic effect of CAFD and anxiogenic effect of stress in CAFD-fed animals. In addition, tDCS promoted state-dependent effects on neuroinflammatory and behavioral parameters in rats chronically exposed to stress and a hyper-palatable diet. These findings provide primary evidence for additional mechanistic and preclinical studies of the tDCS technique for stress-related eating disorders, envisioning clinical applicability.


Interoception in Autism Spectrum Disorder: A review.
This review article summarizes original scientific research published to date on interoception in individuals with Autism Spectrum Disorder (ASD). Sensory processing has been shown to be atypical in ASD, yet physiological processing and subjective experience of internal sensation processing, namely interoception, has not been reported sufficiently in research or clinical settings. There is a small but growing body of scientific research on interoception in ASD, which is relevant to understanding the behavioral and cognitive characteristics inherent in this condition, and may provide a foundation for clinical interventions such as biofeedback, pain management, and brain stimulation techniques. A literature review of original research was performed using major scientific databases. Interoception, which occurs due to multisensory connections and integration of internal afferents in cortical and subcortical areas, is atypical in ASD, but the degree and directionality of this abnormality is not yet clear due to the heterogeneity of the condition. Between-group interoceptive differences in individuals with and without ASD have been repeatedly demonstrated, with a slight tendency towards hyporeactivity in interoceptive awareness in individuals with ASD. Multidimensional research combining neuroimaging with psychophysiological and self-report measures guided by a clear theoretical model is necessary to understand how interoceptive differences link to the behavioral and cognitive characteristics of ASD. Sensory processing models and autism theory should also be updated to incorporate these recent findings.


Adult physical activity behavior: a trend analysis.
One of the health objectives for the nation is to have 60% of adults 18-64 years regularly active in vigorous physical activity by 1990. In this paper an effort is made to determine whether American society is making satisfactory progress toward this goal. Two independent databases are analyzed: time diaries collected from a national sample of American adults in 1981; and the Simmons Market Research Bureau, Inc., survey undertaken in 1984. Participation of adults 25-64 in moderate to vigorous activities that included racquet sports, swimming, hiking, bicycling, skiing, jogging, outdoor gardening, skating, etc. is compared between the two time periods. After adjusting for social desirability bias the results indicated there were a similar number of non-participants of the activities analyzed in 1981 and 1984. There was, however, an increase in the number of adults participating occasionally in vigorous activity, although, there did not appear to be any increase in the number who were regularly active, i.e. at least 3 days/week. Thus, while there are indications that adults 25-64 years are adopting more vigorous activity, less than 20% were regular enough in 1984 for improvements in cardiovascular functioning to occur. Unless there were dramatic increases in the activity status of adults 18-24 years of age which was not assessed in this study, the 1990 goal is unlikely to be met.


Molecular insights into NF2/Merlin tumor suppressor function.
The FERM domain protein Merlin, encoded by the NF2 tumor suppressor gene, regulates cell proliferation in response to adhesive signaling. The growth inhibitory function of Merlin is induced by intercellular adhesion and inactivated by joint integrin/receptor tyrosine kinase signaling. Merlin contributes to the formation of cell junctions in polarized tissues, activates anti-mitogenic signaling at tight-junctions, and inhibits oncogenic gene expression. Thus, inactivation of Merlin causes uncontrolled mitogenic signaling and tumorigenesis. Merlin's predominant tumor suppressive functions are attributable to its control of oncogenic gene expression through regulation of Hippo signaling. Notably, Merlin translocates to the nucleus where it directly inhibits the CRL4(DCAF1) E3 ubiquitin ligase, thereby suppressing inhibition of the Lats kinases. A dichotomy in NF2 function has emerged whereby Merlin acts at the cell cortex to organize cell junctions and propagate anti-mitogenic signaling, whereas it inhibits oncogenic gene expression through the inhibition of CRL4(DCAF1) and activation of Hippo signaling. The biochemical events underlying Merlin's normal function and tumor suppressive activity will be discussed in this Review, with emphasis on recent discoveries that have greatly influenced our understanding of Merlin biology.


Tetrabromobisphenol A, hexabromocyclododecane isomers and polybrominated diphenyl ethers in foodstuffs from Beijing, China: Contamination levels, dietary exposure and risk assessment.
Hexabromocyclododecane (HBCD), tetrabromobisphenol A (TBBPA) and polybrominated diphenyl ether (PBDEs) are three legacy brominated flame retardants (BFRs); however, they are still produced and used in China. In this study, these three BFRs were measured in commonly consumed animal-based and plant-based foodstuffs from Beijing, China, and the dietary intakes of these BFRs by adults in Beijing were estimated to assess the related health concerns. The median levels of TBBPA in animal-based foodstuffs ranged from <LOD to 8.03 ng/g lipid weight (lw), whereas those in all the plant-based food groups were lower than the LOD. The median levels of total HBCD in animal-based foodstuffs were from 1.14 to 5.65 ng/g lw, and α-HBCD was the predominant isomer. The median HBCD level in vegetables was 0.266 ng/g wet weight (ww), whereas γ-HBCD was the most abundant isomer. The median levels of total PBDEs in animal-based foodstuffs were from 3.22 to 13.7 ng/g lw, and BDE-209 was the most abundant congener, comprising a proportion of at least 85% of total PBDEs. The daily dietary intakes of TBBPA, HBCD and PBDEs for adults in Beijing were 2.52, 2.74 and 9.77 ng/kg body weight/day, respectively. Meat consumption was found to be the primary source of BFR dietary intake. A comparison between the calculated estimated daily intakes (EDIs) and the corresponding threshold reference values (TRVs) indicated that daily intake of BFRs via food consumption is unable to cause significant health risks. Likewise, the margin of exposures (MOEs) calculated following the European Food Safety Authority (EFSA) approach were far higher than the threshold, which also proved that the EDIs of BFRs are unlikely to raise significant health concerns.


A comparison between percutaneous and surgical transplantation of autologous skeletal myoblasts in a swine model of chronic myocardial infarction.
Our aim was to compare the efficacy of surgical versus percutaneous administration of skeletal myoblasts (SkM) in a swine model of chronic myocardial infarction and to determine the mechanism(s) involved in their beneficial effect. Two months after induction of myocardial infarction (MI), Goettingen miniature pigs underwent autologous SkM transplant either by direct surgical injection (n=6) or percutaneous access and intramyocardial delivery under fluoroscopic and echocardiographic guidance (n=6). Control animals received media alone (n=4). Functional analysis was performed by 2D echocardiography. Myoblast engraftment, in vivo cell differentiation, vessel formation, fibrosis, and the ratio between collagen type I/III deposition were analyzed in the infarct (IA) and non-infarct area (NIA) by immunohistochemistry. Animals received a median of 407.55+/-115x10(6) BrdU-labeled autologous SkM. Myoblast transplant was associated with a statistically significant increase in left ventricular ejection fraction (p<0.01), increased vasculogenesis and decreased fibrosis (p<0.05), and reduced collagen type I/III ratio in the IA and NIA areas as compared with control animals. No differences were found between groups receiving SkM by percutaneous or surgical access. Our results indicate that increased vasculogenesis and changes in matrix remodeling with decreased fibrosis are associated with the beneficial effect of SkM transplant in chronic MI. The equivalent benefit observed from surgical and percutaneous delivery has important clinical implications.


Location, Location, Location: Mutant NPM1c Cytoplasmic Localization Is Required to Maintain Stem Cell Genes in AML.
In this issue of Cancer Cell, Brunetti and colleagues elucidate the role of mutant NPM1c and its cytoplasmic mislocalization in acute myeloid leukemia. They demonstrate how mutant-specific degradation or relocalization leads to a loss of the stem cell signature characteristic of these leukemias and induces their differentiation.


An outbreak of Burkholderia cenocepacia associated with contaminated chlorhexidine solutions prepared in the hospital.
From October to December 2007, an outbreak of Burkholderia cenocepacia occurred in a secondary care hospital. The 19 B cenocepacia isolated from the patients, the chlorhexidine solutions of each different ward, and the purified water that diluted these solutions exhibited an identical pulsed-field gel electrophoresis pattern. Inadequate preparation of chlorhexidine solutions diluted with contaminated purified water may have resulted in an outbreak of B cenocepacia. Adequate preparation of chlorhexidine solutions should be emphasized.


