Dynamics of the HP1β-PCNA-containing complexes in DNA replication and repair.
Heterochromatin protein 1 (HP1), a small non-histone chromosomal protein, was recently shown to form a complex in vivo with Proliferating Cell Nuclear Antigen (PCNA), a key factor in DNA replication. The complex, which requires HP1β in a form of a dimer, is engaged in DNA repair and replication. We now provide further evidence based on FRET-FLIM live cell studies confirming the association and close proximity between HP1β and PCNA in the complex. We also demonstrate using FRAP, that although HP1β-PCNA complexes are highly mobile in nonreplicating nuclei, when engaged in DNA replication, they become bound and do not exchange with the mobile pool. These observations are in agreement with a notion that a subpopulation of HP1 molecules interact with PCNA in vivo during DNA replication. Similarly, HP1β which is associated with PCNA in regions of DNA repair, is bound and does not exchange with the mobile pool, suggesting that HP1β in association with PCNA may be a component of a DNA repair complex.


Developmental trajectory of appetitive traits and their bidirectional relations with body mass index from infancy to early childhood.
Appetitive traits, including food responsiveness, enjoyment of food, satiety responsiveness and slowness in eating, are associated with childhood body mass index. Change in appetitive traits from infancy to childhood and the direction of causality between appetitive traits and body mass index are unclear. The present study examined the developmental trajectory of appetitive traits and their bidirectional relations with body mass index, from infancy to early childhood. Mothers in the Pregnancy Eating Attributes Study and follow-up (n = 162) reported child appetitive traits using the Baby and Child Eating Behaviour Questionnaires at ages 6 months and 3.5 years, respectively. Standardized body mass index (zBMI) was calculated from child anthropometrics. Cross-lagged panel models estimated bidirectional relations between appetitive traits and zBMI. Food responsiveness, satiety responsiveness and slowness in eating increased from infancy to early childhood. In cross-lagged panel models, lower infant satiety responsiveness (B ± SE = -0.45 ± 0.19, p = .02) predicted greater child zBMI. Infant zBMI did not predict child appetitive traits (p-values >.36). From infancy to early childhood, appetitive traits may amplify. Appetitive traits, particularly satiety responsiveness, appear to influence body mass index during this period, suggesting early intervention targeting these traits may reduce childhood obesity.


Gastroprotection by 4-methylpyrazole against ethanol in humans.
4-Methylpyrazole (4-MP), a specific inhibitor of alcohol dehydrogenase, exerts gastroprotection of unusually long duration in rats. We tested the hypothesis that pretreatment with 4-MP might protect the human gastric mucosa against alcohol-induced acute injury. Fourteen healthy volunteers received pretreatment with either 4-MP, 15 mg/kg body weight dissolved in 50 ml of orange juice, or placebo and 2 hr later 100 ml of 40% ethanol. The endoscopic appearance of the gastric mucosa was evaluated and scored (scale 0-5) and mucosal biopsies were obtained just before pretreatment and 30 min after ethanol for histologic examination and prostaglandin E2 measurement. In the 4-MP group the mean endoscopic injury score was significantly lower than that in placebo group, in both the body and the antrum. Histologically, 4-MP significantly reduced disruption of surface epithelium and completely prevented the deep hemorrhagic mucosal lesions. In the 4-MP group no changes in gastric mucosal PGE2 levels were detected. In rats, 4-MP did not inhibit gastric acid output, whereas it markedly increased the adherent gastric mucus evaluated by the alcian blue recovery method. When lipid peroxidation was induced by carbon tetrachloride in hepatic microsomes, 4-MP caused significant inhibition of malondialdehyde generation. We conclude that 4-MP provides significant protection of the human stomach against alcohol-induced acute mucosal injury. 4-MP, besides inhibiting the conversion of alcohol to acetaldehyde, might protect the gastric mucosa by increasing adherent gastric mucus and by scavenging free radicals.


Effect of an acute injection of melatonin on the basal secretion of hypophyseal hormones in prepubertal and pubertal healthy subjects.
It is well known that the pineal gland can modulate the secretion of pituitary hormones. Melatonin, the main hormone produced by the pineal gland, acts at the hypothalamic site, whereas hypophyseal sensitivity to melatonin seems to change with age. To investigate the influence of pubertal development on the role of the pineal gland in the regulation of the secretion of pituitary hormones, FSH, LH, Prl, TSH and GH responses to melatonin were evaluated in a group of 9 prepubertal and 10 pubertal healthy subjects of both sexes. Melatonin was given im at a dose of 0.2 mg/kg body weight at 3 p.m. Venous blood samples were drawn -20, 0, 20, 40, 60, 90, 120, 180 and 240 min, after melatonin injection. According to the same experimental protocol, venous blood samples were collected during a saline infusion on a separate occasion. FSH, LH, Prl, TSH and GH plasma levels were measured with RIA. In pubertal subjects, a significant rise in the mean Prl levels was seen 90 min after melatonin as compared with those during saline infusion. The Prl melatonin response area was significantly lower in prepubertal treated subjects and significantly higher in pubertal ones compared with the respective controls. The mean GH values showed a significant decrease 120 min after melatonin only in prepubertal subjects; no significant variations were seen in 8 of 10 pubertal subjects, whereas in the last 2 a marked increase was observed.(ABSTRACT TRUNCATED AT 250 WORDS)


[Diabetes and the kidneys].
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and requires renal replacement therapy. Regular screening for microalbuminuria is indispensable for early diagnosis. To prevent or at least delay the onset of DN and progressive renal failure in type 1 and type 2 diabetics, glucose control, blood pressure control and, in particular, the blocking of the renin-angiotensin system are the most effective renoprotective measures. Other factors influencing the course of DN are cigarette smoking and hyperlipidaemia. The latest trials have been reviewed and a treatment involving the cooperation of general practitioners, nephrologists and diabetologists has been suggested.


Susceptibility to beta-lactam antibiotics and gentamicin of gram-negative bacilli isolated from hospitalized patients: a Swedish multicenter study.
A total of 952 blood and 1543 urine isolates of gram-negative bacilli from hospitalized patients in 1986-1987 were consecutively collected by 10 Swedish laboratories and tested for susceptibility to 8 beta-lactam antibiotics and to gentamicin. The isolates were mostly Escherichia coli (58% and 44%, respectively) and Klebsiella sp. (17% and 18%). Resistance to ampicillin in blood and urine isolates was found in 35% and 45%, respectively, to piperacillin in 5% and 6%, to cephalothin in 26% and 34%, to cefuroxime in 12% and 22%, to cefotaxime in 3% and 5%, to ceftazidime in 1% and 1%, to imipenem in 0.5% and 0.1%, to aztreonam in 3% and 2%, and to gentamicin in 0.8% and 0%. Resistance of clinically important gram-negative bacilli to new beta-lactam antibiotics and to gentamicin is infrequent in Sweden.


Complementation of buried lysine and surface polar residues in a designed heterodimeric coiled coil.
The coiled coil is an attractive target for protein design. The helices of coiled coils are characterized by a heptad repeat of residues denoted a to g. Residues at positions a and d form the interhelical interface and are usually hydrophobic. An established strategy to confer structural uniqueness to two-stranded coiled coils is the use of buried polar Asn residues at position a, which imparts dimerization and conformational specificity at the expense of stability. Here we show that polar interactions involving buried position-a Lys residues that can interact favorably only with surface e' or g' Glu residues also impart structural uniqueness to a designed heterodimeric coiled coil with the nativelike properties of sigmoidal thermal and urea-induced unfolding transitions, slow hydrogen exchange and lack of ANS binding. The position-a Lys residues do not, however, confer a single preference for helix orientation, likely reflecting the ability of Lys at position a to from favorable interactions with g' or e' Glu residues in the parallel and antiparallel orientations, respectively. The Lys-Glu polar interaction is less destabilizing than the Asn-Asn a-->a' interaction, presumably reflecting a higher desolvation penalty associated with the completely buried polar position-a groups. Our results extend the range of approaches for two-stranded coiled-coil design and illustrate the role of complementing polar groups associated with buried and surface positions of proteins in protein folding and design.


Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, attenuates postoperative cognitive dysfunction in aging mice.
Postoperative cognitive dysfunction (POCD) is a recognized clinical entity characterized with cognitive deficits after anesthesia and surgery, especially in aged patients. Previous studies have shown that histone acetylation plays a key role in hippocampal synaptic plasticity and memory formation. However, its role in POCD remains to be determined. Here, we show that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, attenuates POCD in aging Mice. After exposed to the laparotomy, a surgical procedure involving an incision into abdominal walls to examine the abdominal organs, 16- but not 3-month old male C57BL/6 mice developed obvious cognitive impairments in the test of long-term contextual fear conditioning. Intracerebroventricular (i.c.v.) injection of SAHA at the dose of (20 μg/2 μl) 3 h before and daily after the laparotomy restored the laparotomy-induced reduction of hippocampal acetyl-H3 and acetyl-H4 levels and significantly attenuated the hippocampus-dependent long-term memory (LTM) impairments in 16-month old mice. SAHA also reduced the expression of cleaved caspase-3, inducible nitric oxide synthase (iNOS) and N-methyl-D-aspartate (NMDA) receptor-calcium/calmodulin dependent kinase II (CaMKII) pathway, and increased the expression of brain-derived neurotrophic factor (BDNF), synapsin 1, and postsynaptic density 95 (PSD95). Taken together, our data suggest that the decrease of histone acetylation contributes to POCD and may serve as a target to improve the neurological outcome of POCD.


Influence of gamma radiation on the physical and sensory properties of two Brazilian rice cultivars.
Little has been reported about the effects of gamma radiation on the physical and sensory characteristics of rice. Samples were irradiated with 60 Co in doses 0, 1, 2 and 5 kGy, on a rate of 0.4 kGy h-1 . The evaluation of instrumental color showed that increasing doses promoted the yellowing (higher b* value) of the rice grains. Hardness was decreased and stickiness was increased in cooked rice with increasing doses. Sensory evaluation using quantitative descriptive analysis showed that increasing doses promoted higher occurrence of yellowish appearance, emergence of burnt aroma, and an increase of bitter and burnt taste. The sensory acceptance test by 9-point hedonic scale showed alteration of the samples irradiated with 5 kGy in all evaluated attributes (appearance, color, aroma, taste and texture). The lowest dose (1 kGy), however, had good acceptability by the panelists. Rice may be subjected to 1 kGy dose of gamma radiation without changes or with small changes in physical properties and with good overall acceptability. © 2016 Society of Chemical Industry.


