Zinc oxide nanoparticles and spironolactone-enhanced Nrf2/HO-1 pathway and inhibited Wnt/β-catenin pathway in adenine-induced nephrotoxicity in rats.
To investigate the renoprotective, the antioxidant, and the anti-inflammatory impact of a combination of SPL and ZnO-NPs to combat against chronic kidney disease (CKD). In total, 50 males of rats were distributed into 5 groups (10 rats each); normal group, adenine sulfate (0.25% in diet for 10 days) (CKD) group. After the last dose of adenine sulfate, rats were divided into three groups: SPL + Adenine sulfate group; rats were treated orally by mixing SPL (20 mg/kg/day) into chow for 8 weeks, ZnO-NPs + Adenine sulfate group; rats were injected intraperitoneally with ZnO-NPs (5 mg/kg) three times weekly for 8 weeks, ZnO-NPs + SPL + Adenine sulfate group; rats were injected with the same previous doses for 8 weeks. Each of SPL and ZnO-NPs up-regulated antioxidant genes (Nrf2 and HO-1), down-regulated fibrotic and inflammatory genes (TGF-β1, Wnt7a, β-catenin, fibronectin, collagen IV, α-SMA, TNF-α, and IL-6) compared to CKD. Furthermore, a combination of SPL and ZnO-NPs resulted in a greater improvement in the measured parameters than a single treatment. The therapeutic role of SPL was enhanced by the antioxidant and the anti-inflammatory role of ZnO-NPs, which presented a great renoprotective effect against CKD.


Decreased expression of stem cell factor in esophageal and gastric mucosa after esophagogastric anastomosis for cancer: potential relevance to motility.
Esophageal replacement with gastric tube is a well-established reconstruction of the alimentary tract after esophagectomy in cancer patients. The resulting molecular events in the transposed gastric tube and residual esophagus have yet to be investigated. Stem cell factor (SCF) was recently shown to be critical for signaling in gastrointestinal motility. SCF expression is here correlated with changes in mucosal morphology, acid and biliary reflux, and motility in the residual esophagus and gastric tube. Thirteen patients surgically resected for squamous esophageal carcinoma with gastric tube replaced by esophagogastric anastomosis underwent upper endoscopy, esophageal manometry, 24-hour pH monitoring, and bile reflux detection. Esophageal and gastric mucosa samples were examined for SCF expression by immunohistochemical and semiquantitative reverse transcriptase-polymerase chain reaction analysis and for SCF serum levels by enzyme-linked immunosorbent assay. All patients showed severe residual esophagus hypoperistalsis and no gastric tube motor activity. The 24-hour pH monitoring was positive in most; 24-hour bile detection was mostly negative. SCF levels in the residual esophageal and gastric tube mucosa were dramatically decreased compared with those of normal subjects. The correlation between SCF and slow-wave activity was positive. Hypomotility of the residual esophagus and gastric tube seems closely associated with disruption of the SCF/c-kit signaling pathway. However, the absence of notable relations between mucosal changes after chronic exposure to acid, biliary gastric content, and SCF expression indicates that this analysis cannot be considered part of endoscopic follow-up.


Rho GTPases link cellular contractile force to the density and distribution of nanoscale adhesions.
The ability of cells to adhere and to exert contractile forces governs their capacity to move within an organism. The cytoskeletal regulators of the Rho GTPase proteins are involved in control of the contractile forces of cells. To elucidate the basis of cell migration, we analyzed contractile forces and nanoscale adhesion-related particles in single cells expressing constitutively active variants of Rho GTPases by using traction-force microscopy and ultra-high-resolution stimulated emission depletion microscopy, respectively. RhoAV14 induced large increases in the contractile forces of single cells, with Rac1L61 and RhoDV26 having more moderate effects. The RhoAV14- and RhoDV26-induced forces showed similar spatial distributions and were accompanied by reduced or unaltered cell spreading. In contrast, the Rac1L61-induced force had different, scattered, force distributions that were linked to increased cell spreading. All three of these Rho GTPase activities caused a loss of thick stress fibers and focal adhesions and a more homogenous distribution of nanoscale adhesion-related particles over the ventral surface of the cells. Interestingly, only RhoAV14 increased the density of these particles. Our data suggest a Rac1-specific mode for cells to generate contractile forces. Importantly, increased density and a more homogenous distribution of these small adhesion-related particles promote cellular contractile forces.


Management of malunited mandibular condylar fractures.
The non-surgical treatment of mandibular condylar fractures, may occasionally result in articular imbalance and temporomandibular joint dysfunction. This may be attributed to condylar head displacement and resorption, resulting in a shortened vertical ramus and lost posterior vertical facial height. Restoring the vertical ramus height is essential in the treatment of such dysfunction, and may be accomplished by unilateral, or bilateral ramus osteotomies. Four examples of patients treated with mandibular ramus osteotomies to restore vertical ramus height, with subsequent improvement in occlusal balance and function are presented. The use of the sagittal split mandibular osteotomy and the external vertical ramus osteotomy, stabilized with small osseous plates, and monocortical screws, is discussed.


Embryonation and infectivity of Ascaris suum eggs. A comparison of eggs collected from worm uteri with eggs isolated from pig faeces.
Ascaris suum eggs were collected from pig faeces or dissected from worms obtained from the same pigs. Eggs from the two sources were allowed to embryonate in 0.1 N H2SO4, in 1% buffered formalin or in tap water. The embryonation of the sulphuric acid and water cultures occurred at the same speed, while the formalin cultures developed slightly more slowly. By experimental inoculation of helminth-free pigs and subsequent counting of white spots in the livers and larvae in the lungs day 7 p.i., the infectivity of eggs dissected from worm uteri and embryonated in sulphuric acid (a normal laboratory procedure) was compared with that of eggs collected from faeces and embryonated in water (i.e. more naturally developed eggs). The results suggest that the two types of eggs were equally infective. For this reason the common practice of using Ascaris eggs dissected from worms for experimental infections might be acceptable.


Evidence for acyl chain trans/gauche isomerization during the thermal pretransition of dipalmitoyl phosphatidylcholine bilayer dispersions.
In order to clarify, in dipalmitoyl phosphatidylcholine multilayers, the effect of the 34 degrees C thermal pretransition on the acyl chain intramolecular disordering process, Raman spectra of dipalmitoyl phosphatidylcholine gels at 20 and 34 degrees C were compared in the 1000--1200 cm-1 skeletal C-C stretching region. In addition to an overall intensity decrease associated with a change in chain packing characteristics, the growth of intensity in the 1080--1090 and 1122 cm-1 regions in the 34--20 degrees C) difference spectrum clearly indicates that the thermal pretransition is accompanied by an increase in the population of hydrocarbon chain gauche rotamers toward the center of the bilayer.