[INHERITANCE OF EPIDERMIS PIGMENTATION IN SUNFLOWER ACHENES].
Inheritance of epidermis pigmentation in the pericarp of sunflower seeds was studied. Inheritance of pigmentation was confirmed by three alleles Ew (epidermis devoid of pigmentation), Estr (epidermal pigmentation in strips), Edg (solid pigmentation). Dominance of the lack of epidermis pigmentation over striped epidermis and striped epidermis over solid pigmentation was established. It was shown that the striped epidermis pigmentation and the presence of testa layer are controlled by two genes, expression of which is independent from each other. Yellowish hypodermis was discovered in the sample I2K2218, which is inherited monogenically dominantly.


A randomized-controlled trial of blonanserin and olanzapine as adjunct to antipsychotics in the treatment of patients with schizophrenia and dopamine supersensitivity psychosis: The ROADS study.
Dopamine supersensitivity psychosis (DSP) is a key factor contributing to the development of antipsychotic treatment-resistant schizophrenia. We examined the efficacy and safety of blonanserin (BNS) and olanzapine (OLZ) as adjuncts to prior antipsychotic treatment in patients with schizophrenia and DSP in a 24-week, multicenter (17 sites), randomized, rater-blinded study with two parallel groups (BNS and OLZ add-on treatments) in patients with schizophrenia and DSP: the ROADS Study. The primary outcome was the change in the Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 24. Secondary outcomes were changes in the PANSS subscale scores, Clinical Global Impressions, and Extrapyramidal Symptom Rating Scale (ESRS), and changes in antipsychotic doses. The 61 assessed patients were allocated into a BNS group (n = 26) and an OLZ group (n = 29). The PANSS total scores were reduced in both groups (mean ± SD: -14.8 ± 24.0, p = 0.0042; -10.5 ± 12.9, p = 0.0003; respectively) with no significant between-group difference (mean, -4.3, 95 %CI 15.1-6.4, p = 0.42). The BNS group showed significant reductions from week 4; the OLZ group showed significant reductions from week 8. The ESRS scores were reduced in the BNS group and the others were reduced in both groups. The antipsychotic monotherapy rates at the endpoint were 26.3 % (n = 6) for BNS and 23.8 % (n = 5) for OLZ. The concomitant antipsychotic doses were reduced in both groups with good tolerability. Our results suggest that augmentations with BNS and OLZ are antipsychotic treatment options for DSP patients, and BNS may be favorable for DSP based on the relatively quick responses to BNS observed herein.


Where does brain neural activation in aesthetic responses to visual art occur? Meta-analytic evidence from neuroimaging studies.
Here we aimed at finding the neural correlates of the general aspect of visual aesthetic experience (VAE) and those more strictly correlated with the content of the artworks. We applied a general activation likelihood estimation (ALE) meta-analysis to 47 fMRI experiments described in 14 published studies. We also performed four separate ALE analyses in order to identify the neural substrates of reactions to specific categories of artworks, namely portraits, representation of real-world-visual-scenes, abstract paintings, and body sculptures. The general ALE revealed that VAE relies on a bilateral network of areas, and the individual ALE analyses revealed different maximal activation for the artworks' categories as function of their content. Specifically, different content-dependent areas of the ventral visual stream are involved in VAE, but a few additional brain areas are involved as well. Thus, aesthetic-related neural responses to art recruit widely distributed networks in both hemispheres including content-dependent brain areas of the ventral visual stream. Together, the results suggest that aesthetic responses are not independent of sensory, perceptual, and cognitive processes.


Novel Pyridine-Based Hydroxamates and 2'-Aminoanilides as Histone Deacetylase Inhibitors: Biochemical Profile and Anticancer Activity.
Starting from the N-hydroxy-3-(4-(2-phenylbutanoyl)amino)phenyl)acrylamide (5 b) previously described by us as a HDAC inhibitor, we prepared four aza-analogues, 6-8, 9 b, as regioisomers containing the pyridine nucleus. Preliminary screening against mHDAC1 highlighted the N-hydroxy-5-(2-(2-phenylbutanoyl)amino)pyridyl)acrylamide (9 b) as the most potent inhibitor. Thus, we further developed both pyridylacrylic- and nicotinic-based hydroxamates (9 a, 9 c-f, and 11 a-f) and 2'-aminoanilides (10 a-f and 12 a-f), related to 9 b, to be tested against HDACs. Among them, the nicotinic hydroxamate 11 d displayed sub-nanomolar potency (IC50 : 0.5 nM) and selectivity up to 34 000 times that of HDAC4 and from 100 to 1300 times that of all the other tested HDAC isoforms. The 2'-aminoanilides were class I-selective HDAC inhibitors, generally more potent against HDAC3, with the nicotinic anilide 12 d being the most effective (IC50HDAC3 =0.113 μM). When tested in U937 leukemia cells, the hydroxamates 9 e, 11 c, and 11 d blocked over 80 % of cells in G2/M phase, whereas the anilides did not alter cell-cycle progress. In the same cell line, the hydroxamate 11 c and the anilide 10 b induced about 30 % apoptosis, and the anilide 12 c displayed about 40 % cytodifferentiation. Finally, the most potent compounds in leukemia cells 9 b, 11 c, 10 b, 10 e, and 12 c were also tested in K562, HCT116, and A549 cancer cells, displaying antiproliferative IC50 values at single-digit to sub-micromolar level.


Pulmonary function, functional capacity and quality of life in adults with cystic fibrosis.
As there are few studies on the impact of respiratory and functional status on the quality of life domains in adults with cystic fibrosis, this study aimed to evaluate the association between respiratory function, functional capacity and quality of life in these subjects. This is a cross-sectional study, where adults with clinical and laboratorial diagnoses of CF fibrosis underwent pulmonary function tests, the six-minute walk distance test (6MWT) and responded to the Cystic Fibrosis Questionnaire-Revised (CFQ-R). Descriptive statistics was used to summarize the findings. The associations were tested by means of Pearson's or Spearman tests, and the significance level was set at 5%. The 21 patients who completed the study presented with reduced quality of life in all CFQ-R domains, obstructive pulmonary disease and reduced 6MWT distance. The following associations were found between pulmonary function and CFQ-R domains: forced vital capacity - FVC (%) and treatment burden and digestive symptoms (r=-0.433, p<0.05; r=-0.443, p<0.05, respectively), forced expiratory volume in one second - FVC ratio - FEV1/FVC (%) and physical functioning, social and respiratory symptoms (r=0.5, p<0.05; r=0.58, p<0.01; r=0.45, p<0.05, respectively), residual volume (%) and physical functioning (r=0.49, p<0.05), airways' resistance - Raw and physical functioning and emotional functioning (r=-0.44, p<0.05; r=-0,46, p<0.05, respectively), carbon monoxide diffusing capacity (%pred) and physical functioning (r=-0,51; p<0.05). Adults with CF have reduced quality of life, which in part is associated with the severity of their lung function.


Monitoring patient mechanics during mechanical ventilation.
This article provides a review of respiratory mechanics that can be monitored in ventilator-dependent patients during passive and spontaneous breathing. Special focus is placed on resistance, compliance, and work of breathing. A description of methods and techniques, and a summary of clinical observations and applications in critically-ill patients are also included.


Zinc, copper and immunological markers in the circulation of well nourished patients with ulcerative colitis.
Few studies have been carried out on the trace element status in patients with ulcerative colitis (UC). Many trace elements are critical for the normal development and function of the immune system. This study was conducted in order to assess the serum levels of zinc and copper and the possible interrelation(s) between them and various immunological markers in the circulation of well nourished patients with UC. The serum levels of zinc, copper, soluble interleukin-2 receptors (sIL-2Rs), interleukin-1beta (IL-1beta), interleukin-2 (IL-2), tumour necrosis factor-alpha (TNF-alpha), non-organ specific autoantibodies (RF, ANA, ANCA, anti-dsDNA and anticardiolipin), C3C and C4 components of the complement system and ceruloplasmin were determined in 75 well nourished patients with UC (32 patients with active and 43 with inactive disease). Thirty-three healthy individuals were also investigated. The mean concentrations (microg/dl) of zinc and copper were significantly higher (P < 0.0005 and P = 0.0001, respectively) either in active (202.3 +/- 115.2 and 141.7 +/- 31.4, respectively) or in inactive disease (204.5 +/- 170.3 and 137.4 +/- 24.5, respectively) compared with healthy controls (93.6 +/- 49.8 and 85 +/- 41.2, respectively). The levels of copper were positively correlated with the C3C (r = 0.41, P < 0.0005), C4 (r = 0.38, P < 0.001) and ceruloplasmin (r = 0.44, P < 0.0005), whereas zinc was correlated with C3C (r = 0.32, P = 0.0005) and ANA (P = 0.01). Autoantibodies of at least one specificity (AUBS) were found in 77.3% of the patients. The mean levels (U/ml) of sIL-2Rs were significantly higher (P = 0.0001) in active disease (604.3 +/- 213.0) than in inactive UC (411.5 +/- 165.1) and in patients with ANA (P < 0.05), ANCA (P = 0.01) or AUBS (P < 0.05). The sIL-2Rs were correlated with the C4 (r = 0.40, P < 0.005) and the ESR (r = 0.43, P = 0.0001). These findings indicate that even in well nourished patients with UC, high serum levels of copper and zinc are present. The latter alterations of zinc and copper are correlated with haematological parameters of relapse of the disease or with acute phase proteins suggesting a relationship with the inflammatory process of UC. Further studies on the colonic tissue will address the role of zinc and copper in the inflammatory and immune reactions observed in this disease process.