Interoceptive sensibility differentiates the predictive pattern of emotional reactivity on depression.
The role of emotional reactivity in the psychopathology of depression has been studied widely but not comprehensively. Inconsistencies in existing literature indicate the presence of other factors may affect this dynamic. An individual's method of processing their physiological sensations is a third variable because emotions are psychophysiological. This study identified the predictiveness of ease of activation, intensity, and duration of negative and positive emotions on depressive symptoms differentiated by interoceptive sensibility (IS). A total of 270 community participants filled-in questionnaires assessing their IS, habitual emotional reactivity, depressive severity, and response bias. A two-step clustering analysis identified the IS characteristics. Negative and positive reactivity models among each IS cluster were tested using bootstrapping regression, controlling for gender and response bias. IS can be clustered into "high IS," "low IS," and "worriers." Both positive and negative reactivity's predictiveness patterns on depression were different between IS clusters. Lower positive reactivity predicted depression among individuals with low IS (harder to activate positive emotions) and worriers (shorter duration of positive emotions) but not among individuals with high IS. Those with high IS also exhibited the highest positive reactivity. Ease of activating negative emotions predicted depression among high IS individuals, and a longer duration of negative emotions predicted depression among worriers. IS may affect the psychopathology of depression through subjective emotional reactivity. Thus, IS characteristics can be incorporated into intervention plans.


Removal of beta-2-microglobulin by diffusion alone is feasible using highly permeable dialysis membranes.
Techniques of filtration with high flux dialysis membranes are capable of easily removing beta-2-microglobulin (beta-2-M) (MW: 11,800) from renal failure patients. However, hemodialysis is preferred as a method of removing beta-2-M in terms of cost and operation. The present study elucidates the permeability characteristics for beta-2-M of newly developed cellulosic and synthetic polymer membranes for hemodialysis to determine the diffusive clearance for beta-2-M. The authors did dialysis experiments with 3H-labeled water and 125I-labeled beta-2-M to obtain the solute permeability of cellulosic and synthetic polymer membranes. Radioactivity of a single hollow fiber after dialysis experiments for predetermined periods was measured in a gamma counter. Through analysis of radioactivity data, they obtained solute permeability data, from which diffusive clearance for beta-2-M was calculated. With wet cellulose triacetate membranes, values for inside diameter, wall thickness, and water content were 205 +/- 10 microns (N = 100), 12.4 +/- 1.5 microns (N = 200), and 78 vol%, respectively. The cellulose triacetate membranes had a solute permeability for beta-2-M of (4.12 +/- 1.83) x 10(-5) cm/sec (N = 25) and a pure water permeability of 60 ml/m2/hr/mmHg. Diffusive clearance for beta-2-M was calculated to be 39 ml/min at a plasma flow rate of 160 ml/min and a dialysate flow rate of 500 ml/min. The diffuse clearance of capillary dialyzers composed of regenerated cellulose and synthetic polymer membranes ranged from 23 to 19 ml/min.(ABSTRACT TRUNCATED AT 250 WORDS)


Dissociable behavioural outcomes of visual statistical learning.
Statistical learning refers to the extraction of probabilistic relationships between stimuli and is increasingly used as a method to understand learning processes. However, numerous cognitive processes are sensitive to the statistical relationships between stimuli and any one measure of learning may conflate these processes; to date little research has focused on differentiating these processes. To understand how multiple processes underlie statistical learning, here we compared, within the same study, operational measures of learning from different tasks that may be differentially sensitive to these processes. In Experiment 1, participants were visually exposed to temporal regularities embedded in a stream of shapes. Their task was to periodically detect whether a shape, whose contrast was staircased to a threshold level, was present or absent. Afterwards, they completed a search task, where statistically predictable shapes were found more quickly. We used the search task to label shape pairs as "learned" or "non-learned", and then used these labels to analyse the detection task. We found a dissociation between learning on the search task and the detection task where only non-learned pairs showed learning effects in the detection task. This finding was replicated in further experiments with recognition memory (Experiment 2) and associative learning tasks (Experiment 3). Taken together, these findings are consistent with the view that statistical learning may comprise a family of processes that can produce dissociable effects on different aspects of behaviour.


Risk factors for falls in adults with rheumatoid arthritis: a prospective study.
To investigate the association between potential risk factors and falls in community-dwelling adults with rheumatoid arthritis (RA). We followed patients for 1 year of followup in a prospective cohort study with monthly falls calendars and telephone calls. Lower extremity muscle strength, postural stability, number of swollen and tender joints, functional status, history of falling, fear of falling, pain, fatigue, medication, and use of steroids were assessed as risk factors for falls. A total of 386 women and 173 men with RA (n = 559) ages 18-88 years completed baseline assessments and 535 participants (96%) completed 1-year followup. Bivariate logistic regression showed that falls risk was not associated with age or sex. Multivariate logistic regression revealed that a history of multiple falls in the previous 12 months was the most significant predictive risk factor (odds ratio [OR] 5.3, 95% confidence interval [95% CI] 2.3-12.3). The most significant modifiable risk factors were swollen and tender lower extremity joints (OR 1.7, 95% CI 1.1-2.7), psychotropic medication (OR 1.8, 95% CI 1.1-3.1), and fatigue (OR 1.13, 95% CI 1.02-1.2). Adults with RA are at high risk of falls. In clinical practice, high-risk fall patients with RA can be identified by asking whether patients have fallen in the past year. Important risk factors highlighted in this study include swollen and tender lower extremity joints, fatigue, and use of psychotropic medications.


Telomere attrition and decreased fetuin-A levels indicate accelerated biological aging and are implicated in the pathogenesis of colorectal cancer.
Increasing chronological age is a risk factor for many types of cancer including colorectal. An understanding of the biology of aging and factors which regulate it may provide insight into cancer pathogenesis. The role of telomere biology in both the cancer and aging process could prove useful in this regard. Using quantitative PCR, we determined telomere length in the peripheral blood leukocytes of 64 colorectal cancer (CRC) patients and 1,348 controls. We also measured telomere length in 32 colorectal tumor samples and matched normal tissue. We aimed to assess whether telomere lengths were reflected in circulating mediators of inflammation and redox control factors, including fetuin-A, a circulating modulator of calcium homeostasis. CRC patients had shorter telomeres [adjusted mean ratio of relative telomere repeat copy number to single-copy gene number (RelT/S) = 0.61] compared with chronologically older controls (mean age = 75, adjusted mean RelT/S = 0.70; ANCOVA, P = 0.004). Telomere length in tumor tissue [median = 0.43, interquartile range (IQR) = 0.40] was significantly shorter than adjacent normal tissue (median = 0.65, IQR = 0.28; P = 0.004). Patients with low fetuin-A levels were shown to have significantly shorter telomeres (P = 0.041). Patients with rectal tumors had significantly higher levels of fetuin-A than those with colonic tumors (P = 0.045). We have observed that patients with CRC display clear evidence of telomere attrition compared with controls. This is congruent with accelerated biological aging in the pathogenesis of CRC. An imbalance in redox control mechanisms and calcium homeostasis may be a contributing factor to telomere dynamics in our patients. Furthermore, fetuin-A levels can be used to distinguish between colon and rectal cancers.


Variation of young normal-hearing thresholds measured using different audiometric earphones: implications for the acoustic coupler and the ear simulator.
This paper questions the necessity for two calibration devices to measure the acoustic output from different types of audiometric earphones. International standards give the audiometric zero for TDH39 earphones on the IEC 60318-3 acoustic coupler; the IEC 60318-1 ear simulator is intended for other supra-aural earphone types. If hearing threshold samples from young, healthy ears were found to be more variable using TDH39 earphones, then that earphone and its coupler might be taken out of service. The audiological literature yielded threshold survey results for over 5100 otologically normal ears of subjects aged 31 years or less. These independent samples showed smaller variation for TDH39 samples than for samples using other earphones; this finding does not support abandoning the TDH39 and its coupler. Nevertheless, benefits accrue from calibrating TDH39 output to the audiometric zero as measured on the ear simulator.


Potent HIV-1 Protease Inhibitors: Stereoselective Synthesis of a Dipeptide Mimic.
The synthesis of a differentially protected dipeptide mimic 10 in enantiomerically pure form is described. The key step involves the epimerization of the C-2 center of the lactone 4, hydrolysis and protection of the resulting hydroxy acid, followed by Curtius rearrangement to introduce the urethane functionality. The scope and versatility of this isostere has been demonstrated by its conversion to potent HIV-1 protease inhibitors with nanomolar potencies. Also, established through the synthesis of compound 13 and 14, the 3S hydroxyl configuration of the dipeptide isostere 1 is the preferred configuration for its potency. The present synthesis is efficient and provides an access to other dipeptide mimics with a great deal of structural diversity.


Regulation of acute phase protein genes by hepatocyte-stimulating factors, monokines and glucocorticoids.
The synthesis of all the major acute phase plasma proteins is stimulated in rat hepatoma and primary cultures of hepatocytes by three, structurally and functionally distinct groups of hormones: 1) hepatocyte-stimulating factors (HSF) and interleukin-6 (IL-6); 2) interleukin-1 (IL-1) and tumor necrosis factor (TNF); and 3) glucocorticoids. Each plasma protein gene requires a specific combination of these 3 hormone types for maximal expression. One set of acute phase proteins, including alpha 2-macroglobulin, alpha 1-antichymotrypsin ( = contrapsin), cysteine protease inhibitor ( = thiostatin), alpha 1-antitrypsin, ceruloplasmin and fibrinogens are predominantly regulated by the keratinocyte-derived HSF-III/-II or IL-6, while a second set of proteins, including alpha 1-acid glycoprotein (AGP), haptoglobin and complement C3 are predominantly regulated by keratinocyte-derived HSF-I, IL-1 or TNF. In conjunction with the above peptide hormones, glucocorticoids synergistically enhance the stimulated expression of most, but not all, acute phase proteins. An exceptionally strong synergy between HSF (or IL-6), IL-1 and glucocorticoids is noted for the activation of the AGP gene. To elucidate the molecular mechanisms of regulation, we have identified the cis-acting genetic elements through which all these hormones control the transcriptional activity of the AGP gene. It appears that acute phase activates a specific nuclear binding protein in the rat liver that interacts with the peptide hormone responsive element located 5 kb upstream of the transcriptional start site.