Task-sharing interventions for improving control of diabetes in low-income and middle-income countries: a systematic review and meta-analysis.
Task-sharing interventions using non-physician health-care workers might be a potential diabetes management strategy in health systems that are constrained by physician shortages, such as those in low-income and middle-income countries (LMICs). We did a systematic review and meta-analysis of task-sharing intervention strategies for managing type 2 diabetes in LMICs. We searched PubMed, Embase, and CINAHL from database inception to Sept 25, 2019, for studies that were randomised control trials or cluster randomised trials with task-shifted or task-shared interventions delivered to adults (≥18 years) by non-physician health workers versus usual care, done in LMICs with glycated haemoglobin (HbA1c) or fasting blood sugar (FBS) as outcome measures. The methodological quality of included studies was assessed using the Cochrane risk of bias tool. Random-effects model meta-analysis was used to estimate the population average pooled mean difference for HbA1c and FBS with 95% CIs. Our study protocol was registered in the PROSPERO database (CRD42018081015). We found 4213 studies from the literature search, of which 46 (1·1%) were eligible for the narrative synthesis, including a total of 16 973 participants. 16 of these studies were excluded from the meta-analysis due to high risk of bias. 24 studies with a total of 5345 participants were included in the meta-analysis of HbA1c and 18 studies with a total of 3287 participants for FBS. Interventions led to an average reduction in HbA1c when tasks were delivered by nurses (averaged pooled mean difference -0·54% [95% CI -0·89 to -0·18]; I2=80%) and pharmacists (-0·91% [-1·15 to -0·68]; I2=58%), but not when they were delivered by dietitians (-0·50% [-1·10 to 0·09]; I2=54%) or community health workers (0·05% [0·03 to 0·07]; I2=0%). A reduction in average FBS was also observed when interventions were delivered by pharmacists (average pooled mean difference -36·26 mg/dL [-52·60 to -19·92]; I2=78%) but not nurses (-7·46 mg/dL [-18·44 to 3·52]; I2=79%) or community health workers (-5·41 [-12·74 to 1·92]; I2=71%). Only one study reported on FBS when tasks were delivered by dietitians, with a mean difference of -35·00 mg/dL (-65·96 to -4·04). Task sharing interventions with non-physician healthcare workers show moderate effectiveness in diabetes management in LMIC settings. Although relatively high heterogeneity limits the interpretation of the overall findings, interventions led by pharmacists and nurses in LMICs with relatively high physician density are effective strategies in the management of diabetes. Wellcome Trust-Department of Biotechnology India Alliance.


Combined electrophysiological assessment of the visual system in central serous retinopathy.
Six subjects suffering from idiopathic central serous retinopathy were examined during the acute phase using a battery of neurophysiological tests. The records (using skin electrodes) included the electro-oculogram (EOG), the white light electroretinogram (ERG) during various stages of dark and light adaptation, and the flash and pattern reversal visual evoked potentials. Results obtained from the affected eye were compared with those from the healthy eye. The values of the healthy eye were not significantly different from our normal control group. The EOGs of the affected eyes were not significantly different from those of the healthy eyes. The 'a' wave of the ERG during light adaptation was significantly (P less than 0.05) smaller in the affected eye. The amplitudes of the other components and the latencies of all components were not affected. The latency of the PR-VEP of the affected eye in all subjects was prolonged in comparison with the unaffected eye. In 3 subjects the latency was prolonged by more than 2 S.D.s compared with our control group. The amplitude of the PR-VEP in 5 of our 6 subjects was slightly but significantly (P less than 0.02) smaller in the affected eye. There was no correlation between amplitude and latency changes.


Transforming growth factor beta1 receptor II is downregulated by E1A in adenovirus-infected cells.
Transforming growth factor beta1 (TGF-beta1) signaling is compromised in many tumors, thereby allowing the tumor to escape the growth-inhibitory and proapoptotic activities of the cytokine. Human adenoviruses interfere with a number of cellular pathways involved in cell cycle regulation and apoptosis, initially placing the cell in a "tumor-like" state by forcing quiescent cells into the cell cycle and also inhibiting apoptosis. We report that adenovirus-infected cells resemble tumor cells in that TGF-beta1 signaling is inhibited. The levels of TGF-beta1 receptor II (TbetaRII) in adenovirus-infected cells were decreased, and this decrease was mapped, by using virus mutants, to the E1A gene and to amino acids 2 to 36 and the C-terminal binding protein binding site in the E1A protein. The decrease in the TbetaRII protein was accompanied by a decrease in TbetaRII mRNA. The decrease in TbetaRII protein levels in adenovirus-infected cells was greater than the decrease in TbetaRII mRNA, suggesting that downregulation of the TbetaRII protein may occur through more than one mechanism. Surprisingly in this context, the half-lives of the TbetaRII protein in infected and uninfected cells were similar. TGF-beta1 signaling was compromised in cells infected with wild-type adenovirus, as measured with 3TP-lux, a TGF-beta-sensitive reporter plasmid expressing luciferase. Adenovirus mutants deficient in TbetaRII downregulation did not inhibit TGF-beta1 signaling. TGF-beta1 pretreatment reduced the relative abundance of adenovirus structural proteins in infected cells, an effect that was potentiated when cells were infected with mutants incapable of modulating the TGF-beta signaling pathway. These results raise the possibility that inhibition of TGF-beta signaling by E1A is a means by which adenovirus counters the antiviral defenses of the host.