Transoral laser microsurgery for managing laryngeal stenosis after reconstructive partial laryngectomies.
To retrospectively analyze our experience of transoral laser microsurgery (TLM) for treating postoperative laryngeal obstruction (POLO) after supracricoid and supratracheal laryngectomy (open partial horizontal laryngectomy [OPHL]) types 2 and 3, and to investigate potential relationships between patients' clinical features and their functional outcomes. A retrospective cohort study. The prognostic influence of clinical and surgical parameters on functional outcomes was investigated in a univariate statistical setting in terms of decannulation rate (DR), time to tracheostomy closure (TTC), and number of laser procedures required (NLP). OPHL type 2 was associated with a better functional outcome than OPHL type 3 in terms of DR, TTC, and NLP (P = .03, P = .02, and P = .02, respectively). Annular and semicircumferential stenoses developed more frequently after OPHL type 3, and were particularly difficult to manage with TLM. Fixation of the residual arytenoid was a negative prognostic factor in terms of functional outcome in terms of DR, TTC, and NLP (P = .0002, P = .08, and P = .08, respectively). There is no standardized laser treatment for POLO; it must be tailored to individual patients. Identifying prognostic factors influencing functional outcome could help surgeons to earmark patients less likely to benefit from TLM for the treatment of POLO, and enable an adequate preoperative counseling, given the high probability of repeat postoperative TLM procedures. 4 Laryngoscope, 2016 127:359-365, 2017.


Analysis of clinical and physical dosimetric factors that determine the outcome of severe acute radiation pneumonitis in lung cancer patients.
We conducted a retrospective statistical analysis of clinical and physical dosimetric factors of lung cancer patients who had previously undergone lung and/or mediastinal radiotherapy and died of or survived severe acute radiation pneumonitis (SARP). Our study was the first to reveal the heterogeneity in clinical factors, physical dosimetric factors, and SARP onset time that determined the clinical outcomes of lung cancer patients who developed SARP. The clinical characteristics, physical dosimetry factors, and SARP onset time of deceased and surviving patients were retrospectively analyzed. SPSS 20.0 was used for data analysis. Student's t-test was used for intergroup comparison, and a Mann-Whitney U test was used for data with skewed distribution. Qualitative data were represented using frequencies (%), and Fisher's exact test or χ2 test was used for intergroup comparison of nonparametric data. Binary logistic analysis was used for univariate and multivariate analyses. Differences with a P < 0.05 were considered statistically significant. Univariate analysis revealed that the potential predictors of SARP death were as follows: ipsilateral lung V5 and V30, contralateral lung V5, V10, and V30, total lung V5, V10, and V30, mean lung dose, mean heart dose, and maximum spinal cord dose. Multivariate analysis showed that ipsilateral lung V5 and total lung V5 were predictors that determined the final outcome of SARP patients. In addition, we analyzed the time from the completion of radiotherapy to SARP onset, and found significant difference between the two groups. There was no decisive correlation between clinical characteristics and SARP outcome (i.e., death or survival) in lung radiotherapy patients. Ipsilateral lung V5 and total lung V5 were independent predictors of death in SARP patients.


Free and bound cortisol, corticosterone, and metabolic adaptations during the early inflammatory response to an intramammary lipopolysaccharide challenge in dairy cows.
Glucocorticoids, particularly cortisol and corticosterone, are key homeostatic regulators during metabolic and endocrine adaptations including inflammatory responses. Besides the established response of total cortisol (TC) concentrations during inflammatory processes in dairy cows, we investigated changes of corticosterone, free cortisol (FC), and serum albumin as the main protein of unspecific cortisol binding, in response to an intramammary lipopolysaccharide (LPS) challenge. Furthermore, we evaluated relationships of glucocorticoid responses with concomitant alterations of metabolites and their endocrine regulators, insulin and glucagon. Blood samples of 10 multiparous Holstein dairy cows (26.8 ± 3.4 d in milk, previous lactation yield: 7,601 ± 938 kg; mean ± SD) were obtained every 30 min up to 5 h after the LPS instillation, and rectal temperature and heart rate were measured in parallel. Corticosterone was measured by enzyme immunoassay, TC by radioimmunoassay, and the proportion of FC by ultrafiltration. A mixed model was used to evaluate differences within the investigated parameters among selected time points (0, 3.5, and 5 h relative to the intramammary LPS administration). Rectal temperature increased up to 41.6 ± 0.1°C at 5 h after the LPS application. Concentrations of TC and corticosterone increased until 3.5 h, and the proportion of FC relative to TC more than doubled until 3.5 h after LPS administration. Serum albumin concentration was reduced at 5 h compared with initial values, whereas concentrations of insulin, glucagon, and glucose were increased after 5 h compared with 0 h. In conclusion, the stimulation of the immune system by the intramammary LPS administration is accompanied by distinct metabolic and endocrine changes. Corticosterone and TC concentrations react similarly in response to the LPS challenge and earlier compared with metabolic adaptations. The increased need of active cortisol is covered by both increased secretion and a higher percentage of FC.


Treatment of hemorrhoids in day surgery: stapled hemorrhoidopexy vs Milligan-Morgan hemorrhoidectomy.
Recently, it has been demonstrated that surgical treatment of hemorrhoids in a day-care basis is possible and safe. The aim of this study was to compare the Longo stapled hemorrhoidopexy (SH) and the Milligan-Morgan hemorrhoidectomy (MMH). One hundred seventy one patients (95 cases in SH group and 76 cases in MMH group) entered the study: 83 cases were III degree hemorrhoids, 88 IV degree. A priori and a post hoc power analysis were performed. Results, prospectively collected, were compared using chi squared test and student t test. Visual analog scale was used for pain evaluation. Postoperative pain, duration of pain, wound secretion, bleeding, resumption of a normal lifestyle, and postoperative complication were evaluated. Surgical time was 28.41+/-10.78 for MMH and 28.30+/-13.28 min in SH (P=0.94). Postoperative pain was not different between MMH and SH during the first two postoperative days (4.73+/-2.91 vs 5.1+/-3.048; P=0.4), during the following 6 days, patients treated with SH had less pain (4.63+/-2.04 in MMH vs 3.60+/-2.35 in SH; P=0.006). In the SH group, seven patients needed further hospital stay for complicated course. SH showed higher incidence of anal fissure compared with MMH (6.3% vs 0%; P=0.025) but no differences in urinary retention, anal stricture, urgency, or anal hemorrhage. This study confirms that SH is associated with less postoperative pain and shorter postoperative symptoms, compared with MMH. SH may be a viable addition to the therapy for hemorrhoids with some advantages in early postoperative pain and some disadvantages in postoperative complications and costs.


Reduction of androstenone perception in pan-fried boar meat by different masking strategies.
Consumers highly sensitive to androstenone María (AND) will probably reject meat from entire male pigs, which tends to have high levels of this hormone. To avoid this, the effect of different masking strategies (sprinkling with mixed spices or fennel, marinating and breading with garlic-parsley or curry) on the sensory parameters of pork loin chops obtained from entire animals with high levels of AND (1.0-2.9 mg kg-1 AND in fat) and castrated animals (<0.4 mg kg-1 AND in fat), both with low levels of skatole (<0.1 mg kg-1 skatole in fat) was investigated. The garlic-parsley breadcrumbs led to the highest reduction in the perception of AND compared with the other masking strategies used, and preserved the juiciness of the product. There was a negative correlation between AND and fat content. AND odor and flavor can be reduced in meat from entire male pigs by using suitable strategies, the best strategy being the garlic-parsley breadcrumbs. © 2017 Society of Chemical Industry.