PATTERNS OF VARIATION IN AQUATIC AMBYSTOMATID SALAMANDERS: KINEMATICS OF THE FEEDING MECHANISM.
Patterns of variation in the feeding mechanism of three species of ambystomatid salamanders (Ambystoma dumerilii, A. mexicanum, and A. ordinarium) were studied to provide insight into the nature of variation in kinematic parameters of the jaw mechanism associated with prey capture. A nested analysis of variance design provided an assessment of the amount of variation in six kinematic variables (measured from 200 frames/sec films of feeding behavior) both among species and among individuals within species. For all six variables, a highly significant proportion of the variance was explained at the intraspecific level. Among species, the most robust discriminators were variables associated with movement of the hyoid. The variables reflecting gape and lifting of the head provided no significant discrimination among species and had large error variances. The hyoid apparatus is the most phylogenetically conservative component of the feeding mechanism in lower vertebrates and was the most stereotyped component of feeding behavior within the salamander species studied here.


Potential suppression of multidrug-resistance-associated protein 1 by coumarin derivatives: an insight from molecular docking and MD simulation studies.
Human MRP1 protein plays a vital role in cancer multidrug resistance. Coumarins show promising pharmacological properties. Virtual screening, ADMET, molecular docking and molecular dynamics (MD) simulations were utilized as pharmacoinformatic tools to identify potential MRP1 inhibitors among coumarin derivatives. Using in silico ADMET, 50 hits were further investigated for their selectivity toward the nucleotide-binding domains (NBDs) of MRP1 using molecular docking. Accordingly, coumarin, its symmetrical ketone derivative Lig. No. 4, and Reversan were candidates for focused docking study with the NBDs domains compared with ATP. The result indicates that Lig. No. 4, with the best binding score, interacts with NBDs via hydrogen bonds with residues: GLN713, LYS684, GLY683, CYS682 in NBD1, and GLY1432, GLY771, SER769 and GLN1374 in NBD2, which mostly overlap with ATP binding residues. Moreover, doxorubicin (Doxo) was docked to the transmembrane domains (TMDs) active site of MRP1. Doxo interaction with TMDs was subjected to MD simulation in the NBDs free and occupied with Lig. No. 4 states. The results showed that Doxo interacts more strongly with TMD residues in inward facing feature of TMDs helices. However, when Lig. No. 4 exists in NBDs, Doxo interactions are different, and TMD helices show more outward-facing conformation. This result may suggest a partial competitive inhibition mechanism for the Lig. No. 4 on MRP1 compared with ATP. So, it may inhibit active complex formation by interfering with ATP entrance to NBDs and locking MRP1 conformation in outward-facing mode. This study suggests a valuable coumarin derivative that can be further investigated for potent MRP1 inhibitors.Communicated by Ramaswamy H. Sarma.


Head movements while recognizing speech arriving from behind.
Listeners' head movements were measured during speech recognition with simultaneous maskers. Both the target and masker were behind the listener, separated by 30°. Frequent head turns during speech recognition were observed for four of the ten listeners. For those four, head turns were more frequent at lower target-to-masker ratios (TMRs) and were oriented toward the target speech source. When the masker was competing speech the ultimate head orientation angle was larger at lower TMRs. These observed head movements are not consistent with a strategy that maximizes either the target level at a single ear or binaural unmasking of speech.


[Changes in active cysteine cathepsins in lysosomes from tissues thyroid papillary carcinomas with various biological characteristics].
To clarify possible role of cysteine cathepsin H, B and L in the proteolytic processes that contribute to the progression of tumor growth in the thyroid, we studied their activity in lysosomes isolated from the tissue of papillary carcinomas. It was shown that for these enzymes there is a dependence of the changes in their activity on a number of biological characteristics of the tumors. Thus, the sharp increase in the activity ofcathepsin H observed in lysosomes of tissue carcinomas category T2 and T3, with intra-and ekstrathyroid and lymphatic invasion of tumor cells. An increase in the activity of cathepsin B is set in the lysosomes of tissue heterogeneous follicular structure, especially in the presence of solid areas, in comparison with typical papillary tumors and in the lysosomes of tissue carcinomas in intrathyroid and cathepsin L-at extrathyroid invasion. A common feature of the enzymes is to increase the activity of cathepsins in lysosomes of tissue nonencapsulated papillary carcinomas. These enzymes probably do not take part in the invasion of tumor cells into blood vessels and in the mechanisms of tumor metastasis to regional lymph nodes. The latter shows no changes in the activity of cathepsins in lysosomes of tissue carcinomas category N1. The results indicate the different role of cathepsin H, B and L in thyroid carcinogenesis, where each enzyme has its specific function.


Advanced interatrial block predicts recurrence of atrial fibrillation after accessory pathway ablation in patients with Wolff-Parkinson-White syndrome.
Paroxysmal atrial fibrillation (AF) frequently occurs in patients with Wolff-Parkinson-White (WPW) syndrome. Although successful ablation of the accessory pathway (AP) eliminates paroxysmal AF in some patients, in other patients it can recur. We investigated the clinical utility of advanced interatrial block (IAB) for predicting the risk of AF recurrence in patients with verified paroxysmal AF and WPW syndrome after successful AP ablation. This retrospective study included 103 patients (70 men, 33 women; mean age, 44 ± 16 years) with WPW syndrome who had paroxysmal AF. A resting 12-lead electrocardiogram was performed immediately after successful AP ablation to evaluate the presence of advanced IAB, which was defined as a P-wave duration of >120 ms and biphasic [±] morphology in the inferior leads. During the mean follow-up period of 30.9 ± 20.0 months (range, 2-71 months), 16 patients (15.5%) developed AF recurrence. Patients with advanced IAB had significantly reduced event-free survival from AF (P < .001). Cox regression analysis with adjustment for the left atrial diameter and CHA2 DS2 -VASc score identified advanced IAB (hazard ratio, 9.18; 95% confidence interval [CI], 2.30-36.72; P = .002) and age > 50 years (hazard ratio, 12.64; 95% CI, 1.33-119.75; P = .027) as independent predictors of AF recurrence. Advanced IAB was an independent predictor of AF recurrence after successful AP ablation in patients with WPW syndrome.


Kagome superconductors AV3Sb5 (A = K, Rb, Cs).
The quasi-two-dimensional kagome materials AV3Sb5 (A = K, Rb, Cs) were found to be a prime example of kagome superconductors, a new quantum platform to investigate the interplay between electron correlation effects, topology and geometric frustration. In this review, we report recent progress on the experimental and theoretical studies of AV3Sb5 and provide a broad picture of this fast-developing field in order to stimulate an expanded search for unconventional kagome superconductors. We review the electronic properties of AV3Sb5, the experimental measurements of the charge density wave state, evidence of time-reversal symmetry breaking and other potential hidden symmetry breaking in these materials. A variety of theoretical proposals and models that address the nature of the time-reversal symmetry breaking are discussed. Finally, we review the superconducting properties of AV3Sb5, especially the potential pairing symmetries and the interplay between superconductivity and the charge density wave state.


Dermal cell damage induced by topical application of non-steroidal anti-inflammatory drugs is suppressed by trehalose co-lyophilization in ex vivo analysis.
Topical administration of non-steroidal anti-inflammatory drugs (NSAIDs) is generally considered safer than oral administration, although the former can occasionally induce cutaneous irritation. We hypothesized that the cutaneous irritation by topical NSAIDs might be suppressed by trehalose, which has protective effects on biological membranes. Using the three-dimensional cultured human skin model, Living Skin Equivalent-high, we found that cutaneous damage due to NSAIDs was reduced by concomitant use of trehalose and that this effect of trehalose was reinforced by co-lyophilization of NSAIDs with trehalose. The anti-inflammatory effect of co-lyophilized NSAIDs with trehalose was comparable to that seen with NSAIDs alone in a rat model. Our results suggest that co-lyophilization of NSAIDs with trehalose might be a novel procedure that can help prevent NSAIDs-induced skin irritation.


COVID-19 testing systems and their effectiveness in small, semi-isolated groups for sports events.
In this study, we quantitatively assessed the effectiveness of systems for COVID-19 testing in small groups of sport teams that are semi-isolated from the general population by countermeasures against infection. Two types of group were assumed, and the dynamics of infection within each group was modeled by using a compartment model of infectious disease. One group (Group A) comprised domestic professional sports teams that play many games over a season while remaining within a relatively small region. Polymerase chain reaction (PCR) tests were routinely conducted once every 2 weeks, and the number of infected individuals that could not be quarantined after identification by testing or checking for symptoms was defined as the risk. The other group (Group B) comprised teams that travel across borders for mass-gathering events like the Olympic and Paralympic Games. The teams were isolated for 2 weeks at their destination; frequent testing and checking for symptoms was conducted, and any infected individuals were quarantined. The number of infected individuals participating in games after the isolation period was defined as the risk. In Group A, the number of infected individuals detected by routinely conducted PCR testing was lower than the number of infected individuals detected by checking for symptoms, indicating that routine testing every 2 weeks was not very effective. In Group B, daily PCR testing was the most effective, followed by daily antigen testing. Dual testing, in which individuals with a positive antigen test were given an additional PCR test, was the least effective with an effect equal to PCR testing every other day. These results indicate that repeated testing does not necessarily increase the detection of infected individuals.


Universal Relation between Entropy and Kinetics.
Relating thermodynamic and kinetic properties is a conceptual challenge with many practical benefits. Here, based on first principles, we derive a rigorous inequality relating the entropy and the dynamic propagator of particle configurations. It is universal and applicable to steady states arbitrarily far from thermodynamic equilibrium. Applying the general relation to diffusive dynamics yields a relation between the entropy and the (normal or anomalous) diffusion coefficient. The relation can be used to obtain useful bounds for the late-time diffusion coefficient from the calculated steady-state entropy or, conversely, to estimate the entropy based on measured diffusion coefficients. We demonstrate the validity and usefulness of the relation through several examples and discuss its broad range of applications, in particular, for systems far from equilibrium.