Suicide spectrum among young people during the COVID-19 pandemic: A systematic review and meta-analysis.
There are concerns that suicidal behaviors are arising among adolescents. The COVID-19 pandemic could have worsened the picture, however, studies on this topic reported contrasting results. This work aimed to summarise findings from the worldwide emerging literature on the rates of suicidality among young people during the COVID-19 pandemic. A systematic review and meta-analysis were performed, searching five electronic databases for studies published from January 1, 2020 until July 27, 2022. Studies reporting rates for each of the three considered outcomes (suicide, suicidal behaviors, and suicidal ideation) among young people under 19 years old during the COVID-19 pandemic were included. Random-effects meta-analyses were conducted, and the intra-study risk of bias was assessed. When pre-COVID-19 data were available, incidence rate ratio (IRR) and prevalence ratio (PR) estimates were calculated between the two periods. All the analyses were performed according to the setting explored: general population, emergency department (ED), and psychiatric services. The review protocol was registered on PROSPERO (CRD42022308014). Forty-seven observational studies were selected for more than 65 million subjects. The results of the meta-analysis showed a pooled annual incidence rate of suicides of 4.9 cases/100,000 during 2020, accounting for a non-statistically significant increase of 10% compared to 2019 (IRR 1.10, 95% CI: 0.94-1.29). The suicidal behaviors pooled prevalence during the COVID-19 pandemic was higher in the psychiatric setting (25%; 95% CI: 17-36%) than in the general population (3%; 1-13%) and ED (1%; 0-9%). The pooled rate of suicidal ideation was 17% in the general population (11-25%), 36% in psychiatric setting (20-56%) and 2% in ED (0-12%). The heterogeneity level was over 97% for both outcomes in all settings considered. The comparison between before and during COVID-19 periods highlighted a non-statistically significant upward trend in suicidal behaviors among the general population and in ED setting. The only significant increase was found for suicidal ideation in psychiatric setting among studies conducted in 2021 (PR 1.15; 95% CI: 1.04-1.27), not observed exploring 2020 alone. During the pandemic, suicide spectrum issues seemed to follow the known pattern described in previous studies, with higher rates of suicidal ideation than of suicidal behaviors and suicide events. Governments and other stakeholders should be mindful that youth may have unique risks at the outset of large disasters like the COVID-19 pandemic and proactive steps are necessary to address the needs of youth to mitigate those risks. The present study was funded by the University of Torino (CHAL_RILO_21_01).


Fire spread predictions: Sweeping uncertainty under the rug.
Predicting fire spread and behavior correctly is crucial to minimize the dramatic consequences of wildfires. However, our capability of accurately predicting fire spread is still very limited, undermining the utility of such simulations to support decision-making. Improving fire spread predictions for fire management purposes, by using higher quality input data or enhanced models, can be expensive, unfeasible or even impossible. Fire managers would benefit from fast and inexpensive ways of improving their decision-making. In the present work, we focus on i) understanding if fire spread predictions can be improved through model parameter calibration based on information collected from a set of large historical wildfires in Portugal; and ii) understanding to what extent decreasing parametric uncertainty can counterbalance the impact of input data uncertainty. Our results obtained with the Fire Area Simulator (FARSITE) modeling system show that fire spread predictions can be continuously improved by 'learning' from past wildfires. The uncertainty contained in the major input variables (wind speed and direction, ignition location and fuel models) can be 'swept under the rug' through the use of more appropriate parameter sets. The proposed framework has a large potential to improve future fire spread predictions, increasing their reliability and usefulness to support fire management and decision making processes, thus potentially reducing the negative impacts of wildfires.


Extrapulmonary manifestations of adenovirus type 7 pneumonia simulating Reye syndrome and the possible role of an adenovirus toxin.
Three children developed extensive extrapulmonary disease in the course of fatal adenovirus type 7 pneumonia. Several clinical features, including the unexpected onset of coma, suggested the development of Reye syndrome, but biochemical and histopathologic findings were inconsistent with this diagnosis. Virologic and pathologic studies did not reveal evidence of extrapulmonary adenovirus infection, despite clinical involvement of the liver, skeletal muscle, and central nervous system. The detection in premortem sera from all three patients of adenovirus penton antigen, known to be cytotoxic in vitro, suggests a possible mechanism for the production of extrapulmonary pathology in the absence of extrapulmonary virus infection.


Purkinje cell-specific deletion of CREB worsens alcohol-induced cerebellar neuronal losses and motor deficits.
Exposure to alcohol during pregnancy can kill developing fetal neurons and lead to fetal alcohol spectrum disorder (FASD) in the offspring. However, not all fetuses are equally vulnerable to alcohol toxicity. These differences in vulnerability among individuals are likely due, at least in part, to genetic differences. Some genes encode neuroprotective molecules that act through signaling pathways to protect neurons against alcohol's toxic effects. One signaling pathway that can protect cultured neurons against alcohol-induced cell death in vitro is the cAMP pathway. A goal of this study was to determine whether the cAMP pathway can exert a similar neuroprotective effect against alcohol in vivo. A key molecule within the cAMP pathway is cAMP response element binding protein (CREB). In this study, CREB was specifically disrupted in cerebellar Purkinje cells to study its role in protection of cerebellar neurons against alcohol toxicity. Mice with Purkinje cell-specific knockout of CREB were generated with the Cre-lox system. A 2 × 2 design was used in which Cre-negative and Cre-positive mice received either 0.0 or 2.2 mg/g ethanol by intraperitoneal (i.p.) injection daily over postnatal day (PD) 4-9. Stereological cell counts of cerebellar Purkinje cells and granule cells were performed on PD 10. Motor function was assessed on PD 40 using the rotarod. Purkinje cell-specific disruption of CREB alone (in the absence of alcohol) induced only a small reduction in Purkinje cell number. However, the loss of CREB function from Purkinje cells greatly increased the vulnerability of Purkinje cells to alcohol-induced cell death. While alcohol killed 20% of Purkinje cells in the Cre-negative (CREB-expressing) mice, alcohol killed 57% of Purkinje cells in the Cre-positive (CREB-nonexpressing) mice. This large loss of Purkinje cells did not lead to similar alcohol-induced losses of granule cells. In the absence of alcohol, lack of CREB function in Purkinje cells had no effect on rotarod performance. However, in the presence of alcohol, disruption of CREB in Purkinje cells substantially worsened rotarod performance. Disruption of a single gene (CREB) in a single neuronal population (Purkinje cells) greatly increases the vulnerability of that cell population to alcohol-induced cell death and worsens alcohol-induced brain dysfunction. The results suggest that the cAMP pathway can protect cells in vivo against alcohol toxicity and underline the importance of genetics in determining the neuropathology and behavioral deficits of FASD.


Electrostatic interaction and surface S vacancies synergistically enhanced the photocatalytic degradation of ceftriaxone sodium.
ZnIn2S4 ultrathin 2D nanosheets with a positive surface charge are synthesized by a hydrothermal method and different contents of surface S vacancies are induced via heat treatment of as-prepared ZnIn2S4 (ZIS). As the S vacancies contents increased, the photocatalytic degradation efficiency of ceftriaxone (CTRX) sodium is promoted. Especially, ZIS-300 shows the best degradation efficiency (88.8%) for an initial CTRX concentration of 10 mg L-1 in 2 h. It is found that S vacancies cause the electron density of surface metal atoms (Zn, In) to be decreased, which makes the effective adsorption and activation of ceftriaxone anions through electrostatic adsorption interactions. Meanwhile, S vacancies also serve as active centers to promote the absorption of O2 and gather electrons to form •O2- species. The photogenerated holes quickly transfer to the surface of the catalyst to directly degrade the adsorbed CTRX. Thus, the photocatalytic CTRX degradation efficiency is significantly improved. Finally, a possible mechanism for over defective ZIS is proposed. This work provides a feasible strategy for the efficient degradation of antibiotics from the perspective of electrostatic adsorption and molecule activation.