Correlation Between Clinical Findings at Admission and Glasgow Outcome Scale Score in Children with Traumatic Brain Injury.
Traumatic brain injury has different pathophysiology and outcomes in children and adults. This study investigated the relationship between clinical and laboratory findings at admission and Glasgow Outcome Scale (GOS) score in children with traumatic brain injury. This prospective cross-sectional single-center study enrolled 444 children 1-16 years old admitted to the neurosurgery ward from 2016 to 2020. Clinical data and laboratory information were extracted from the records of these patients at admission, and the relationship with GOS score at discharge was investigated. The 444 patients include 249 (56.08%) boys and 195 (43.92%) girls with a mean age of 7.32 ± 4.4 years. There was no correlation between GOS score and sex (P = 0.12), age (P = 0.16), serum potassium level (P = 0.08), platelet level (P = 0.21), and blood glucose (P = 0.18). There was a significant relationship between GOS score and hypotension (P = 0.03), hyponatremia (P = 0.04), prothrombin time (P = 0.03), partial thromboplastin time (P = 0.03), pupil size (P = 0.02), pupil reaction to light (P = 0.04), and Glasgow Coma Scale score (P = 0.04). Clinical and laboratory findings such as hypotension, hyponatremia, prothrombin time, partial thromboplastin time, pupil size, pupil reaction to light, and Glasgow Coma Scale score at admission could affect GOS score at discharge and result in poor outcomes in children with traumatic brain injury.


Kinetics of beta-glucosidase production by Saccharomyces cerevisiae recombinants harboring heterologous bgl genes.
The maximum productivity of beta-glucosidase by Saccharomyces cerevisiae recombinants under the control of GALI promoter was 100 IU l(-1) h(-1). The highest productivity of beta-glucosidase by a S. cerevisiae recombinant was 16-fold more than that supported by Cellulomonas biazotea. The recombinants also co-produced ethanol from cellobiose: maximum product yield and productivity were 0.5 and 1.1 g ethanol g(-1) cellobiose and g ethanol l(-1) h(-1), respectively.


Immunohistological analysis in the distribution of cells in the fetal porcine adenohypophysis.
Adenohypophyses of porcine fetuses from 25 to 110 days of gestation were studied by immunohistochemical staining to ascertain the ontogeny of specific cell types and their spatial distribution in the pars distalis. No hormone-containing cells were found before 30 days of gestation. ACTH cells were observed first at 40 days, while GH and LH cells appeared first at 60 days. PRL cells were initially detected at 105 days. ACTH immunoreactive cells were also observed in the pars intermedia at 40 days. Blood capillaries were interposed between cell cords of the pars distalis after 40 days of gestation. ACTH cells were evenly distribution in all areas of the pars distalis except the rostral area (sex zone). GH cells were densely distributed in lateral wings of the pars distalis and immediately anterior to Rathke's lumen. PRL cells resembled GH cells in their distribution pattern, but PRL cells were fewer in number. LH cells were scattered in the sex zone of the pars distalis from 60 to 80 days of gestation. After 90 days, they became scattered throughout the pars distalis but were more numerous in the sex zone than in other areas. The inductive elements of adenohypophysial cells from Rathke's pouch epithelia are discussed. We hypothesize that cell cords of specific areas facing Rathke's lumen may differentiate into specific cell types of the pars distalis during fetal life.


Incidence and risk factors of admission deep venous thrombosis in nonagenarians and centenarians with intertrochanteric fracture: a retrospective study.
The objective of this study was to identify the risk factors for admission deep venous thrombosis (aDVT) and proximal aDVT in nonagenarians and centenarians with intertrochanteric fracture (IF). We collected statistics on nonagenarians and centenarians with IF admitting from January 2010 to October 2022. Patients with aDVT were considered as the aDVT group and those without aDVT as the non-aDVT group. Additionally, we also conducted a subgroup analysis based on the location of aDVT to investigate the predictors of proximal aDVT. The demographics, comorbidities and admission laboratory examinations of patients were computed by univariate analysis, logistic regression analysis, and receiver operating characteristic (ROC) curve analysis. In our study, the rate of aDVT (109 of 318) was 34.3%, and 5.7% (18 of 318) of patients had proximal aDVT. Logistic regression analysis showed that female patients and a high level of D-dimer were risk factors for aDVT. Similarly, hypoproteinemia and a high level of D-dimer were found to be risk factors for proximal aDVT. ROC curve analysis indicated the cut-off values of D-dimer to predict the aDVT and proximal aDVT were 1.28 mg/L and 1.485 mg/L, respectively. Our findings investigated the risk factors of aDVT and proximal aDVT in nonagenarians and centenarians with IF and identified the cut-off values of D-dimer, helping us assess the risk of aDVT and proximal aDVT to manage early targeted interventions.


Effect of ribonucleotides on substrate availability for DNA polymerase assays in cytoplasmic fractions of rat intestinal mucosa.
The deoxyribonucleoside triphosphate substrates for DNA synthesis were hydrolysed during the DNA polymerase (EC 22.214.171.124) assay with cytoplasmic subcellular fractions of rat intestinal mucosa. Presumably because of phosphatase (EC 126.96.36.199) activity in these fractions, inorganic phosphate was liberated from the nucleotides, and radioactive thymidine triphosphate was shown to be degraded to thymidine di-and mono-phosphate, thymidine, and thymine. Addition of ATP to the postmicrosomal supernatant increased its DNA polymerase activity by sparing the deoxyribonucleotide precursors from enzymatic degradation.


[SUNCT syndrome--case report and review of the literature].
The SUNCT syndrome is a recently described headache disorder characterised by shortlasting, unilateral headache attacks with conjunctival injection and tearing. Our report presents a further case and compares the findings in our patient with those in the cases described earlier. In addition, we review the literature and discuss possible aetiological and pathogenetic factors as well as the differential diagnosis of SUNCT syndrome, trigeminal neuralgia and cluster headache syndromes.


Clear cell sarcoma of the kidney in a 62-year-old patient presenting with generalized pruritus.
Clear cell sarcoma of the kidney (CCSK) is the second most common renal tumor in children following Wilms' tumor. CCSK is extremely rare in adults, with only 25 adult cases reported in the medical literature. We reported a 62-year-old man with a right renal mass presenting only with generalized pruritus who underwent radical right nephrectomy. With immunostaining, tumor cells were positive for expressed vimentin, neural cell adhesion molecule (NCAM, CD56), and Ki-67 and focally positive for p53, CD10 and Bcl-2. The histopathological diagnosis was CCSK. Two weeks after the operation, the generalized pruritus ended. One month after the operation, the patient started treatment with a regimen combining doxorubicin, vincristine, cyclophosphamide, and etoposide. At the 20-month follow-up visit, there was no evidence of local recurrence or metastases. In a patient presenting with generalized pruritus, further evaluation for an underlying malignancy should be considered. It is difficult to distinguish CCSK from undifferentiated renal neoplasms. Immunohistochemistry could help to make exact histopathological diagnoses. The BCL-6 corepressor (BCOR) gene could play a significant role in CCSK tumorigenesis and be a good marker for CCSK diagnosis. Surgery with combination chemotherapy and radiation therapy could be used to treat CCSK in older patients.


Microsatellite status and immunohistochemical features of ovarian clear-cell carcinoma.
Ovarian clear-cell carcinoma (OCC) is known to have a poor prognosis and selected genetic features of OCC remain unknown. We investigated microsatellite instability (MSI) and the expression of the DNA mismatch repair-related protein, p53. MSI was examined by polymerase chain reaction using mono-, di-, tri- and tetranucleotide repeat markers, and hMSH2, hMLH1, hMSH6, MSH3 and p53 were determined immunohistochemically in 24 cases of OCC. A total of 9 (37.5%) cases exhibited MSI. Two cases (8.3%) exhibited MSI-H in mononucleotide repeat loci with the negative expression of hMLH1, while another 7 cases (29.2%) exhibited selected trinucloetide repeat MSI (MSI-TR). Of these MSI-TR cases, 4 cases (57.1%) were determined to be negative for MSH3, while hMSH2, hMSH6, MSH3 and p53 expressions were normal. Our findings suggest that MSI-TR would be a feature indicating the microsatellite status in OCC, and that the loss of MSH3 expression may promote MSI-TR.