Rapid axoglial signaling mediated by neuregulin and neurotrophic factors.
During peripheral nervous system development, Schwann cells are precisely matched to the axons that they support. This is mediated by axonal neuregulins that are essential for Schwann cell survival and differentiation. Here, we show that sensory and motor axons rapidly release heparin-binding forms of neuregulin in response to Schwann cell-derived neurotrophic factors in a dose-dependent manner. Neuregulin release occurs within minutes, is saturable, and occurs from axons that were isolated using a newly designed chamber slide apparatus. Although NGF and glial cell line-derived neurotrophic factor (GDNF) were the most potent neurotrophic factors to release neuregulin from sensory neurons, GDNF and BDNF were most potent for motor neurons and were the predominant neuregulin-releasing neurotrophic factors produced by cultured Schwann cells. Comparable levels of neuregulin could be released at a similar rate from neurons after protein kinase C activation with the phorbol ester, phorbol 12-myristate 13-acetate, which has also been shown to promote the cleavage and release of neuregulin from its transmembrane precursor. The rapid release of neuregulin from axons in response to Schwann cell-derived neurotrophic factors may be part of a spatially restricted system of communication at the axoglial interface important for proper peripheral nerve development, function, and repair.


Unusual origin of the flexor digiti minimi brevis muscle.
An unusual origin of the flexor digiti minimi brevis muscle of the right hand was discovered during cadaveric dissection. The muscle originated from the anterior aspect of the transverse fibers of the distal antebrachial fascia and inserted onto the base of the fifth proximal phalanx. When traction was applied to the proximal portion of the muscle, flexion was produced at the fifth metacarpophalangeal joint. Other intrinsic muscles of the hand and the muscles of the flexor forearm compartment had normal morphology. Although muscular anomalies in the hypothenar region have been described, the muscular variant described here was distinct in its origin and size from those previously reported. Knowledge of anomalous muscles in the hand has important clinical significance in routine surgery and in determining associated pathology.


Risk factors for sporadic cryptosporidiosis among immunocompetent persons in the United States from 1999 to 2001.
Many studies have evaluated the role of Cryptosporidium spp. in outbreaks of enteric illness, but few studies have evaluated sporadic cryptosporidiosis in the United States. To assess the risk factors for sporadic cryptosporidiosis among immunocompetent persons, a matched case-control study was conducted in seven sites of the Foodborne Diseases Active Surveillance Network (FoodNet) involving 282 persons with laboratory-identified cryptosporidiosis and 490 age-matched and geographically matched controls. Risk factors included international travel (odds ratio [OR] = 7.7; 95% confidence interval [95% CI] = 2.7 to 22.0), contact with cattle (OR = 3.5; 95% CI = 1.8 to 6.8), contact with persons >2 to 11 years of age with diarrhea (OR = 3.0; 95% CI = 1.5 to 6.2), and freshwater swimming (OR = 1.9; 95% CI = 1.049 to 3.5). Eating raw vegetables was protective (OR = 0.5; 95% CI = 0.3 to 0.7). This study underscores the need for ongoing public health education to prevent cryptosporidiosis, particularly among travelers, animal handlers, child caregivers, and swimmers, and the need for further assessment of the role of raw vegetables in cryptosporidiosis.


Prevalence of Corneal Astigmatism in an NHS Cataract Surgery Practice in Northern Ireland.
Post-operative corneal astigmatism following cataract surgery can leave the patient with visual impairment. Correcting it at the time of surgery with a toric intraocular lens (TIOL) can give patients a better final visual outcome. The purpose was to determine the prevalence of corneal astigmatism in a cataract population and assess the demand for TIOL. Keratometric data was collected and analyzed for all patients who attended for routine cataract surgery under the care of a single surgeon based in Altnagelvin Area Hospital, Northern Ireland (NI). All patients were included between January 2008 and December 2014. Data was collected retrospectively for this observational study. There were 2080 consecutive eyes of 1788 patients. The mean corneal astigmatism was 1.09 ± 0.83. Corneal astigmatism was 1.50D or less in 1621 eyes (78%). It was more than 2.00 D in 242 eyes (11.6%), more than 2.50 D in 127 eyes (6.1%), more than 3.00D in 68 eyes (3.27%) and more than 3.50 D in 45 eyes (2.16%). For routine cataract surgery, 41.3% of eyes had more than 1.00 D of corneal astigmatism and 11.6% had more and 2.00D. Females had more astigmatism than males. This shows the potential demand for the TIOL in this population.


Changes are still needed on multiple co-primary endpoints.
The Food and Drug Administration in the United States issued a much-awaited draft guidance on 'Multiple Endpoints in Clinical Trials' in January 2017. The draft guidance is well written and contains consistent message on the technical implementation of the principles laid out in the guidance. In this commentary, we raise a question on applying the principles to studies designed from a safety perspective. We then direct our attention to issues related to multiple co-primary endpoints. In a paper published in the Drug Information Journal in 2007, Offen et al. give examples of disorders where multiple co-primary endpoints are required by regulators. The standard test for multiple co-primary endpoints is the min test which tests each endpoint individually, at the one-sided 2.5% level, for a confirmatory trial. This approach leads to a substantial loss of power when the number of co-primary endpoints exceeds 2, a fact acknowledged in the draft guidance. We review approaches that have been proposed to tackle the problem of power loss and propose a new one. Using recommendations by Chen et al. for the assessment of drugs for vulvar and vaginal atrophy published in the Drug Information Journal in 2010, we argue the need for more changes and urge a path forward that uses different levels of claims to reflect the effectiveness of a product on multiple endpoints that are equally important and mostly unrelated. Copyright © 2017 John Wiley & Sons, Ltd.


Protective effects of nedocromil sodium and sodium cromoglycate on gastroduodenal ulcers: a comparative study in rats.
Stabilization of mast cells plays a key mechanism to protect gastrointestinal tract from injury. This study presents a comparative evaluation of mast cell stabilizers nedocromil sodium (NDS) and sodium cromoglycate (SCG) in experimental gastric and duodenal ulcers in rats. Wistar rats of either sex were used in this study. Both NDS and SCG, in the doses of 10, 30 and 100 mg/kg were given intraperitoneally for gastric secretion studies and by gavage for antiulcer studies. Acid secretion studies were undertaken in pylorus-ligated rats. Gastric lesions were induced by water immersion restraint stress (WIRS), indomethacin and ethanol whereas duodenal ulcers were produced by cysteamine. The level of glutathione (GSH) and gastric wall mucus were measured in glandular stomach of rats following ethanol-induced gastric lesions. SCG was more effective than NDS in preventing WIRS- and indomethacin-induced gastric lesions whereas reverse was true in ethanol- and cysteamine-induced ulcers. All the 3 doses of SCG offered almost equal protection against WIRS-induced gastric lesions whereas only medium and high dose of NDS provided significant protection in this model of ulcer. NDS significantly inhibited cysteamine-induced duodenal ulcers whereas SCG failed to do so. Pretreatment with NDS or SCG significantly and dose-dependently protected gastric mucosa against ethanol-induced injury, while the former drug appeared to be more effective. The cytoprotective effects of these two drugs were accompanied by the attenuation of ethanol-induced depletion of gastric wall mucus and GSH. The differential effects of NDS and SCG against various gastric lesions rationalize the possible benefits of a combined therapy (NDS+SCG) for the treatment of complex gastroduodenal ulcers.


In-situ freeze-drying - forming amorphous solids directly within capsules: An investigation of dissolution enhancement for a poorly soluble drug.
Conversion into the amorphous form enhances the dissolution of poorly soluble drugs, however the barrier to market for medicines containing an amorphous drug is poor stability. The aim was to produce the amorphous form of a drug within a capsule, without thermal or mechanical stress during manufacture. To facilitate this aim, the mechanism for drug-polymer interaction was explored. Nifedipine and polyvinylpyrrolidone were dissolved in tert-butanol at different drug/polymer ratios. These solutions were dispensed into gelatin capsules and freeze-dried. Differential scanning calorimetry (DSC) & novel FT-IR analysis based on peak symmetry measurements confirmed the absence of crystallinity when polyvinylpyrrolidone exceeded 50%w/w. Capsules containing 10 mg of nifedipine were amorphous and stable for over 3 months at ≈40 °C. Evidence of hydrogen bonding between the N-H group of nifedipine and the C=O group of PVP was observed and this interaction inhibited nifedipine crystallisation. PVP's high affinity for water and the nifedipine-polymer interaction lead to a significant dissolution rate enhancement. The freeze-dried capsule, 10%w/w nifedipine/PVP, had the highest dissolution rate constant of 0.37 ± 0.05 min-1, and the lowest time to achieve 50% dissolution or t1/2 of 1.88 ± 0.05 min. This formulation reached 80% dissolved in less than 6 min whereas the equivalent marketed liquid filled nifedipine capsule took 3 times longer to reach 80% dissolution.


Top-down modulation of brain responses in spelling error recognition.
The task being undertaken can influence orthographic, phonological and semantic processes. In linguistic research, two tasks are most often used: a task requiring a decision in relation to the presented word and a passive reading task which does not require a decision regarding the presented word. The results of studies using these different tasks are not always consistent. This study aimed to explore brain responses associated with the process of recognition of spelling errors, as well as the influence of the task on this process. Event-related potentials (ERPs) were recorded in 40 adults during an orthographic decision task to determine correctly spelled words and words written with errors that did not change the phonology and during the passive reading. During spelling recognition, the early stages up to 100 ms after the stimulus were automatic and did not depend on the requirements of the task. The amplitude of the N1 component (90-160 ms) was greater in the orthographic decision task, but did not depend on the correct spelling of the word. Late word recognition after 350-500 ms was task dependent, but spelling effects were similar across the two tasks: misspelled words evoked an increase in the amplitude of the N400 component related to lexical and semantic processing regardless of the task. In addition, the orthographic decision task modulated spelling effects, this was reflected in an increase in the amplitude of the P2 component (180-260 ms) for correctly spelled words compared with misspelled words. Thus, our results show that spelling recognition involves general lexico-semantic processes independent of the task. Simultaneously, the orthographic decision task modulates the spelling-specific processes necessary to quickly detect conflicts between orthographic and phonological representations of words in memory.