A new species of Nehvizdya (Ginkgoales) from the Lower Cretaceous of the Iberian Ranges (Spain).
A new species of the formerly monospecific genus Nehvizdya Hlustík, Nehvizdya penalveri sp. nov. is described from the Albian of the Escucha Formation (Eastern Iberian Ranges, Teruel, Spain). The type species Nehvizdya obtusa Hlustík was first found in the Lower-Middle Cenomanian Peruc Member of the Peruc-Korycany Formation (Bohemian Massif, Czech Republic). Both taxa closely resemble each other, not only in leaf shape and venation pattern, but also in their epidermal structures and the occurrence of resin bodies. The Spanish species, however, is notable for its marked amphistomatic leaves with stomatal apparatus, which have inner folds inside the stomatal pits. Comparison with Eretmophyllum andegavense Pons et al. from the Cenomanian of the Baugeois Clays (Maine-et-Loire, France) allows us to transfer this species to the genus Nehvizdya Hlustík. The new combination proposed is Nehvizdya andegavense (Pons et al.) comb. nov. A taphonomic analysis in this layer appears to characterise a biocoenosis formed from N. penalveri sp. nov. and Frenelopsis alata (K. Feistmantel) Knoblock. Similar associations have been described in the Czech and French Cenomanian. In all three cases, the associations grew around coastal lagoons and ponds where they formed a shrubby halophyte vegetation.


Expression, modulation and signalling of IL-17 receptor in fibroblast-like synoviocytes of patients with rheumatoid arthritis.
Interleukin-17 (IL-17) has been characterized as a proinflammatory cytokine produced by CD4+ CD45RO+ memory T cells. Overproduction of IL-17 was detected in the synovium of patients with rheumatoid arthritis (RA) compared to patients with osteoarthritis. In contrast to the restricted expression of IL-17, the IL-17 receptor (IL-17R/CDw217) is expressed ubiquitously. Using a real-time RT-PCR assay, we detected similar absolute levels of IL-17R mRNA expression in fibroblast-like synoviocytes (SFC) from patients with RA (mean 9 pg/microg total RNA; ranged from 0.1 pg to 96 pg IL-17R mRNA/microg total RNA) compared to synoviocytes of non-RA patients. Analysis of the IL-17R surface expression confirmed the results obtained for IL-17R mRNA expression. Exposure of SFC to IL-17 led to a mRNA induction of CXC chemokines IL-8, GRO-alpha and GRO-beta. An anti-IL-17 antibody blocked these effects of IL-17. The MAPK p38 appears necessary for the regulation of IL-8, GRO-alpha and GRO-beta expression as shown by inhibition with SB203580. The inhibitors genistein (tyrosine kinase inhibitor) and calphostin C (inhibitor of protein kinase C) reduced significantly the IL-17-stimulated mRNA expression of IL-8, GRO-alpha and GRO-beta in SFC, whereas PD98059 (inhibitor of MEK-1/2) was without effect. Pharmacological drugs used in therapy of RA, such as cyclosporin and methotrexate, induced a fourfold increase of IL-17R mRNA expression and augmented the IL-17-stimulated IL-8 expression. Our results support the hypothesis that IL-17/IL-17R may play a significant role in the pathogenesis of RA contributing to an unbalanced production of cytokines as well as participating in connective tissue remodelling.


Clinical features, muscle biopsy scores, myositis specific antibody profiles and outcome in juvenile dermatomyositis.
Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy of childhood. To analyze clinical features, paraclinical examinations, MSAs, treatment response and long-term outcome in a JDM cohort METHODS: 58 patients (35F, 23 M) from a tertiary referral center in the last two decades are included. Mean age at onset was 8.1 ± 4.3, with a mean follow-up period of 5.66±3.59 years. Dermatological manifestations (91%) and muscle weakness (76%) were the key diagnostic elements. Elevated serum creatine kinase levels (86%), electromyography (23/25), muscle MRI (12/15), and muscle biopsy (n = 35) were compatible with the diagnosis. Out of 46 patients tested, 34 (76%) had autoantibodies, with NXP2 (21.7%), followed by TIF1g (17.4%), MDA5 (8.7%), and Mi-2 (8.7%). Presence of TIF1g and NXP2 indicated a severe course; and Ku a much severe course compared to previous studies. Corticosteroids (100%) combined with methotrexate (93%) was the initial treatment. Biological disease modifying anti-rheumatic drugs (DMARDs) were used in 22% of the cohort. Calcinosis (36%) was the most common long-term complication, associated with disease onset ≤6 years, higher muscle biopsy scores and MDA5 positivity. Complete remission was achieved in 65.5% of the patients in a median 24 (IQR 11.8-42.5) months with a relapse rate of 26.3%. 43.9% of NXP2 and 33.3% of TIF-1 g positive patients had a relapse. Course was monophasic (31%), polyphasic (17.2%), chronic (51.8%) without mortality. Integration of clinical features with laboratory and biopsy findings may help to predict prognosis and guide treatment in JDM. In our cohort calcinosis was associated with age, MDA5 autoantibodies, and muscle biopsy scores.


[Study of the small bowel and mesentery in Crohn's disease: comparison of ultrasonics, x-ray computed tomography and small bowel transit in 18 patients].
The advantages of tomodensitometry and ultrasonography were compared with those of small bowel series in Crohn's disease of the small bowel in 18 patients. These two examinations give results which are inferior to those of small bowel series, for the positive diagnosis and the evaluation of the intraluminal extension of the disease, since their sensitivity was only 60 p. cent in identifying the pathological loop. On the contrary, their advantage lies in the evaluation of the intraluminal extension of the disease, which was correctly demonstrated with ultrasonography in 22 p. cent of cases, and tomodensitometry in 45 p. cent. This confirms the supplementary value of these two examinations in the study of the mesenteric involvement of the disease, screening of abscesses, and makes desirable a prospective evaluation of the influence of mesenteric abnormalities on the prognosis and surgical indications.