Battles with iron: manganese in oxidative stress protection.
The redox-active metal manganese plays a key role in cellular adaptation to oxidative stress. As a cofactor for manganese superoxide dismutase or through formation of non-proteinaceous manganese antioxidants, this metal can combat oxidative damage without deleterious side effects of Fenton chemistry. In either case, the antioxidant properties of manganese are vulnerable to iron. Cellular pools of iron can outcompete manganese for binding to manganese superoxide dismutase, and through Fenton chemistry, iron may counteract the benefits of non-proteinaceous manganese antioxidants. In this minireview, we highlight ways in which cells maximize the efficacy of manganese as an antioxidant in the midst of pro-oxidant iron.


Constrained evolution of a quantitative character by pleiotropic mutation.
The long-term response to directional selection and its selection limit are derived for a quantitative character that is controlled by pleiotropic mutations with direct deleterious effect on fitness. Directional selection is assumed to be weaker than the selection acting directly on mutations via deleterious effects (purging selection), which renders all mutations to eventual elimination. The analysis embedding this restrictive assumption indicates that the evolutionary response of the character starting from an equilibrium state, in which mutation and purging selection balance but no directional selection is operating, decreases monotonically with time at an exponential rate. And the fading rate of responses is mostly determined by the direct deleterious effect. Contrary to the expectation by the standard selection limit theory based on fixation of extant genetic variation, the present model predicts that the selection limit depends on the intensity of directional selection, the limit being proportional to the ratio of the directional selection intensity to the direct deleterious effect. A slightly larger genetic variance is maintained at the selection limit than would be without directional selection.


Complex regional haemodynamic effects of anandamide in conscious rats.
1. Experiments were carried out in conscious, chronically instrumented, male, Sprague-Dawley rats to delineate the regional haemodynamic effects of the putative endogenous cannabinoid, anandamide, (0.075 - 3 mg kg(-1)), and to dissect some of the mechanisms involved. 2. At all doses of anandamide, there was a significant, short-lived increase in mean arterial blood pressure associated with vasoconstriction in renal, mesenteric and hindquarters vascular beds. 3. The higher doses (2.5 and 3 mg kg(-1)), caused an initial, marked bradycardia accompanied, in some animals, by a fall in arterial blood pressure which preceded the hypertension. In addition, after the higher doses of anandamide, the hindquarters vasoconstriction was followed by vasodilatation. 4. Although some of the effects described above resembled those of 5-HT (25 microg kg(-1)), the bradycardia and hypotensive actions of the latter were abolished by the 5HT(3)-receptor antagonist, azasetron, whereas those of anandamide were generally unaffected. 5. None of the cardiovascular actions of anandamide were influenced by the CB(1)-receptor antagonist, AM 251, but its bradycardic effect was sensitive to atropine, and its hindquarters vasodilator action was suppressed by the beta(2)-adrenoceptor antagonist, ICI 118551. 6. The results differ, in several aspects, from those previously reported in anaesthetized animals, and underscore the important impact anaesthesia can have on responses to anandamide.


Regulation of Cell Migration and β1 Integrin Trafficking by the Endosomal Adaptor GGA3.
The integrin family of cell adhesion receptors link extracellular matrices to intracellular signaling pathways and the actin cytoskeleton; and regulate cell migration, proliferation and survival in normal and diseased tissues. The subcellular location of integrin receptors is critical for their function and deregulated trafficking is implicated in various human diseases. Here we identify a role for Golgi-localized gamma-ear containing Arf-binding protein 3 (GGA3), in regulating trafficking of β1 integrin. GGA3 knockdown reduces cell surface and total levels of α2, α5 and β1 integrin subunits, inhibits cell spreading, reduces focal adhesion number, as well as cell migration. In the absence of GGA3, integrins are increasingly retained inside the cell, traffic toward the perinuclear lysosomal compartment and their degradation is enhanced. Integrin traffic and maintenance of integrin levels are dependent on the integrity of the Arf binding site of GGA3. Furthermore, sorting nexin 17 (SNX17), a critical regulator of integrin recycling, becomes mislocalized to enlarged late endosomes upon GGA3 depletion. These data support a model whereby GGA3, through its ability to regulate SNX17 endosomal localization and through interaction with Arf6 diverts integrins from the degradative pathway supporting cell migration.


Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.


A unified theory of the meaning of some spatial relational terms.
This paper presents a unified account of the meaning of the spatial relational terms right, left, in front of, behind, above and below. It claims that each term has three types of meanings, basic, deictic and intrinsic, and that the definitions of each type of meaning are identical in form for all six terms. Restrictions on the use of the terms, which are different for above and below than for the rest, are explained by a general constraint on all uses of spatial relational terms, the framework vertical constraint. This constraint depends on the existence of a fourth type of meaning for above and below, one defined by the framework in which the related objects are located. It is argued that a theory centred on the framework vertical constraint is preferable to one centred on the principle of canonical orientation (Levelt, 1984).


Defining the layers of a sensory cilium with STORM and cryoelectron nanoscopy.
Primary cilia carry out numerous signaling and sensory functions, and defects in them, "ciliopathies," cause a range of symptoms, including blindness. Understanding of their nanometer-scale ciliary substructures and their disruptions in ciliopathies has been hindered by limitations of conventional microscopic techniques. We have combined cryoelectron tomography, enhanced by subtomogram averaging, with superresolution stochastic optical reconstruction microscopy (STORM) to define subdomains within the light-sensing rod sensory cilium of mouse retinas and reveal previously unknown substructures formed by resident proteins. Domains are demarcated by structural features such as the axoneme and its connections to the ciliary membrane, and are correlated with molecular markers of subcompartments, including the lumen and walls of the axoneme, the membrane glycocalyx, and the intervening cytoplasm. Within this framework, we report spatial distributions of key proteins in wild-type (WT) mice and the effects on them of genetic deficiencies in 3 models of Bardet-Biedl syndrome.


Vibration of osteoblastic cells using a novel motion-control platform does not acutely alter cytosolic calcium, but desensitizes subsequent responses to extracellular ATP.
Low-magnitude high-frequency mechanical vibration induces biological responses in many tissues. Like many cell types, osteoblasts respond rapidly to certain forms of mechanostimulation, such as fluid shear, with transient elevation in the concentration of cytosolic free calcium ([Ca2+ ]i ). However, it is not known whether vibration of osteoblastic cells also induces acute elevation in [Ca2+ ]i . To address this question, we built a platform for vibrating live cells that is compatible with microscopy and microspectrofluorometry, enabling us to observe immediate responses of cells to low-magnitude high-frequency vibrations. The horizontal vibration system was mounted on an inverted microscope, and its mechanical performance was evaluated using optical tracking and accelerometry. The platform was driven by a sinusoidal signal at 20-500 Hz, producing peak accelerations from 0.1 to 1 g. Accelerometer-derived displacements matched those observed optically within 10%. We then used this system to investigate the effect of acceleration on [Ca2+ ]i in rodent osteoblastic cells. Cells were loaded with fura-2, and [Ca2+ ]i was monitored using microspectrofluorometry and fluorescence ratio imaging. No acute changes in [Ca2+ ]i or cell morphology were detected in response to vibration over the range of frequencies and accelerations studied. However, vibration did attenuate Ca2+ transients generated subsequently by extracellular ATP, which activates P2 purinoceptors and has been implicated in mechanical signaling in bone. In summary, we developed and validated a motion-control system capable of precisely delivering vibrations to live cells during real-time microscopy. Vibration did not elicit acute elevation of [Ca2+ ]i , but did desensitize responses to later stimulation with ATP.