Comparison of the fast track diagnostics respiratory 21 and Seegene Allplex multiplex polymerase chain reaction assays for the detection of respiratory viruses.
Real-time multiplex PCR assays are increasingly used for respiratory virus detection, and offer automated analysis in a closed tube system, but they have the disadvantage of low-throughput due to multiplexing limitations. In this study, the established fast-track respiratory 21 assay (FTD) (fast-track diagnostics, Junglinster Luxembourg) was compared to the new Seegene Allplex assay (Seegene) (Seegene Inc. Seoul, Korea) which offers greater multiplexing as multiple targets can be detected in each fluorescence channel. The Seegene Allplex assay is quicker to perform than previous Seegene respiratory multiplex assays. The assays were evaluated using 199 mostly upper respiratory tract samples. A respiratory pathogen was found in 127/199 (63.8%) of samples by the FTD assay and 123/199 (61.8%) using the Seegene assay. Kappa agreement was between 0.87 and 1 for all targets except human bocavirus and adenovirus. Although the performance of the assays were similar, the Seegene assay had the advantage of simultaneous detection of two gene targets for each of the common Influenza A subtypes, improved throughput of 30 samples per run and automated result analysis. The FTD assay could only test 17 samples per run but validation for use on several different real-time thermal cyclers made it easier to integrate into an existing laboratory system. Both assays were cost effective compared to in-house multiplex PCR respiratory virus screening.


The elastic constants and ultrastructure organization of regenerated basement membrane (lens capsule).
The regenerated basement membrane of the crystalline lens of the rat has been found to have the following elastic constants: a Young's modulus of elasticity of 0.6 +/- 0.48 X 10(6) N m-2 at low stress and 7.8 +/- 2.0 X 10(6) N m-2 at rupture, an ultimate stress of 19.7 +/- 7.0 X 10(5) N m-2, and a maximum percentage elongation of 33.7 +/- 6.1%. Electron microscopic observations of ultrasonicated fragments of the entire membrane show long filaments in parallel arrays and sheets. The filaments show a periodicity of 3.4 nm and a spacing of 3.2 nm. Electron microscopic observations of regenerated membrane treated with collagenase show a poorly staining matrix with separate short thin and thick non-periodic filaments, their diameters being 1.4 nm and 2.5 nm respectively. In addition, strands project from the ends of filaments with a diameter between 0.5 and 1.0 nm. The reduced ultimate strength and Young's modulus of elasticity at rupture in regenerated membrane as compared with normal membrane is considered to be due to the preponderance of thinner filaments in the former. Normal membrane contains not more than 33% of thin filaments whereas regenerated membrane contains at least 78% of such filaments. A comparison of the diameters of thin and thick filaments indicates that thick filaments are probably composed of five strands while thin ones contain three strands.


Socioeconomic factors and maternal and child health care.
A sample of mothers was interviewed between 12 and 18 months after delivery of a liveborn infant. Data were gathered concerning planned parenthood, prenatal care, the child's care in the first year of life, and socioeconomic factors. Among socioeconomic variables, maternal education was found to be the single best parameter in terms of detecting differences within the sample with regard to levels of birth control, prenatal care, and child care.


Targeting the Metabolic Reprogramming That Controls Epithelial-to-Mesenchymal Transition in Aggressive Tumors.
The epithelial-to-mesenchymal transition (EMT) process allows the trans-differentiation of a cell with epithelial features into a cell with mesenchymal characteristics. This process has been reported to be a key priming event for tumor development and therefore EMT activation is now considered an established trait of malignancy. The transcriptional and epigenetic reprogramming that governs EMT has been extensively characterized and reviewed in the last decade. However, increasing evidence demonstrates a correlation between metabolic reprogramming and EMT execution. The aim of the current review is to gather the recent findings that illustrate this correlation to help deciphering whether metabolic changes are causative or just a bystander effect of EMT activation. The review is divided accordingly to the catabolic and anabolic pathways that characterize carbohydrate, aminoacid, and lipid metabolism. Moreover, at the end of each part, we have discussed a series of potential metabolic targets involved in EMT promotion and execution for which drugs are either available or that could be further investigated for therapeutic intervention.


Prospective Qualitative and Quantitative Analysis of Real-Time Peer Review Quality Assurance Rounds Incorporating Direct Physical Examination for Head and Neck Cancer Radiation Therapy.
Our department has a long-established comprehensive quality assurance (QA) planning clinic for patients undergoing radiation therapy (RT) for head and neck cancer. Our aim is to assess the impact of a real-time peer review QA process on the quantitative and qualitative radiation therapy plan changes in the era of intensity modulated RT (IMRT). Prospective data for 85 patients undergoing head and neck IMRT who presented at a biweekly QA clinic after simulation and contouring were collected. A standard data collection form was used to document alterations made during this process. The original pre-QA clinical target volumes (CTVs) approved by the treating-attending physicians were saved before QA and compared with post-QA consensus CTVs. Qualitative assessment was done according to predefined criteria. Dice similarity coefficients (DSC) and other volume overlap metrics were calculated for each CTV level and were used for quantitative comparison. Changes are categorized as major, minor, and trivial according to the degree of overlap. Patterns of failure were analyzed and correlated to plan changes. All 85 patients were examined by at least 1 head and neck subspecialist radiation oncologist who was not the treating-attending physician; 80 (94%) were examined by ≥3 faculty members. New clinical findings on physical examination were found in 12 patients (14%) leading to major plan changes. Quantitative DSC analysis revealed significantly better agreement in CTV1 (0.94 ± 0.10) contours than in CTV2 (0.82 ± 0.25) and CTV3 (0.86 ± 0.2) contours (P=.0002 and P=.03, respectively; matched-pair Wilcoxon test). The experience of the treating-attending radiation oncologist significantly affected DSC values when all CTV levels were considered (P=.012; matched-pair Wilcoxon text). After a median follow-up time of 38 months, only 10 patients (12%) had local recurrence, regional recurrence, or both, mostly in central high-dose areas. Comprehensive peer review planning clinic is an essential component of IMRT QA that led to major changes in one-third of the study population. This process ensured safety related to target definition and led to favorable disease control profiles, with no identifiable recurrences attributable to geometric misses or delineation errors.


Cultivation-based strategies to find efficient marine biocatalysts.
Marine bacteria have evolved to survive in the marine environment by using unique physiological, biochemical and metabolic features and the ability to produce enzymes and compounds which may have commercial value. The Azores archipelago presents several ecosystems with strong volcanic activity where bacteria thrive under e.g. high temperatures. In this study, samples collected in the island of São Miguel were screened for biocatalysts possessing e.g. lipase, esterase, amylase, and inulinase activities. After isolation of several hundred bacterial strains, high throughput screening methods allowed the fast identification of biocatalysts. The first cultivation tests were performed on 24-wells microtiter plates with online oxygen monitoring and bacteria able to grow within 24 h were selected for further process development. Bacteria able to produce the desired enzymes were selected for the first round of tests. Four Bacillus strains presented high inulinase activity. The next step in process development was the determination of key parameters for enzyme activity such as temperature, pH, salinity and substrate concentration. The highest inulinase activity, 2.2 gsugars /gprotein h, was attained when the supernatant of a culture of a Bacillus subtilis strain was used in a magnetically stirred bioreactor. This study demonstrates how bacterial strains from marine environments may be used successfully in biotechnological processes.


Loneliness and related factors among people with schizophrenia in Japan: a cross-sectional study.
WHAT IS KNOWN ABOUT THE SUBJECT?: Loneliness among people diagnosed with schizophrenia is a serious problem. Recent studies have focused on the loneliness; however, no study has examined the relationships between loneliness and both individual and environmental factors comprehensively. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: The main results indicated that the community-dwelling people diagnosed with schizophrenia in Japan as well as in other countries experienced higher levels of loneliness. Both individual and environmental factors were related to loneliness. Increasing the self-efficacy for community life and self-esteem of individual factors, and not being socially isolated and increasing community integration of environmental factors would improve their loneliness. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Health practitioners, in particular, public health nurses in mental health care, should work to develop a partnership with people diagnosed with schizophrenia, their family members, friends and other community-dwelling people in order to decrease and prevent loneliness. For individuals diagnosed with schizophrenia, interventions by cooperating with community resources and using the technique of nurses to assist them with continuous community activity could be useful. For environmental interventions, population approach such as developing daily programmes which family members can participate in, and cooperating with educational institutions and community events could have a positive effects. Introduction Loneliness among people diagnosed with schizophrenia living in communities can decrease quality of life and may contribute to suicide. Aim The aim of this study was to examine the levels of loneliness among Japanese people diagnosed with schizophrenia and to identify individual and environmental factors related to their loneliness. Method A cross-sectional survey was conducted with 264 people diagnosed with schizophrenia who use local activity support centres in urban areas. The self-administered questionnaires included questions on loneliness, demographic characteristics, individual factors including self-efficacy for community life and self-esteem, and environmental factors including social isolation, community integration and service use. Results The study results indicated that people diagnosed with schizophrenia in Japan experience higher levels of loneliness, corroborating results from other countries. Multiple regression analysis showed that a lower level of self-efficacy for community life, self-esteem, community integration and social isolation predicted a higher level of loneliness, accounting for 55.3% of variance. Implications for Practice Public health nurses in mental health care in Japan can work with individuals diagnosed with schizophrenia and communities using the technique to assist them with continuous activity and cooperating with community resources and educational institutions in order to decrease and prevent loneliness.


Par4 is required for platelet thrombus propagation but not fibrin generation in a mouse model of thrombosis.
Thrombin, a central mediator of hemostasis and thrombosis, converts fibrinogen to fibrin and is a potent platelet activator. Activated platelets provide a surface for assembly of the tenase and prothrombinase complexes required for thrombin generation. The role of thrombin-induced platelet activation in platelet accumulation and its interplay with fibrin deposition during thrombus assembly has not been fully defined. We studied these processes during laser-induced thrombus formation by using real-time digital fluorescence microscopy in mice lacking protease-activated receptor-4 (Par4), which is necessary for thrombin responsiveness in mouse platelets. Juxtamural platelet accumulation immediately after laser injury was not different in wild-type and Par4(-/-) mice. However, subsequent growth of platelet thrombi was markedly diminished in Par4(-/-) mice. At the time of maximal thrombus size in wild type, platelet accumulation was more than 10-fold higher in wild type than in Par4(-/-) mice. P-selectin expression, a marker of platelet activation, was reduced and delayed in Par4(-/-) thrombi. In contrast to platelet activation and accumulation, the rate and amount of fibrin deposition, predominantly intramural and juxtamural in this model, were indistinguishable in Par4(-/-) and wild-type mice. These results suggest that platelet activation by thrombin is necessary for normal propagation of a platelet thrombus at a distance from the injured vessel wall and hence for normal thrombus growth. However, platelet activation by thrombin is unnecessary for initial and limited accumulation of platelets at or near the vessel wall, and this limited accumulation of platelets and/or platelet-independent mechanism(s) of thrombin generation are sufficient for normal fibrin deposition in this model.