The Case against Commercial Antivirus Software: Risk Homeostasis and Information Problems in Cybersecurity.
New cybersecurity technologies, such as commercial antivirus software (AV), sometimes fail to deliver on their promised benefits. This article develops and tests a revised version of risk homeostasis theory, which suggests that new cybersecurity technologies can sometimes have ill effects on security outcomes in the short run and little-to-no effect over the long run. It tests the preliminary plausibility of four predictions from the revised risk homeostasis theory using new survey data from 1,072 respondents. The estimations suggest the plausible operation of a number of risk homeostasis dynamics: (1) commercial AV users are significantly more likely to self-report a cybersecurity event in the past year than nonusers, even after correcting for potential reverse causality and informational mechanisms; (2) nonusers become somewhat less likely to self-report a cybersecurity event as the perceived riskiness of various e-mail-based behaviors increases, while commercial AV users do not; (3) the negative short-run effect of commercial AV use on cybersecurity outcomes fade over time at a predicted rate of about 7.03 percentage points per year of use; and (4) after five years of use, commercial AV users are statistically indistinguishable from nonusers in terms of their probability of self-reporting a cybersecurity event as perceptions of risky e-mail-based behaviors increase.


Inter- and intra-individual variability in human skin barrier function: a large scale retrospective study.
In vitro transepidermal tritiated water flux measurements are frequently used to evaluate skin barrier integrity for quality control purposes. However, research in this area to date has been largely based upon small-scale studies, each involving relatively few skin permeation measurements. In order to enhance our understanding in this area, we have conducted a much larger scale retrospective statistical analysis of tritiated water kp values. These values reflected the permeability of 2400 skin samples that were derived from 112 female volunteers over a 4 year period. It was found that the population of tritiated water kp values constituted a positively skewed, non-Normal distribution. Mean kp was 2.04 x 10(-3)cm/h while the 95th percentile was 4.50 x 10(-3)cm/h. Both values are higher than those reported in previous smaller studies. Hence, our study indicates that previously suggested upper limits for tritiated water flux are too low and that they be revised upwards to a value of 4.5 x 10(-3)cm/h. Analysis was also performed on smaller data subsets allowing inter-individual and intra-individual comparisons. For intra-individual kp variability, site-related differences yielded a non-Normal, positively skewed pattern in most individuals. Inter-individual variability was Normally-distributed and showed scatter that was much smaller in magnitude.


Validation of the modified Ranson versus Glasgow score for pancreatitis in a Singaporean population.
The characteristics of patients with acute pancreatitis in multi-ethnic Singapore differ from that of the populations used in formulating the modified Ranson and Glasgow scores. The use of these scoring systems has not previously been validated in the Singaporean setting. This study aims to validate and compare the prognostic use of the modified Ranson and Glasgow scores, and to determine the superiority of one score over the other in predicting the outcome for acute pancreatitis in the Singaporean population. This is a 3-year retrospective study of patients diagnosed with acute pancreatitis at our centre. Patients with chronic pancreatitis, acute on chronic pancreatitis, iatrogenic pancreatitis, pancreatic cancer as well as those with incomplete Ranson or Glasgow scores were excluded from the study. Case notes and computer records were reviewed for local complications of pancreatitis and organ failure. Receiver operator characteristic (ROC) curves of the Ranson and Glasgow scores were plotted for the prediction of severity and mortality. Between January 2010 and December 2012, 230 cases were diagnosed with acute pancreatitis. A majority of the patients had mild pancreatitis (n = 194, 84.3%), and the overall 30-day mortality rate was 3.5% (n = 8). ROC of the Ranson and Glasgow scoring systems for mortality showed an area under curve (AUC) of 0.854 (P = 0.001) and 0.776 (P = 0.008), respectively. For severity, the AUC for the modified Ranson and Glasgow score was calculated to be 0.694 and 0.668, respectively. The ROC curves of Ranson and Glasgow scores for mortality are comparable with that published in earlier studies. In a Singaporean population, the Ranson score is more accurate in the prediction of mortality. However, both scoring systems are poor predictors for severity of acute pancreatitis.


Murine splenocytes release an inhibitory peptide of lymphocyte DNA synthesis into serum-free culture medium.
Murine splenocytes release a novel repressing activity of Concanavalin A-induced lymphocyte DNA synthesis. This activity was purified by gel filtration, ion exchange and thin layer chromatography. It was characterized to be a heat-stable peptide whose molecular weight was estimated to be about 1 000 daltons. The strong inhibition by this peptide was observed when added at early periods of the cell culture. This factor does not affect early RNA synthesis in lymphocytes, but nucleotide (UTP) incorporation at early periods was considerably decreased. In addition, although the factor inhibits drastically lymphocyte DNA synthesis, the cell viability is not changed significantly. These results suggest that the peptide suppresses the cell membrane function at early periods and specifically blocks the concomitant DNA synthesis.


Indandione-Terminated Quinoids: Facile Synthesis by Alkoxide-Mediated Rearrangement Reaction and Semiconducting Properties.
A series of 1,3-indandione-terminated π-conjugated quinoids were synthesized by alkoxide-mediated rearrangement reaction of the respective alkene precursors, followed by air oxidation. This new protocol allows access to quinoidal compounds with variable termini and cores. The resulting quinoids all show LUMO levels below -4.0 eV and molar extinction coefficients above 105 L mol-1 cm-1 . The optoelectronic properties of these compounds can be regulated by tuning the central cores as well as the aryl termini ascribed to the delocalized frontier molecular orbitals over the entire molecular skeleton involving aryl termini. n-Channel organic thin-film transistors with electron mobility of up to 0.38 cm2 V-1 s-1 were fabricated, showing the potential of this new class of quinoids as organic semiconductors.


Health Care Rationing in a Just Society: The Clinical Effectiveness Model.
Representing 18% of gross domestic product, and projected to increase to 20% by 2022, health care costs in the United States are an unsustainable expense. The clinical effectiveness model of cost containment is an ethical and self-sustaining paradigm that can assist bending the health care-cost curve. As envisioned by Buyx et al, clinically effective care is aimed at making the practice of medicine more explicitly evidence based with the goals of improving clinical success, efficiency, and value. I provide a vision for applying the clinical effectiveness model to the American health care system. I illustrate its use with 2 examples from the practice of child neurology: DOC-band (helmet therapy) for the treatment of positional plagiocephaly-relatively inexpensive but ineffective, and adrenocorticotropic hormone for the treatment of infantile spasms-expensive but effective.