Case studies of clinical hemodialysis membranes: influences of membrane morphology and biocompatibility on uremic blood-membrane interactions and inflammatory biomarkers.
End stage renal disease (ESRD) patients depend on hemodialysis (HD) as a life-sustaining treatment, but HD membrane properties play a critical role in blood activation during HD and can lead to severe patient outcomes. This study reports on a series of investigations on the common clinical HD membranes available in Canadian hospitals to explore the key reasons behind their susceptibility to blood activation and unstable cytokine. Clinical HD membranes composed of cellulose triacetate (CTA) and polyvinylpyrrolidone: polyarylethersulfone (PAES: PVP) were thoroughly characterized in terms of morphology and chemical composition. Membrane-surface interactions with uremic blood samples after HD treatment were probed using Fourier Transform Infra-Red (FTIR) and Raman spectroscopic techniques in order to understand changes in chemistry on membrane fibers. In addition, as part of this innovative study, we utilized Molecular Modeling Docking to examine the interactions of human blood proteins and membrane models to gain an in-depth understanding of functional group types responsible for perceived interactions. In-vitro adsorption of fibrinogen on different clinical HD membranes was compared at similar clinical operating conditions. Samples were collected from dialysis patients to ascertain the extent of inflammatory biomarkers released, before, during (30 and 90 min) and after dialysis (4 h). Collected blood samples were analyzed using Luminex assays for the inflammatory biomarkers of Serpin/Antithrombin-III, Properdin, C5a, 1L-1α, 1L-1β, TNF-α, IL6, and vWF. We have likewise incubated uremic blood in vitro with the two membrane materials to determine the impact that membrane materials pose in favor of activation away from the hydrodynamics influences. The results of our morphological, chemical, spectroscopic, and in vitro incubation analyses indicate that CTA membranes have a smoother surface and higher biocompatibility than PAES: PVP membranes, however, it has smaller pore size distribution, which results in poor clearance of a broad spectrum of uremic toxins. However, the rougher surface and greater hydrophilicity of PAES: PVP membranes increases red blood cell rupture at the membrane surface, which promotes protein adsorption and biochemical cascade reactions. Molecular docking studies indicate sulfone functional groups play an important role in the adsorption of proteins and receptors. PAES: PVP membranes result in slower but greater adsorption of fibrinogen, but are more likely to experience reversible and irreversible fouling as well as backfiltration. Our major finding is that a single dialysis session, even with a more biocompatible membrane such as CTA, increases the levels of complement and inflammation factors, but to a milder extent than dialysis with a PAES membrane.


Splenogonadal fusion-a rare congenital anomaly demonstrated by 99Tc-sulfur colloid imaging: case report.
A case report illustrating the value of spleen scanning in the diagnosis of a rare anomaly characterized by fusion of the spleen and left testis is described. This malformation results from faulty organogenesis during the fifth to the eighth week of fetal development. Only 65 cases have been reported in the world literature. In most instances, the anomaly is recognized as an incidental finding at autopsy or at surgical exploration of the abdomen. In 20% of cases the anomaly is associated with osseous malformations such as peromelia, ectromelia, micrognathia, and talipes.


Listeria meningitis complicating a patient with ulcerative colitis on concomitant infliximab and hydrocortisone.
Infliximab, a monoclonal antibody directed against tumour necrosis factor, is an effective therapy for moderate-to-severe ulcerative colitis and Crohn's disease. Uncommonly, serious opportunistic infections have occurred in patients after infliximab administration. Here, we describe meningitis caused by Listeria monocytogenes developing in a 37-year-old man with ulcerative colitis refractory to intravenous corticosteroids 10 days after receiving his first infusion of infliximab. With the increasing use of tumour necrosis factor-α-neutralizing agents, clinicians should be aware of the risk of opportunistic infections caused by L. monocytogenes in patients with inflammatory bowel disease following infliximab treatment. The half-life of infliximab is 9.5 days; therefore, patients tend to be more susceptible in the immediate period following infusion. Patients receiving anti-TNF therapy should be advised to avoid foods such as soft cheeses and unpasteurized dairy products.


Demoralization, depression and anxiety in postpartum women of culturally and linguistic diverse backgrounds in Australia.
The present study aims to investigate whether mothers from Culturally and Linguistically Diverse (CALD) backgrounds present with higher levels of demoralization in comparison with their non-minority counterparts, and to explore potential correlations between demoralization and anxiety as well as depression in the same sample of mothers. Women admitted to a public tertiary care teaching hospital were invited to participate in the study within 24-48 hours following delivery. The study compared women who did not regard English as their main spoken language to native English-speaking women. Women were asked to complete the demographic Kissane Demoralization Scale (KDS) and Being a Mother Scale (BaM-13) questionnaires. Participants were contacted by phone, 6 to 8 weeks after they had completed the KDS and the BaM-13 questionnaires, to complete an Edinburgh Postnatal Depression Scale (EPDS) and State Trait Anxiety Scale (STAI) questionnaires. Mothers of CALD background presented with significantly higher scores on the KDS (p<0.001), STAI (p<0.001) and EPDS (p<0.001) scales in comparison with their non-CALD counterparts. Furthermore, when mothers were reassessed after 6 to 8 weeks, higher KDS scores in the postnatal period predicted significantly higher anxiety and depression scores, according to STAI (p<0.001) and the EPDS (p<0.001), respectively. The results of this study reveal that, mothers of CALD background manifest higher levels of demoralization as well as anxiety and depression in the postpartum period when compared with their non-CALD counterparts.


Management of delayed-onset skin flap complications after pediatric cochlear implantation.
To review delayed-onset skin flap complications associated with pediatric cochlear implantation (CI) in our institute, analyze the etiology, and explore effective treatment strategies. Retrospective analyses of 811 children who had undergone cochlear implantation between January 2003 and March 2019 were performed. Twelve (1.48%) patients developed skin flap complications after CI. We present a classification of flap issues and wound histopathology following cochlear implantation. The interventions for flap problems included drug treatment, aspiration, local wound care, revision surgery, and explantation depending on the clinical situation. The temporalis myofascial reconstructive option is discussed. Seven subjects were cured with conservative treatment. Five cases with flap infection or necrosis underwent revision surgery, with wound closure in three cases (60%) and revision surgery with explantation in the remaining two cases (40%). Explantation ultimately led to wound healing in all cases. They all achieved excellent performance through re-implantation. Flap complications after CI are rare but treatable. Comprehensive treatments should be developed to achieve a stable and healed wound for CI.


Caries-preventing effect of a hydroxyapatite-toothpaste in adults: a 18-month double-blinded randomized clinical trial.
Dental caries is a worldwide challenge for public health. The aim of this 18-month double-blinded, randomized, clinical trial was to compare the caries-preventing effect of a fluoride-free, hydroxyapatite toothpaste (test) and a toothpaste with sodium fluoride (1450 ppm fluoride; positive control) in adults. The primary endpoint was the percentage of subjects showing no increase in overall Decayed Missing Filled Surfaces (DMFS) index. The study was designed as non-inferiority trial. Non-inferiority was claimed if the upper limit of the exact one-sided 95% confidence interval for the difference of the primary endpoint DMFS between test and control toothpaste was less than the predefined margin of non-inferiority (Δ ≤ 20%). In total, 189 adults were included in the intention-to-treat (ITT) analysis; 171 subjects finished the study per protocol (PP). According to the PP analysis, no increase in DMFS index was observed in 89.3% of subjects of the hydroxyapatite group and 87.4% of the subjects of the fluoride group. The hydroxyapatite toothpaste was not statistically inferior to a fluoride toothpaste with regard to the primary endpoint. Hydroxyapatite was proven to be a safe and efficient anticaries agent in oral care. NCT04756557.


Dissociating behavioral, autonomic, and neuroendocrine effects of androgen steroids in animal models.
Developments in behavioral assessment, autonomic and/or baseline reactivity, psychopharmacology, and genetics, have contributed significantly to the assessment of performance-enhancing drugs in animal models. Particular classes of steroid hormones: androgenic steroids are of interest. Anecdotally, the performance enhancing effects of androgens are attributed to anabolic events. However, there is a discrepancy between anecdotal evidence and investigative data. While some androgen steroids may promote muscle growth (myogenesis), effects of androgens on performance enhancement are not always seen. Indeed, some effects of androgens on performance may be attributable to their psychological and cardiovascular effects. As such, we consider androgen effects in terms of their behavioral, autonomic, and neuroendocrine components. Techniques are discussed in this chapter, some of which are well established, while others have been more recently developed to study androgen action. Androgens may be considered for their positive impact, negative consequence, or psychotropic properties. Thus, this review aims to elucidate some of the effects and/or mechanisms of androgens on behavioral, autonomic, and/or neuroendocrine assessment that may underlie their controversial performance enhancing effects.