Penehyclidine hydrochloride preserves the intestinal barrier function in patients undergoing cardiopulmonary bypass.
The study objective was to investigate the protective effect of penehyclidine hydrochloride on intestinal barrier function integrity and its therapeutic potential on endotoxemia and systemic inflammatory response in patients undergoing cardiopulmonary bypass. Forty patients undergoing cardiac valve replacement with cardiopulmonary bypass were enrolled in the study. All patients were randomly divided into the penehyclidine hydrochloride or control group (20 patients in each group). Patients in the penehyclidine hydrochloride group received an intravenous injection of 0.05 mg/kg penehyclidine hydrochloride 10 minutes before cardiopulmonary bypass, and those in the control group were given the same volume of saline. Blood samples for blood glucose, lactic acid, intestinal fatty acid binding protein, D-lactate, serum endotoxin (lipopolysaccharide), interleukin-6, and interleukin-10 measurements were collected during the following time points: immediately after anesthesia induction (T0), 10 minutes after the release of aortic-clamping (T1), immediately after weaning from cardiopulmonary bypass (T2), 2 hours postoperatively (T3), 6 hours postoperatively (T4), and 18 hours postoperatively (T5). Blood glucose, lactic acid, intestinal fatty acid binding protein, D-lactate, lipopolysaccharide, interleukin-6, and interleukin-10 were significantly increased at all postoperative time points. At specific postoperative time points, blood glucose, lactic acid, intestinal fatty acid binding protein, D-lactate, lipopolysaccharide, and interleukin-6 were statistically lower in the penehyclidine hydrochloride group than in the control group. Postoperatively, interleukin-10 did not differ between the penehyclidine hydrochloride and control groups. Penehyclidine hydrochloride preserves intestinal barrier function integrity, attenuates endotoxemia, and inhibits systemic inflammatory response in patients undergoing cardiopulmonary bypass, possibly by improving intestinal microcirculation and depressing stress response.


Binding of Copper Ions with Octapeptide Region in Prion Protein: Simulations with Charge Transfer Model.
Copper ions are important cofactors of many metalloproteins. The binding dynamics of proteins to the copper ion is important for biological functions but is less understood at the microscopic level. What are the key factors determining the recognition and the stabilization of the copper ion during the binding? Our work investigates the binding dynamics of the copper ion with a simple system (the N-terminus of PrP) using simulation methods. To precisely characterize the protein?ion interaction, we build up an effective copper?peptide force field based on quantum chemistry calculations. In our model, the effects of charge transfer, protonation/deprotonation, and induced polarization are considered. With this force field, we successfully characterize the local structures and the complex interactions of the octapeptide around the copper ion. Furthermore, using an enhanced sampling method, the binding/unbinding processes of the copper ion with the octapeptide are simulated. Free-energy landscapes are generated in consequence, and multiple binding pathways are characterized. It is observed that various native ligands contribute differently to the binding processes. Some residues are related to the capture of the ion (behaving like ?arm?s), and some others contribute to the stabilization of the coordination structure (acting like ?core?s). These different interactions induce various pathways. Besides, a nonnative binding ligand is determined, and it has essential contributions and modulations to the binding pathways. With all these results, the picture of copper?octapeptide binding is outlined. These features are believed to happen in many ion?peptide interactions, such as the cooperative stabilization between the coordinations with neighboring backbone nitrogens and an auxiliary intermediate coordination with the neighboring oxygen from the N-terminal direction. We believe that our studies are valuable to understand the complicated ion?peptide binding processes.


Simulation of intermediate transport in nanoscale scaffolds for multistep catalytic reactions.
Efficient catalytic cascades that involve several sequential reactions are found frequently in nature. The efficiency of multi-step biochemical pathways is enhanced by substrate channelling, wherein the product of one reaction is directed toward and acts as substrate to the next sequential reaction. Such mechanisms can partially overcome diffusion, which is often fast compared to reaction rates, and promotes loss of intermediates. Biochemical substrate channelling is achieved by the architecture and scaffolding of enzymes, and mimicking these natural structures could lead to innovative catalyst designs. We investigate the efficiency of two channelling approaches - electrostatic interactions and surface adsorption - through continuum modelling, to identify the limits of these modes and the extent to which they can interact. The model considers transport between two active sites where an intermediate is produced at the first active site and consumed at the second. The system includes mass transport through diffusion and migration, and reaction kinetics at the active sites. The effectiveness of this model is quantified by yield of the second reaction relative to the first. Channelling via proximity between active sites and via surface adsorption are found to be inefficient, requiring high values of the rate constant at the second active site to obtain significant yields. The introduction of electrostatic interactions, however, leads to yields of over 90% at much lower values of the rate constant.


Photodynamic therapy with a cationic functionalized fullerene rescues mice from fatal wound infections.
Fullerenes are under intensive study for potential biomedical applications. We have previously reported that a C60 fullerene functionalized with three dimethylpyrrolidinium groups (BF6) is a highly active broad-spectrum antimicrobial photosensitizer in vitro when combined with white-light illumination. We asked whether this high degree of in vitro activity would translate into an in vivo therapeutic effect in two potentially lethal mouse models of infected wounds. We used stable bioluminescent bacteria and a low light imaging system to follow the progress of the infection noninvasively in real time. An excisional wound on the mouse back was contaminated with one of two bioluminescent Gram-negative species, Proteus mirabilis (2.5 × 10(7) cells) and Pseudomonas aeruginosa (5 × 10(6) cells). A solution of BF6 was placed into the wound followed by delivery of up to 180 J/cm(2) of broadband white light (400-700 nm). In both cases there was a light-dose-dependent reduction of bioluminescence from the wound not observed in control groups (light alone or BF6 alone). Fullerene-mediated photodynamic therapy of mice infected with P. mirabilis led to 82% survival compared with 8% survival without treatment (p < 0.001). Photodynamic therapy of mice infected with highly virulent P. aeruginosa did not lead to survival, but when photodynamic therapy was combined with a suboptimal dose of the antibiotic tobramycin (6 mg/kg for 1 day) there was a synergistic therapeutic effect with a survival of 60% compared with a survival of 20% with tobramycin alone (p < 0.01). These data suggest that cationic fullerenes have clinical potential as an antimicrobial photosensitizer for superficial infections where red light is not needed to penetrate tissue.


Transcultural Validation of the Nordic Age Discrimination Scale for the Spanish-Speaking Working Populations.
Negative stereotypes about older workers can result in different types of age discrimination. The aim of this study was to run a transcultural adaptation and validation of the Nordic Age Discrimination Scale (NADS) into Spanish. Three independent samples of Chilean (N = 301), Colombian (N = 150), and Spanish (N = 209) workers over the age of 45, from different sectors and professional categories, answered a questionnaire including the NADS scale, measures of perceptions of inequality, workplace harassment and several scales related to outcome variables to test criterion and construct validity. The reliability index for the NADS was .85, a similar value for both Cronbach's alpha (α) and McDonald's omega (ω). CFA by country suggest good fit of this single-dimension structure in a final version of 5 items, and it presents scalar invariance; using the modification indices, partial invariance is achieved at the level of the variance of the errors. Both criterion and construct validity were verified, with strong evidence for criterion validity, and moderate results for construct validity. Therefore, the Spanish version of NADS had a single-dimension structure and adequate psychometric properties being a useful tool in measuring perceptions of age discrimination in different countries.


Potent Intestinal Mucosal Barrier Enhancement of Nostoc commune Vaucher Polysaccharide Supplementation Ameliorates Acute Ulcerative Colitis in Mice Mediated by Gut Microbiota.
Ulcerative colitis (UC) is evolving into a global burden with a substantially increasing incidence in developing countries. It is characterized by inflammation confined to mucosa and is recognized as an intestinal barrier disease. The intestinal microbiota plays a crucial role in UC pathogenesis. N. commune has long been appreciated as a healthy food and supplement worldwide and polysaccharides account for 60%. Here, we examined the amelioration of N. commune polysaccharides against acute colitis in mice induced by DSS and assessed the mediating role of gut microbiota. An integrated analysis of microbiome, metabolomics, and transcriptomics fully elaborated it markedly enhanced intestinal mucosal barrier function, including: increasing the relative abundance of Akkermansia muciniphila, uncultured_bacterium_g__norank_f__Muribaculaceae, and unclassified_g__norank_f__norank_o__Clostridia_UCG-014; decreasing microbiota-derived phosphatidylcholines and thromboxane 2 levels mapped to arachidonic acid metabolism; improving mucin2 biosynthesis and secretion; enhancing ZO-1 and occludin expression; reducing neutrophil infiltration; regulating the level of colitis-related inflammatory cytokines; involving inflammation and immune function-associated signaling pathways. Further, the mediation effect of gut microbiota was evaluated by administering a cocktail of antibiotics. In conclusion, our results demonstrated that N. commune polysaccharides predominantly reinforced the gut microbiota-mediated intestinal mucosal barrier to confer protection against UC and exhibited dramatic prebiotic-like functions, providing an alternative or complementary treatment for UC.


Diffuse Layer Effect on Electron-Transfer Kinetics Measured by Scanning Electrochemical Microscopy (SECM).
Recent theoretical and experimental studies revealed strong effects of the electrical double layer (EDL) on mass transfer at nanometer-sized electrodes and in electrochemical nanogaps. Although the EDL effect is much stronger in weakly supported media, it can significantly influence the kinetics of electron-transfer processes involving multicharged ionic redox species, even at high concentrations of supporting electrolyte. We measured the kinetics of Fe(CN)64- oxidation in 1 M KCl solution at the Pt nanoelectrode used as a tip in the scanning electrochemical microscope. The apparent standard rate constant values extracted from tip voltammograms without double-layer correction increased markedly with the decreasing separation distance between the tip and substrate electrodes. The same steady-state voltammograms were fitted to the theory including the EDL effect and yielded the rate constant essentially independent of the separation distance.