Daytime Land Surface Temperature Extraction from MODIS Thermal Infrared Data under Cirrus Clouds.
Simulated data showed that cirrus clouds could lead to a maximum land surface temperature (LST) retrieval error of 11.0 K when using the generalized split-window (GSW) algorithm with a cirrus optical depth (COD) at 0.55 μm of 0.4 and in nadir view. A correction term in the COD linear function was added to the GSW algorithm to extend the GSW algorithm to cirrus cloudy conditions. The COD was acquired by a look up table of the isolated cirrus bidirectional reflectance at 0.55 μm. Additionally, the slope k of the linear function was expressed as a multiple linear model of the top of the atmospheric brightness temperatures of MODIS channels 31-34 and as the difference between split-window channel emissivities. The simulated data showed that the LST error could be reduced from 11.0 to 2.2 K. The sensitivity analysis indicated that the total errors from all the uncertainties of input parameters, extension algorithm accuracy, and GSW algorithm accuracy were less than 2.5 K in nadir view. Finally, the Great Lakes surface water temperatures measured by buoys showed that the retrieval accuracy of the GSW algorithm was improved by at least 1.5 K using the proposed extension algorithm for cirrus skies.


Differential methylation status of imprinted genes in nuclear transfer derived ES (NT-ES) cells.
Compared with fertilized embryo derived ES (F-ES) cells, somatic cell nuclear transfer (SCNT) produced ES (NT-ES) cells were proposed appropriate for cell transplantation based therapies. Although previous studies indicated that NT-ES cells and F-ES cells were transcriptionally and functionally indistinguishable, characterization of DNA methylation patterns of imprinted genes in NT-ES cells is lacking. Here, we show that DNA methylation patterns in the differentially methylated region (DMR) of paternally imprinted gene, H19, displayed distinct abnormalities in certain NT-ES and F-ES cell lines after long-term culture in vitro. DNA methylation profiles of H19 appeared very dynamic in most ES cell lines examined, either hypermethylation or hypomethylation could be observed in specific ES cell lines. In contrast to H19, maternally imprinted genes, Mest and Peg3, showed relatively stable methylation patterns in ES cells, especially Peg3, which displayed better capability in enduring long-term culture in vitro. Our results indicate that abnormal methylation profiles of certain imprinted genes could be observed in both NT-ES and F-ES cell lines after long-term culture in vitro although these cell lines were proved to be pluripotent with germline transmission competent. Stringent screening of epigenetically normal NT-ES cells might be potentially necessary for further therapeutic application of these cells.


Biopsychosocial Factors Associated With Attention Problems in Children After Traumatic Brain Injury: A Systematic Review.
The aim of this review was to examine biopsychosocial factors associated with an increased risk of attention problems after a traumatic brain injury in children. A systematic review of the literature was conducted using data sources of MEDLINE, PsycINFO, and CINAHL up to August 30, 2020. Literature primarily examined pediatric patients with traumatic brain injury and attention problems. Risk factors for attention problems posttraumatic brain injury examined in all articles were identified and grouped into broad categories of biological, psychological, and social factors. Methodological quality of each study was assessed using the modified Downs and Black checklist. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines from 2009 were used in completing this review. Forty articles met inclusion criteria for this study. Overall findings were mixed but suggested that younger age at injury, presence of preinjury attention-deficit/hyperactivity disorder, poorer preinjury adaptive functioning, lower socioeconomic status, and poorer family functioning were associated with increased risk of developing attention problems posttraumatic brain injury. Development of attention problems after pediatric traumatic brain injury is complex and influenced by an array of biologic, environmental/social, injury-related, and host factors. Evidence is mixed, and further study is needed to better understand the relationships between these factors and how they influence attention after traumatic brain injury. Nonetheless, screening for attention problems in children with risk factors may allow for earlier identification and intervention, minimizing negative impacts of attention problems after traumatic brain injury in children. Limitations of this study included heterogeneity of studies and overall low to moderate methodological quality of studies included as measured by the modified Downs and Black checklist. Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME. Upon completion of this article, the reader should be able to: (1) Describe the importance of recognizing and identifying attention problems after traumatic brain injury in children; (2) Identify risk factors for development of attention problems after pediatric traumatic brain injury; and (3) Recognize gaps in existing literature regarding predictors of attention problems after pediatric traumatic brain injury. Advanced. The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.


Solvothermal preparation of Ti3+ self-doped TiO2-x nanotube arrays for enhanced photoelectrochemical performance.
Ti3+ self-doped TiO2-x nanotube arrays (TiO2-x NTs) were prepared by solvothermal treatment in KBH4 ethanol solution followed by calcination, and were characterized by field-emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and UV-vis diffusion reflection spectroscopy (DRS). The photoelectrochemical properties of TiO2-x NTs prepared in different KBH4 concentrations were investigated. The TiO2-x NTs exhibited high visible light response, visible light photocurrent and photoelectrocatalytic activities. The active species and photocatalytic mechanism for the dye degradation were proposed, and the improved photoelectrochemical performance was attributed to the synergistic effect of the narrowed energy gap and enhanced electron transportation. The ability to improve the photoelectrochemical properties of TiO2-x electrode materials should open up new opportunities for high-performance solar cells and photocatalysts.


A Two-Tiered Strategy for Preventing Complications of Bereavement in the First Thirteen Months Post-Loss: A Pilot Study Using Peer Supports with Professional Therapist Back-up.
This feasibility and acceptance pilot study for preventing complications of bereavement within the first year post loss recruited 20 adult grievers within 9 months of becoming bereft and assigned consenting subjects to peer supporters trained by a non-profit bereavement support organization for weekly or bi-weekly telephone-based peer support until month 13 post-loss. Subjects who met DSM-5 criteria for major depressive disorder or showed an Inventory of Complicated Grief (ICG) score exceeding 19, 6 months or more post loss, were assigned to 12 to 16 weeks of interpersonal psychotherapy (IPT) with an experienced therapist. Eight and six subjects completed the protocol assigned to peer support and IPT, respectively, with pre/post Patient Health Questionnaire-9 scores of 5.38 (2.45) versus 3.25 (4.13) (p = 0.266) and 16.67 (7.17) versus 8.40 (5.73) (p =0.063); and pre/post ICG scores of 12.50 (4.72) versus 5.00 (2.51) (p = 0.016) and 35.17 (5.12) versus 8.4 (5.73) (p = 0.063). Implications of this two-tiered model of early intervention for preventing complications of grief are discussed.