[Thoracoscopic diagnosis and therapy of lung metastases].
The purpose of this study was to evaluate the impact of thoracoscopy on staging and therapy of peripheral pulmonary nodules in patients with a cancer history. Videothoracoscopy (VATS) was performed in patients presenting peripheral pulmonary nodules (< 3cm) in CT-scan. 65 patients (63%) presented less than 3 nodules and 39 patients (37%) had multiple lesions in the lungs. History revealed a primary gastro-intestinal cancer in 35 patients (34%), a sarcoma in 26 patients (25%), breast cancer in 13 patients (13%) and miscellaneous primary cancer in 22 patients (21%). VATS was performed under general anesthesia using a standard equipment (Olympus). Double lumen endotracheal intubation was carried out. Thoracoscopic pulmonary resection was accomplished with endoscopic stapler (Autosuture Multi-Fire Endo GIA 30). The specimens were removed in a retrieval bag and a tube was inserted into the thoracic cavity. In 24 patients (23%) conversion to thoracotomy was performed, because of adhesions (n = 12), technical reasons (n = 8), no tumor detectable (n = 4). Thoracoscopic wedge resection for coin lesions was performed in 61 of the 80 patients (76%). Three patients underwent decortication and in 16 patients biopsy was sufficient for therapeutical considerations. Additional informations in comparison to conventional diagnostic were found in 39 patients (49%). The treatment regimen altered in 32 patients (40%). In this study VATS proved to be a sensitive technique for staging of pulmonary coin lesions. Additional informations were achieved in 49% and therapeutic strategy was changed in 40% of the patients due to the distant spread of malignancy or detection of benign lesions obtained by thoracoscopic staging.


A Novel Hybrid Technique in the Treatment of Dystrophic Scoliosis Secondary to Neurofibromatosis Type 1 Lacking Pedicles in the Apical Area.
A retrospective observational study. To introduce a novel hybrid technique using segmentation correction (SC) and to compare it with traditional correction (TC) in treating dystrophic scoliosis secondary to neurofibromatosis type 1 (NF1-S) lacking pedicles in the apical area. We reviewed the NF1-S cases lacking pedicles diagnosed in our hospital between January 2015 and December 2019. Patients were divided into the SC and TC groups and were followed up for at least 2 years. The degree of deformities, correction rate, and vertebral rotatory subluxation (RS) were assessed before the operation, post-traction, post operation, and during follow-up visits. A total of 27 patients were included in the SC group and 21 in the TC group. There was no significant difference in the 2 groups before the surgery regarding age, height, weight, degree of deformities, and spinal flexibility. The correction rate of patients in the SC group was higher (57.7% ± 17.3% vs. 40.9% ± 19.0%, P = 0.002) than in the TC group. During the 2-year follow-up, the loss of Cobb angles of the SC group in both coronal and sagittal planes were lower than those of the TC group (coronal plane, 1.2° ± 1.1° vs. 2.0° ± 1.4°, P = 0.039; sagittal plane, 0.9° ± 0.5° vs. 1.7° ± 1.0°, P = 0.002). The SC technique showed better deformity correction than TC, suggesting that SC may be an alternative method for treating NF1-S patients lacking pedicles in the apical area.


Role of sodium in mitochondrial membrane depolarization induced by P2X7 receptor activation in submandibular glands.
The effect of ATP on mitochondrial membrane depolarization in rat submandibular glands was investigated. Exposure of the cell suspension to high concentrations of ATP induced a sustained depolarization of mitochondrial membrane. This effect was blocked in the presence of magnesium and reproduced by low concentrations of 2',3'-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate (BzATP), suggesting the implication of the P2X(7) purinergic receptor. This point was confirmed by comparison of the response to ATP by wild-type and P2X(7) knock-out (P2X(7)R(-/-)) mice. Mitochondria took up calcium after ATP stimulation but the depolarization of the mitochondrial membrane by ATP was not affected by the removal of calcium from the extracellular medium. It was nearly fully suppressed in the absence of sodium and partially blocked by the mitochondrial Na/Ca exchanger inhibitor 7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (CGP-37157). Both ATP and monensin increased the uptake of extracellular sodium (as shown by the depolarization of the plasma membrane) but the sodium ionophore did not affect the mitochondrial membrane potential. It is concluded that the activation of P2X(7) receptors depolarizes the mitochondrial membrane. The uptake of extracellular sodium is necessary but not sufficient to induce this response.


Is high pressure postdilation safe in bioresorbable vascular scaffolds? Optical coherence tomography observations after noncompliant balloons inflated at more than 24 atmospheres.
Optical coherence tomography (OCT) was used to investigate integrity and expansion of bioresorbable drug-eluting scaffolds (BVS) after high-pressure postdilation (HPPD). Because of concerns about the risk of BVS damage, postdilation was not recommended and applied in the existing randomized studies and most registries. Recent real world data suggest incomplete BVS expansion cause higher rates of thrombosis. In vivo confirmation of the safety of high pressure postdilation is of paramount importance. Data from final OCT examination of consecutive implanted BVS, postdilated with noncompliant (NC) balloons at pressure ≥24 atm were analyzed. The following stent performance indices were assessed with OCT: mean and minimal lumen and scaffold area, residual area stenosis (RAS), incomplete strut apposition (ISA), tissue prolapse, eccentricity index (EI), symmetry index (SI), strut fractures, and edge dissections. Twenty-two BVS postdilated at high pressure were analyzed. The average maximal postdilation balloon inflation (maxPD) was 28 ± 3 atm. High pressure OPN NC Balloon (SIS Medical AG, Winterthur Switzerland) was used in 41% of postdilations with a maximal PD of 30 ± 4.7 atm. Final mean and minimal lumen area were 6.8 ± 1.4 and 5.5 ± 1.4 mm(2) , respectively. OCT showed low percentage of RAS (16 ± 9.6%), and low percentage of ISA (1.8 ± 2.4%). Mean EI was 0.86 ± 0.02 and SI 0.35 ± 0.14. OCT analysis showed one edge dissection and no scaffold fractures. BVS deployment optimization using HPPD does not cause BVS disruption and is associated with a good BVS expansion, low rate of strut malapposition and edge dissections.


A finite element model of the shoulder: application to the changes of biomechanical environment induced by postoperative malrotation of humeral shaft fracture.
The humerus fracture is one of the most commonly occurring fractures. In this research, we attempted to evaluate and compare the extent of malrotation and biomechanical environment after surgical treatment of humeral shaft fractures. A finite element (FE) model of the shoulder was built based on Computed Tomography (CT) data of a patient with a humeral shaft fracture. The muscle group around the shoulder joint was simulated by spring elements. The changes of shoulder stresses under rotation were analyzed. The biomechanics of the normal shoulder and postoperative malrotation of the humeral shaft was analyzed and compared. During rotations, the maximum stress was centered in the posterosuperior part of the glenoid for the normal shoulder. The von Mises shear stresses were 4.40 MPa and 4.89 MPa at 40° of internal and external rotations, respectively. For internal rotation deformity, the shear contact forces were 7-9 times higher for the shoulder internally rotated 40° than for the normal one. For external rotation deformity, the shear contact forces were about 3-5 times higher for the shoulder with 40° external rotation than the normal one. Postoperative malrotation of humeral shaft fracture induced the changes of the biomechanical environment of the shoulders. The peak degree of malrotation was correlated with increased stresses of shoulders, which could be paid attention to in humeral shaft fracture treatment. We hoped to provide information about the biomechanical environment of humeral malrotation.


Spinal muscular atrophies.
Spinal muscular atrophies (SMA) are genetic disorders characterized by degeneration of lower motor neurons. The most frequent form is caused by mutations of the survival motor neuron 1 gene (SMN1). The identification of this gene greatly improved diagnostic testing and family-planning options of SMA families. SMN plays a key role in metabolism of RNA. However, the link between RNA metabolism and motor neuron degeneration remains unknown. A defect in mRNA processing likely generates either a loss of function of some critical RNA or abnormal transcripts with toxic property for motor neurons. Mutations of SMN in various organisms highlighted an essential role of SMN in motor axon and neuromuscular junction development or maintenance. The quality of life of patients has greatly improved over recent decades through the improvement of care and management of patients. In addition, major advances in translational research have been made in the field of SMA. Various therapeutic strategies have been successfully developed aiming at acting on SMN2, a partially functional copy of the SMN1 gene which remains present in patients. Drugs have been identified and some are already at preclinical stages. Identifying molecules involved in the SMA degenerative process should represent additional attractive targets for therapeutics in SMA.