A Community-Based Participatory Approach to Understanding HIV/AIDS in the Ethiopian Community.
The rate of HIV/AIDS in Washington, D.C remains at epidemic levels and is most prevalent in the black community, with foreign-born blacks accounting for an increasing proportion of HIV infections in the Washington DC area. The Ethiopian community is among the subgroups that are especially impacted by HIV/AIDS. Yet, seldom does research on the epidemiology of HIV/AIDS break data into diverse subgroups, accounting for the distinct needs based on cultural or ethnic differences. This paper reports on the qualitative findings from a community participatory action research study that involved interviewing 60 Ethiopian-immigrants and nine community-based providers about their attitudes toward HIV/AIDS, and to elicit their ideas about how to improve HIV/AIDS prevention, promotion, and treatment approaches targeting the Ethiopian community. Findings show that stigma remains the largest barrier to accessing HIV/AIDS treatment among Ethiopians in the Washington, D.C. area. Therefore, strategies to reduce HIV/AIDS must address stigmatizing beliefs and be met with cultural sensitivity when developing community prevention and treatment outreach programs designed to reduce HIV/AIDS among Ethiopians.


Comparison of levobupivacaine and levobupivacaine with fentanyl in infraumbilical surgeries under spinal anaesthesia.
Intrathecal opioids added to low dose local anesthetics in spinal anaesthesia intensifies sensory block without affecting sympathetic blockade. Aim was to evaluate the safety and efficacy of intrathecal levobupivacaine plain versus levobupivacaine plus fentanyl in infraumbilical surgeries. In a prospective randomized double blind study, 100 patients of American Society of Anesthesiologists grades I and II of either sex, 20-65 years of age were included after approval from the Ethics Committee. Informed consent was taken and patients were randomly divided into two groups of 50 each, to receive either 2 ml of 0.5% isobaric levobupivacaine (group L) or 2 ml of 0.5% isobaric levobupivacaine + 25 μg fentanyl (group LF) intrathecally. Patients were monitored for sensory and motor block characteristics, postoperative analgesia, haemodynamics and side effects and complications for 24 h. Onset of sensory block and time to maximum sensory block was rapid in group LF (4.8 ± 1.50 and 8.46 ± 1.87 min) as compared to group L (7.6 ± 1.46 and 15.80 ± 2.43 min) (P < 0.000). Maximum sensory block was T6 in group LF and T8 in group L. Maximum Bromage score was 2 in both groups but was achieved earlier in group LF (P < 0.000). Duration of sensory and motor block was significantly prolonged in group LF (270.98 ± 28.60 and 188.52 ± 9.81 min) as compared to group L (197.58 ± 11.20 and 152.76 ± 9.79 min). Total duration of analgesia was also prolonged in group LF (265.16 ± 26.18 min) as compared to group L (168.16 ± 11.08 min). Patients remained haemodynamically stable and side effects and complications were comparable in both groups. Data was analyzed using "Chi-square test" and "unpaired t-test." Addition of fentanyl to levobupivacaine leads to early onset and prolonged duration of sensory and motor block as well as postoperative analgesia with stable haemodynamics and minimal side effects.


Hepatic metabolite concentration in lactic acidotic sheep.
The concentration of hepatic metabolites associated with energy-producing pathways and hepatic oxygen consumption were measured in clinically normal and lactic acidotic sheep. Significantly (P less than 0.005) lower pyruvate concentrations in livers of acidotic sheep produced significantly larger L-lactate to pyruvate concentration ratios. Glycogen concentrations were significantly (P less than 0.005) lower in liver from acidotic sheep. Oxygen consumption by liver from acidotic sheep was depressed when compared with oxygen consumption by normal sheep liver. Seemingly, limited available carbohydrate substrate and not tissue oxygenation may be limiting aerobic glycolysis in liver of lactic acidotic sheep.


Dielectrophoretic medium exchange around droplets for on-chip fabrication of layer-by-layer microcapsules.
Continuous medium exchange within a microchannel represents a highly sought-after technique in functionalizing micro-objects with coating layers, enabling a myriad of applications ranging from biomedical engineering to materials science. Herein, we introduce a unique medium exchange approach, namely, tilted-angle dielectrophoresis, to accomplish layer-by-layer (LbL) coating on droplets in a wide microchannel. Pairs of adjacent tilted parallel electrodes arranged in a zigzag fashion are exploited to consecutively and repeatedly guide particles/droplets travelling through three parallel laminar streams comprising two reagents and a washing buffer. The performance of medium exchange is demonstrated using PS microparticles and oil droplets. We show that multi-cycle medium exchange, droplet transfer accompanied with purification, and multi-mode medium exchange around different micro-objects are achieved by conveniently regulating the applied voltage and the inlet flow rate, indicating a flexible, versatile and label-free alternative for characterizing and handling colloidal particles. Furthermore, LbL coating on droplets utilizing the presented strategy is implemented in the parallel coating-chemical and washing streams to obtain multiple layers of microcapsules. The linearly increasing fluorescence intensity of the coated droplets with each subsequent fluorescent coating demonstrates the capability of the tilted-angle dielectrophoretic medium exchanger for on-chip generation of LbL microcapsules on demand. The presented medium exchange strategy, together with its unique features of simple geometric configuration, facile control and multifunctionality, can provide a refined alternative for further expanding the utility scope in functional particles and cells.


Epidermal Enzymatic Biosensors for Sweat Vitamin C: Toward Personalized Nutrition.
Recent advances in wearable sensor technologies offer new opportunities for improving dietary adherence. However, despite their tremendous promise, the potential of wearable chemical sensors for guiding personalized nutrition solutions has not been reported. Herein, we present an epidermal biosensor aimed at following the dynamics of sweat vitamin C after the intake of vitamin C pills and fruit juices. Such skin-worn noninvasive electrochemical detection of sweat vitamin C has been realized by immobilizing the enzyme ascorbate oxidase (AAOx) on flexible printable tattoo electrodes and monitoring changes in the vitamin C level through changes in the reduction current of the oxygen cosubstrate. The flexible vitamin C tattoo patch was fabricated on a polyurethane substrate and combined with a localized iontophoretic sweat stimulation system along with amperometric cathodic detection of the oxygen depletion during the enzymatic reaction. The enzyme biosensor offers a highly selective response compared to the common direct (nonenzymatic) voltammetric measurements, with no effect on electroactive interfering species such as uric acid or acetaminophen. Temporal vitamin C profiles in sweat are demonstrated using different subjects taking varying amounts of commercial vitamin C pills or vitamin C-rich beverages. The dynamic rise and fall of such vitamin C sweat levels is thus demonstrated with no interference from other sweat constituents. Differences in such dynamics among the individual subjects indicate the potential of the epidermal biosensor for personalized nutrition solutions. The flexible tattoo patch displayed mechanical resiliency to multiple stretching and bending deformations. In addition, the AAOx biosensor is shown to be useful as a disposable strip for the rapid in vitro detection of vitamin C in untreated raw saliva and tears following pill or juice intake. These results demonstrate the potential of wearable chemical sensors for noninvasive nutrition status assessments and tracking of nutrient uptake toward detecting and correcting nutritional deficiencies, assessing adherence to vitamin intake, and supporting dietary behavior change.


Carditis associated with Mycoplasma pneumoniae infection.
A 16-year-old boy with acute perimyocarditis had serological evidence of Mycoplasma pneumoniae infection. The endomyocardial biopsy specimen showed grade 2 active lymphocytic myocarditis. A T-cell study suggested a cell-mediated immune process in the pathogenesis of carditis. Mycoplasma pneumoniae needs to be considered as a possible cause of acute carditis, and histological findings may influence management.


The impact of epigenomic next-generation sequencing approaches on our understanding of neuropsychiatric disorders.
Patients suffering from psychiatric disorders have a life span burden, which represents an enormous human, family, social, and economical cost. Several concepts have revolutionized our way of appraising neuropsychiatric disorders (NPDs). They result from a combination of genetic factors and environmental insults, and their etiology finds roots in the neurodevelopmental period. As epigenetic mechanisms tightly control brain development, exposure to adverse conditions disturbing the epigenetic landscape of the fetal brain increases the risk of developing NPDs, due to the persistence of abnormal epigenetic signatures, at distance from the initial stimulus. Here, we review these concepts and discuss recent results based on next-generation sequencing (NGS) approaches that have shed light on the mechanisms that underlie the emergence of NPDs, highlighting the importance of epigenetic phenomena. Because epigenetic mechanisms are potentially reversible, unraveling the epigenetic contribution to the etiology of NPDs is key to the design of future therapeutic strategies. Early diagnosis of patients prone to NPDs for early intervention represents a challenge that waits for biomarkers of vulnerability, and could be decisive for improving the outcome and prognosis of "at-risk" patients.


Indole alkaloid glycosides from the aerial parts of Strobilanthes cusia.
Three indole alkaloid glycosides, strobilanthosides A-C (1-3), two known indole alkaloid glucosides (4 and 5), and five phenylethanoid glycosides (8-10) were isolated from the aerial parts of Strobilanthes cusia. The structures of the new compounds were elucidated by spectrometric analysis, and the absolute configurations of 1 and 2 were established by ECD spectrocsopy. N'-β-d-Glucopyranosylindirubin (5) showed weak antibacterial activity (MIC 62.5-125 μM) against Staphylococcus aureus.


Comparison of 12-Hour with 72-Hour Terlipressin Therapy for Bleeding Esophageal Varices.
To determine the efficacy of 12-hour of Terlipressin therapy as compared to 72-hour therapy in preventing rebleeding after endoscopic therapy. Interventional study. Department of Gastroenterology and Hepatology, Shaikh Zayed Hospital, Lahore, from January to March 2016. Cirrhotic patients presenting to our hospital with GI (gastrointestinal) bleeding received Terlipressin 2 mg intravenous bolus, followed by 1mg 6-hourly until undergoing endoscopy. Those with esophageal varices as the source of bleeding underwent band ligation and were recruited. Of the 93 enrolled patients, 90 remained and were randomized into 25 (27.8%) in control Group-Aand 65 (72.2%) in test Group-B. Group-Areceived 72-hour of Terlipressin while Group-B received it for 12-hour. Both groups were monitored for rebleeding for 5 days. Rebleeding occurred in 1 (4%) patient in Group-Aand 3 (4.6%) in Group-B during the 5-day period. All 4 (4.4%) underwent repeat endoscopy. The Group-Apatient and 2 (3%) of 3 Group-B patients showed ulcers over band ligation sites as source of bleed. The third Group-B patient showed varices requiring repeat banding. One (4%) patient (Group-A) died due to persistent encephalopathy. No drug related adverse effects were seen. A12-hour duration of Terlipressin as an adjunct to endoscopic band ligation shows similar results to 72-hour therapy.