Isoliquiritigenin prevents Doxorubicin-induced hepatic damage in rats by upregulating and activating SIRT1.
This study evaluated if the hepatic protective effect of Isoliquiritigenin (ISL) against doxorubicin (DOX)-treated rats involves upregulating sirtuin-1 (SIRT1) signaling. Adult male was divides into 5 groups (n = 6 rats/each) as control (vehicle), ISL (25 mg/kg), DOX (15 mg/kg), DOX + ISL, and DOX + ISL + EX-527 (a SIRT1 inhibitor, 5 mg/kg). ISL and EX-527 were administered 10 days before and after the single treatment of DOX. Also, cultured AML-12 hepatocytes (5 ×104) were treated with 10 µM of ISL for 24 h with or without DOX-treatments (10 µM) and in the presence or absence of EX-527 (5 µM). ISL prevented hepatocyte damage and decreased serum levels of hepatic transaminases, hepatic levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and hepatic mRNA levels of Bax and caspases-3,8, and 9. In the liver of the control and DOX-treated rats, ISL reduced levels of malondialdehyde (MDA) but increased hepatic levels of glutathione (GSH), superoxide dismutase (SOD), and catalase, as well as mRNA levels of Bcl2. In vitro, ISL stimulated cell survival and lowered levels of ROS but increased GSH levels. In vivo and in vitro, in the livers of control and DOX-treated animals, ISL significantly increased the nuclear activity and mRNA levels of SIRT1, enhanced the nuclear levels of Nrf2, and reduced nuclear levels of NF-κB p65. In conclusion, ISL alleviates DOX-induced hepatocyte toxicity by stimulating the Nrf2/antioxidants axis and concomitant suppression of NF-κB, mainly by upregulating/activating SIRT1.


Infections caused by herpes viruses other than cytomegalovirus in solid organ transplant recipients.
Despite great advances in solid organ transplantation (SOT) in recent decades, infection remains a major cause of morbidity and mortality among SOT recipients. Members of the herpesvirus family are the most common viral pathogens causing disease in this patient population. Herpes viruses are large enveloped DNA viruses that commonly reactivate during periods of severe immunosuppression. Currently, infections caused by herpes viruses continue to complicate clinical management of transplant patients. Although cytomegalovirus (CMV) is the most important virus of this family and is the subject of active research, herpes simplex virus (HSV) and varicella-zoster virus (VZV) can also lead to severe disease. Epstein-Barr virus (EBV) associated with post-transplant lymphoproliferative disease is increasingly recognized as a major complication of SOT. There is less information available on the role and impact of other viruses of the herpesvirus family, such as the human herpes virus 6 (HHV-6), human herpes virus 7 (HHV-7) and human herpes virus 8 (HHV-8). This review summarizes current knowledge regarding epidemiology, clinical manifestations, diagnosis, treatment and prevention of infections caused by herpes viruses other than CMV in SOT recipients.


16-Detector multislice CT in the detection of stress fractures: a comparison with skeletal scintigraphy.
To test the hypothesis that the improved resolution afforded by 16-detector computed tomography (CT) would translate to better stress fracture detection when compared with skeletal scintigraphy. Thirty-three cases of suspected stress fractures in 26 patients were investigated using skeletal scintigraphy and 16-detector CT performed on the same day. Planar images of the lower limbs were taken 3h post-injection of 400MBq (99m)Tc-methylene diphosphonate ((99m)Tc-MDP). (99m)Tc-MDP uptake was quantified at suspected fracture sites. CT was performed using a 16-detector multisection machine employing 0.75mm detectors and images reconstructed in 0.5mm increments. Examinations were reported independently and discordant results were compared at follow-up. At initial reporting scintigraphy identified fractures in 13 of the 33 cases and CT identified four of the 33. In one case, on review of the CT images, a fracture was present in the distal fibula that was not initially identified. This resulted in eight scintigraphic-positive CT-negative discordant cases. The (99m)Tc-MDP uptake was significantly lower in the discordant fracture group compared with the concordant group (p<0.01). Despite technological advances in CT, scintigraphy appeared to detect more stress fractures. As such, multidetector CT should not be used as a routine initial investigation in stress fracture detection. The potential use of (99m)Tc-MDP quantification at fracture sites is of interest and may be worth further investigation.


Genetic factors affecting the occurrence, clinical phenotype, and outcome of autoimmune hepatitis.
Autoimmune hepatitis is a polygenic disorder of unknown cause in which the genetic risk factors that affect occurrence, clinical phenotype, severity, and outcome still are being clarified. The susceptibility alleles in white North American and northern European patients reside on the DRB1 gene, and they are DRB1*0301 and DRB1*0401. These alleles encode a 6 amino acid sequence at positions 67-72 in the DRbeta polypeptide chain of the class II molecules of the major histocompatibility complex. This sequence is associated with susceptibility, and lysine at position DRbeta71 is the key determinant. Molecular mimicry between foreign and self-antigens may explain the loss of self-tolerance and the occurrence of concurrent immune diseases in anatomically distant organs. Disease severity is associated with the number of alleles encoding lysine at DRbeta71 (gene dose) and the number of polymorphisms, including those of the tumor necrosis factor-alpha gene, cytotoxic T lymphocyte antigen-4 gene, and tumor necrosis factor-receptor superfamily gene, that can modify the immune response. Individuals in different geographic regions may have different susceptibility alleles that reflect indigenous triggering antigens, and these may provide clues to the etiologic agent. Knowledge of the genetic predispositions for autoimmune hepatitis may elucidate pathogenic mechanisms, identify etiologic agents, characterize susceptible populations, foresee outcomes, and target new therapies. These lessons may be applicable to autoimmune disease in general.


Regulation of fetal lung phosphatidyl choline synthesis by cortisol: role of glycogen and glucose.
Twenty pregnant rabbits were studied in pairs. Half were given cortisol subcutaneously on days 24, 25, and 26 of gestation in dosage of 2 mg/kg/day. Half served as controls and received saline. The fetal lungs were studied on the 27th day of gestation by incubating lung slices in the presence of [6-14C]glucose. Glucose consumption significantly increased in the tissue from animals treated with cortisol, 17.61 "/- 5.56 (SD) mumol/g in the controls (P less than 0.05). The glycogen content of tissue treated with cortisol was significantly reduced compared to the controls, 2.42 +/- 0.97 (SD) mg/g wet lung versus 3.81 +/- 1.05 (SD) mg/g (P less than 0.05). Treatment with cortisol resulted in significantly enhanced incorporation of the 14C label into glycogen and phosphatidyl choline (Tables 3 and 4). These data suggest that glucocorticoids affect fetal lung phosphatidyl choline production by promoting glycogenolysis and increasing glucose incorporation into phosphatidyl choline.