Separation of the pore-forming and cytotoxic activities from natural killer cell cytotoxic factor.
The influence of Ca2+ on the cytotoxic activity of natural killer cell cytotoxic factor (NKCF) was analyzed. When the natural killer susceptible cell line K562 was exposed to NKCF in the presence of 5 mM Ca2+, two peaks of cell damage were found. The first peak was observed after 30-40 min of incubation as a result of pore formation on the surface of target cells. The second was a peak of cytolytic activity which appeared after 24 h of incubation. Upon dilution of the NKCF preparation, only the first peak was observed. Therefore, NKCF produced by large granular lymphocytes in response to K562 consists of different proteins and represents pore-forming and cytolytic activities.


Measurements of geometric illusions, illusory contours and stereo-depth at luminance and colour contrast.
We investigated four geometric optical illusions (Zöllner, Müller-Lyer, Ponzo and Delboeuf), plus illusory contour/border induction (Kanizsa) and depth in random-dot stereograms (Julesz). Two different display conditions were compared: equiluminance with chromaticity contrast and heteroluminance without chromaticity contrast. The main results are as follows. (1) The strength of the four geometric optical illusions is the same under both display conditions. The Zöllner illusion reaches its maximum and levels off at a luminance contrast of about 80%; it disappears at luminance contrasts of less than 15%. (2) No illusory contours are perceived in equiluminant Kanizsa figures. The minimum luminance contrast for illusory contour induction in the Kanizsa square is on average 1.8%, for illusory border induction in the abutting grating illusion it is 5.3%. (3) Random-dot stereograms were found to induce depth equally well in both display modes. The disparity threshold for perceiving depth in isochromatic random-dot stereograms levels off at a luminance contrast of 30%. With larger disparities, depth is perceived down to about 10% contrast. The findings suggest that geometric optical illusions of parallelness (orientation), length and size are mediated by the parvocellular system; furthermore, that stereoscopic depth is mediated both by the magnocellular and the parvocellular systems; and that illusory contours are mediated by the magnocellular system.


Fabrication of regular macro-mesoporous reduced graphene aerogel beads with ultra-high mechanical property for efficient bilirubin adsorption.
Three-dimensional graphene materials have been widely studied in many fields for their role as potential absorbent, especially for bilirubin adsorption. In this study, we developed a simple method to prepare reduced graphene aerogel beads as hemoperfusion materials for fast bilirubin adsorption. The graphene oxide (GO) aerogel beads were produced by self-assembly of GO nanosheet that cross-linked by Ca2+ previously in a coagulation bath, then it was reduced by ascorbic acid and lyophilized to yield the reduced graphene aerogel beads. The beads had a regular macroscopic spherical structure with a diameter of about 1.3-2 mm, where the macroporosity was about 10 μm and the mesoporosity was about 12 nm. The macro-mesoporous structure also gave the reduced graphene aerogel beads ultra-high mechanical strengths and high specific surface area, which were both important for hemoperfusion materials. Moreover, the fixed-bed column adsorption revealed that the reduced graphene aerogel beads manifested excellent bilirubin adsorption (649.512 mg/g) with a rapid adsorption equilibrium time (1.5 h) under the optimized conditions. Even in the bilirubin-enriched blood, the adsorption capacity of the beads could reach 367.14 mg/g. Furthermore, the aerogel beads had a low hemolysis ratio and improved anticoagulant property showing good blood compatibility. Hence, the spherical reduced graphene aerogel beads with millimeter-level size presented a good potential for clinical applications in hemoperfusion therapy.


Follow-up of the first national birth cohort: findings from the Medical Research Council National Survey of Health and Development.
The medical work of a 40 year birth cohort study is described in order to show the continuing associations of childhood factors with later life health, behaviour, illness and survival. Comparisons with the health of children born at later times show the importance of a sensitive monitoring of changes in child health. A summary of work on social and psychological topics is also given, together with a complete list of publications from the study.


An insight into the possible protective effect of pyrrolidine dithiocarbamate against lipopolysaccharide-induced oxidative stress and acute hepatic injury in rats.
Lipopolysaccharide (LPS) is a major cell wall molecule of Gram-negative bacteria known to stimulate the synthesis and secretion of several toxic metabolites, such as reactive oxygen species. In this study, the effect of pyrrolidine dithiocarbamate (PDTC), an antioxidant with nuclear factor-κB inhibitor activity, was evaluated in LPS-induced oxidative stress and acute hepatic injury in rats. Animals were pretreated for 3 consecutive days with PDTC (200 mg/kg/day, i.p.) or saline and animals were then challenged with LPS (6 mg/kg, i.p.) or saline. Six hours after LPS injection, animals were decapitated and blood and liver samples were collected to assess the chosen biochemical parameters. Saline-pretreated animals challenged with LPS revealed extensive liver damage, as evidenced by increases in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transferase (γ-GT). Also, LPS treatment resulted in significant increases in serum lactate dehydrogenase (LDH), tumor necrosis factor-alpha (TNF-α) and nitrite levels. Furthermore, LPS challenge caused oxidative stress as indicated by an increase in hepatic lipid peroxidation measured as thiobarbituric acid reactive substances (TBARS) and a decrease in hepatic reduced glutathione concentration (GSH) as well as decreased activities of superoxide dismutase (SOD) and catalase in hepatic tissues. The administration of PDTC prior to LPS challenge resulted in improved liver functions as evidenced by the decline in serum AST, ALT, γ-GT levels and reduction in serum LDH, TNF-α and nitrite levels. Moreover, PDTC reduced the chosen lipid peroxidation marker, TBARS and increased GSH concentration, and SOD and catalase activities in hepatic tissues. These results indicate that PDTC may be a useful pharmacological agent in alleviating LPS-induced oxidative stress and acute hepatic injury.


Small but Mighty: Nanoparticles Probe Cellular Signaling Pathways.
Mechanical forces play key roles in regulating cellular pathways but are challenging to study using standard biological approaches. In a recent issue of Cell, Seo et al. (2016) present a platform for in vivo single-molecule manipulation, using magnetoplasmonic nanoparticles capable of imaging, localizing, and force-loading receptor proteins at high spatiotemporal resolution.


Strategy to accelerate progress towards the attainment of international development goals and targets related to reproductive health.
Reproductive and sexual ill-health account for 20% of the global burden of ill-health for women, and 14% for men. The strategy presented in this document is the World Health Organization's first global strategy on reproductive health. It was adopted by the 57th World Health Assembly (WHA) in May 2004. Five priority aspects of reproductive and sexual health are targeted: improving antenatal, delivery, postpartum and newborn care; providing high-quality services for family planning, including infertility services; eliminating unsafe abortion; combatting sexually transmitted infections, including HIV, reproductive tract infections, cervical cancer and other gynaecological morbidities; and promoting sexual health. The strategy was developed as a result of extensive consultations in all regions with representatives from ministries of health, professional associations, non-governmental organizations, United Nations partners and other key stakeholders. It lays out actions needed for accelerating progress towards the attainment of the Millennium Development Goals (MDGs) and other international goals and targets relating to reproductive health, especially those from the International Conference on Population and Development in 1994 and its five-year follow-up. "The strong endorsement of this strategy by the WHA represents an unequivocal message that countries are committed to do all they can to achieve the goals and targets of the ICPD Programme of Action adopted in 1994." (Dr Paul Van Look, Director, WHO Department of Reproductive Health and Research).


Introductory Video as a Supplemental Application for General Surgery Residency Candidates: Concept, Implementation, Preliminary Outcomes, and Future Directions.
The residency selection process has changed dramatically over the past several years, primarily due to the COVID-19 pandemic causing a transition to virtual interviews and limiting sub-internship opportunities. Another new major change is the transition of the USMLE Step 1 examination from a numerical score to pass/fail as of January 2022. In anticipation of this major change, our program asked applicants to submit a short video clip expressing their interest. Review of each of the videos was completed by three members of the admission committee and each reviewer was required to complete formal implicit bias training prior to reviewing the videos. Over 1200 general surgery residency applications were received via the Electronic Residency Application Service (ERAS) for the 2022-2023 application cycle. 286 applicants were selected for a formal interview invitation and asked to submit a 2-minute introductory video. In response, 222 (77.62%) of the 286 cohort submitted introductory videos. 210 of these videos (94.59%) were submitted within the first week. The average length of the videos submitted was 105.10 seconds. Using optional introductory videos as a supplemental application has helped to narrow the applicant pool and identify individuals to offer interviews.