Divergent Roles of Central Serotonin in Adult Hippocampal Neurogenesis.
The central serotonin (5-HT) system is the main target of selective serotonin reuptake inhibitors (SSRIs), the first-line antidepressants widely used in current general practice. One of the prominent features of chronic SSRI treatment in rodents is the enhanced adult neurogenesis in the hippocampus, which has been proposed to contribute to antidepressant effects. Therefore, tremendous effort has been made to decipher how central 5-HT regulates adult hippocampal neurogenesis. In this paper, we review how changes in the central serotonergic system alter adult hippocampal neurogenesis. We focus on data obtained from three categories of genetically engineered mouse models: (1) mice with altered central 5-HT levels from embryonic stages, (2) mice with deletion of 5-HT receptors from embryonic stages, and (3) mice with altered central 5-HT system exclusively in adulthood. These recent findings provide unique insights to interpret the multifaceted roles of central 5-HT on adult hippocampal neurogenesis and its associated effects on depression.


Ventricular arrhythmias associated with lidoflazine: side-effects observed in a randomized trial.
Twenty-four patients received either propranolol, lidoflazine (Clinium), or propranolol/lidoflazine combinations in a study designed to evaluate the effect of these drugs in angina pectoris. Five patients developed ventricular tachycardia when receiving either lidoflazine or lidoflazine and propranolol in combination; one of these patients died. In addition, one patient died suddenly while being treated with propranolol alone. Lidoflazine therapy was associated with a significant prolongation of the QT interval of the electrocardiogram. Lidoflazine either alone or in combination with propranolol, appears to induce ventricular tachycardia.


Through the Lipopolysaccharide Glass: A Potent Antimicrobial Peptide Induces Phase Changes in Membranes.
In the following, molecular simulations are used to reveal unexpected behavior within bacterial membranes. We show that lipopolysaccharide molecules found in these membranes form viscous amorphous solids when they are interlinked with monovalent and divalent cations. The bilayers exhibit both liquid and glassy characteristics, due to the coexistence of both liquid and crystalline domains in the bilayer. Polymyxin B1, a potent antimicrobial peptide, is shown to increase order within the lipopolysaccharide bilayers by inducing the formation of crystalline patches. Crucially we are able to decompose the energetics of insertion into their enthalpic and entropic components. The present coarse-grain molecular dynamics study provides unprecedented insights into the antibacterial action of antimicrobial peptides, thus paving the way for development of novel therapeutic agents to treat multiple drug resistant Gram-negative bacteria.


Correlates of Suicide Ideation and Resilience Among Native- and Foreign-Born Adolescents in the United States.
Nearly 20% of U.S. adolescents have considered suicide. Yet, gaps remain in understanding correlates of resilience and suicide risk, especially among populations born outside the United States who may face unique migration- and acculturation-related stressors. This study adds to the literature by exploring correlates of suicide ideation among a diverse population. This study analyzes quantitative data (N = 357) from the Study of Adolescent Lives after Migration to America, in Detroit and Harrisonburg. More than 40% of the sample was born outside the United States, with the majority born in the Middle East and North Africa. Path analysis was used to model dual outcomes of resilience and suicide ideation using measures of hope, school belonging, stressful life events, and being born outside the United States. Suicide ideation and resilience were negatively correlated (ß = -.236[.069]; p < .001). Adolescents with greater hope (ß = .367; p < .001) and school belonging (ß = .407; p < .001) reported higher resilience, while lower levels of school belonging correlated with higher levels of suicide ideation (ß = -.248; p = .009). More stressful life events were associated with suicide ideation (ß = .243; p < .001), while fewer were correlated with resilience (ß = -.106; p = .003). Being born outside the United States was associated with suicide ideation (ß = .186; P-.015), with this finding driven by those from the Middle East and North Africa region, who faced significantly increased risk of suicide ideation (ß = .169; p = .036). Findings suggest that adolescents born in the Middle East and North Africa region may represent a vulnerable group needing targeted and culturally responsive interventions to destigmatize mental health and psychosocial well-being, boost existing sources of resilience, and encourage help-seeking behaviors.


Brain positron emission tomography in patients with myotonic dystrophy type 1 and type 2.
To determine regions of reduced brain metabolism in patients with myotonic dystrophy type 1 (DM1) and type 2 (DM2) using 18F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET), and to analyse their potential association with cognitive deficit. Study included 29 patients (16 DM1 and 13 DM2). FDG-PET and detailed neuropsychological testing were performed in both groups. The most common cognitive findings were executive, visuospatial, and naming dysfunction in DM1, and executive and naming dysfunction in DM2. FDG-PET showed the most prominent glucose hypometabolism in prefrontal, temporal, and pericentral regions in both DM1 and DM2 patients, with additional affection of insula and subcortical grey matter in DM2. In DM1 patients, we found association between right frontotemporal hypometabolism and executive dysfunction (p<0.05). In DM2 patients attention deficit was in association with prefrontal, insular, and striatal hypometabolism, as well as right frontotemporal hypometabolism (p<0.05). Executive dysfunction in DM2 was more common in patients with prefrontal and insular hypometabolism, right parietotemporal and frontotemporal hypometabolism, as well as left striatal hypometabolism (p<0.05). Patients with parietotemporal defect on FDG-PET were more likely to have naming dysfunction (p<0.01). FDG-PET findings corresponded well with the results of neuropsychological testing. FDG-PET may be a good biomarker of central nervous system involvement in DM1 and DM2, but this hypothesis will have to be more strongly supported by larger studies.


Analytical and empirical fluctuation functions of the EEG microstate random walk - Short-range vs. long-range correlations.
We analyze temporal autocorrelations and the scaling behaviour of EEG microstate sequences during wakeful rest. We use the recently introduced random walk approach and compute its fluctuation function analytically under the null hypothesis of a short-range correlated, first-order Markov process. The empirical fluctuation function and the Hurst parameter H as a surrogate parameter of long-range correlations are computed from 32 resting state EEG recordings and for a set of first-order Markov surrogate data sets with equilibrium distribution and transition matrices identical to the empirical data. In order to distinguish short-range correlations (H ≈ 0.5) from previously reported long-range correlations (H > 0.5) statistically, confidence intervals for H and the fluctuation functions are constructed under the null hypothesis. Comparing three different estimation methods for H, we find that only one data set consistently shows H > 0.5, compatible with long-range correlations, whereas the majority of experimental data sets cannot be consistently distinguished from Markovian scaling behaviour. Our analysis suggests that the scaling behaviour of resting state EEG microstate sequences, though markedly different from uncorrelated, zero-order Markov processes, can often not be distinguished from a short-range correlated, first-order Markov process. Our results do not prove the microstate process to be Markovian, but challenge the approach to parametrize resting state EEG by single parameter models.


Implications of heparan sulfate and heparanase in neuroinflammation.
Heparan sulfate proteoglycans (HSPGs), expressed on the cell surface and in the extracellular matrix of most animal tissues, have essential functions in development and homeostasis, and have been implicated in several pathological conditions. The functions of HSPGs are mainly mediated through interactions of the heparan sulfate (HS) polysaccharide side chains with different protein ligands. The molecular structure of HS is highly diverse, expressed in a cell-type specific manner. The flexible yet controlled structure of HS is primarily generated through a strictly regulated biosynthesis process and is further modified post-synthetically, such as desulfation by endosulfatases and fragmentation by heparanase. Heparanase is an endo-glucuronidase expressed in all tissues. The enzyme has been found up-regulated in a number of pathological conditions, implying a role in diseases mainly through degradation of HS. Emerging evidence demonstrates important roles of HS and heparanase in inflammatory reactions, particularly in the regulation of leukocyte activation and extravasation. Neuroinflammation is a common feature of various central nervous system disorders, thus it is a great interest to understand the implications of HS and heparanase in neuroinflammation.


Research on the influence of anaerobic stabilization of various dairy sewage sludge on biodegradation of polycyclic aromatic hydrocarbons PAHs with the use of effective microorganisms.
Sewage sludge was taken from a dairy WWTP belonging to Mlekovita Cooperative in Wysokie Mazowieckie. There were excess sludge, flotation sludge and a mixture of excess and flotation sludge from pre-treatment of dairy sewage. The initial content of 16 PAHs in excess sludge before fermentation was approximately 689µg·kg-1 in dry mass, whereas in post-flotation sludge (which constituted around 30% of raw sludge) it was approximately 95µg·kg-1 in dry mass. A mixture of excess and flotation sludge had the content of 497,7µg·kg-1 in dry mass. Through comparison of particular hydrocarbons content in raw sewage sludge to the total PAHs content, it was shown that tricyclic compounds, which constituted 46,3% of the PAHs sum (excess sludge), and tetracyclic compounds, which constituted 60,0% of the PAHs sum (flotation sludge), were the dominating fractions. In the sludge subjected to fermentation in reactors with mixed sludge and surplus activated sludge, the general trend of the course of changes in concentrations of PAHs was similar. Both in the sludge inoculated with EM and in that not inoculated with EM, a significant increase in the total PAHs contents was observed in the first fermentation phase (acidic fermentation) after 7 days of the process. Addition of EM into the sludge did not prevent the PAHs release, and therefore higher concentrations of PAHs sum were recorded during the hydrolysis stage than in sludge before fermentation. A decrease in the sum of PAHs was observed after 2 weeks of fermentation in relation to the quantity observed after 1 week of fermentation (except from post-flotation sludge). In the following weeks, there was further decrease in the concentration of the 16 PAHs sum in all sludge types. However, in sludge without EM inoculation, it was lower than in sludge with EM inoculation. The loss of the majority of tested hydrocarbons was reported in the final phase of fermentation.


Treating children's aggressive behavior problems using cognitive behavior therapy with virtual reality: A multicenter randomized controlled trial.
This multicenter randomized controlled trial investigated whether interactive virtual reality enhanced effectiveness of Cognitive Behavioral Therapy (CBT) to reduce children's aggressive behavior problems. Boys with aggressive behavior problems (N = 115; Mage = 10.58, SD = 1.48; 95.7% born in Netherlands) were randomized into three groups: CBT with virtual reality, CBT with roleplays, or care-as-usual. Bayesian analyses showed that CBT with virtual reality more likely reduced aggressive behavior compared to care-as-usual for six of seven outcomes (ds 0.19-0.95), and compared to CBT with roleplays for four outcomes (ds 0.14-0.68). Moreover, compared to roleplays, virtual reality more likely enhanced children's emotional engagement, practice immersion, and treatment appreciation. Thus, virtual reality may be a promising tool to enhance CBT effectiveness for children with aggressive behavior problems.