Screening for colorectal cancer: present, past and future.
Colorectal cancer results in 18,000 deaths annually in England and Wales, with 24,000 new cases diagnosed each year. Despite a better understanding of the genetics, and advancement in surgical and anaesthetic techniques, there has been little reduction in mortality and morbidity from this disease over the past 25 years. Colorectal cancer fits recognized criteria for a disease that should be screened in asymptomatic individuals. The putative duration of the adenoma to carcinoma sequence gives an ample window of opportunity to detect and treat colorectal cancer. In this article we have reviewed the strategies involved in screening for colorectal cancer in an asymptomatic population. We have presented trials and arguments for and against the different screening methods and discussed cost effectiveness of screening. In the USA and Canada, major professional organizations and societies now endorse screening; in the UK it is still far from being accepted. We feel that the available evidence shows that colorectal cancer screening has the potential to reduce the morbidity and mortality from this disease and that funding for a mass screening and public education programme should be sought.


Downregulation of the tumour suppressor p16INK4A contributes to the polarisation of human macrophages toward an adipose tissue macrophage (ATM)-like phenotype.
Human adipose tissue macrophages (ATMs) display an alternatively activated (M2) phenotype, but are still able to produce excessive inflammatory mediators. However, the processes driving this particular ATM phenotype are not understood. Genome-wide association studies associated the CDKN2A locus, encoding the tumour suppressor p16(INK4A), with the development of type 2 diabetes. In the present study, p16(INK4A) levels in human ATMs and the role of p16(INK4A) in acquiring the ATM phenotype were assessed. Gene expression of p16 ( INK4A ) in ATMs was analysed and compared with that in monocyte-derived macrophages (MDMs) from obese patients or with macrophages from human atherosclerotic plaques (AMs). Additionally, p16(INK4A) levels were studied during macrophage differentiation and polarisation of monocytes isolated from healthy donors. The role of p16(INK4A) in MDMs from healthy donors was investigated by small interfering (si)RNA-mediated silencing or adenovirus-mediated overproduction of p16(INK4A). Compared with MDMs and AMs, ATMs from obese patients expressed lower levels of p16 ( INK4A ). In vitro, IL-4-induced M2 polarisation resulted in lower p16(INK4A) protein levels after differentiation of monocytes from healthy donors in macrophages. Silencing of p16(INK4A) in MDMs mediated by siRNA increased the expression of M2 marker genes and enhanced the response to lipopolysaccharide (LPS), to give a phenotype resembling that of ATM. By contrast, adenovirus-mediated overproduction of p16(INK4A) in MDMs diminished M2 marker gene expression and the response to LPS. Western blot analysis revealed that p16(INK4A) overproduction inhibits LPS- and palmitate-induced Toll-like receptor 4 (TLR4)-nuclear factor of κ light polypeptide gene enhancer in B cells (NF-κB) signalling. These results show that p16(INK4A) inhibits the acquisition of the ATM phenotype. The age-related increase in p16(INK4A) level may thus influence normal ATM function and contribute to type 2 diabetes risk.


Pressurized Cadaver Model in Cardiothoracic Surgical Simulation.
Simulation is increasingly recognized as an integral aspect of thoracic surgery education. A number of simulators have been introduced to teach component cardiothoracic skills; however, no good model exists for numerous essential skills including redo sternotomy and internal mammary artery takedown. These procedures are often relegated to thoracic surgery residents but have significant negative implications if performed incorrectly. Fresh tissue dissection is recognized as the gold standard for surgical simulation, but the lack of circulating blood volume limits surgical realism. Our aim is to describe the technique of the pressurized cadaver for use in cardiothoracic surgical procedures, focusing on internal mammary artery takedown.


A longitudinal survey of African animal trypanosomiasis in domestic cattle on the Jos Plateau, Nigeria: prevalence, distribution and risk factors.
Trypanosomiasis is a widespread disease of livestock in Nigeria and a major constraint to the rural economy. The Jos Plateau, Nigeria was free from tsetse flies and the trypanosomes they transmit due to its high altitude and the absence of animal trypanosomiasis attracted large numbers of cattle-keeping pastoralists to inhabit the plateau. The Jos Plateau now plays a significant role in the national cattle industry, accommodating approximately 7% of the national herd and supporting 300,000 pastoralists and over one million cattle. However, during the past two decades tsetse flies have invaded the Jos Plateau and animal trypanosomiasis has become a significant problem for livestock keepers. In 2008 a longitudinal two-stage cluster survey on the Jos Plateau. Cattle were sampled in the dry, early wet and late wet seasons. Parasite identification was undertaken using species-specific polymerase chain reactions to determine the prevalence and distribution bovine trypanosomiasis. Logistic regression was performed to determine risk factors for disease. The prevalence of bovine trypanosomiasis (Trypanosoma brucei brucei, Trypanosoma congolense savannah, Trypanosoma vivax) across the Jos Plateau was found to be high at 46.8% (39.0 - 54.5%) and significant, seasonal variation was observed between the dry season and the end of the wet season. T. b. brucei was observed at a prevalence of 3.2% (1% - 5.5%); T. congolense at 27.7% (21.8% - 33.6%) and T. vivax at 26.7% (18.2% - 35.3%). High individual variation was observed in trypanosomiasis prevalence between individual villages on the Plateau, ranging from 8.8% to 95.6%. Altitude was found to be a significant risk factor for trypanosomiasis whilst migration also influenced risk for animal trypanosomiasis. Trypanosomiasis is now endemic on the Jos Plateau showing high prevalence in cattle and is influenced by seasonality, altitude and migration practices. Attempts to successfully control animal trypanosomiasis on the Plateau will need to take into account the large variability in trypanosomiasis infection rates between villages, the influence of land use, and husbandry and management practices of the pastoralists, all of which affect the epidemiology of the disease.


Comparison of the organization and fine structure of a chicken and a Xenopus laevis vitellogenin gene.
The structural organization and the coding nucleotide sequence of the Xenopus laevis A2 and the chicken major vitellogenin genes have been compared. Both genes show the same exon-intron organization. However, the degree of homology between the nucleotide and derived amino acid sequences varies extensively along the genes. Several of the 35 exons are quite similar, and a unique cysteine motif in the lipovitellin II domain is conserved between the two genes. In contrast, one internal region is quite divergent. Part of this region encodes phosvitin, which appears to have evolved rapidly by both point mutations and duplications of serines or short other amino acid stretches. On the basis of these observations, we discuss the possible mechanism of evolution of phosvitin in vertebrates.


Inhibition of Bak-induced apoptosis by HPV-18 E6.
Human papillomavirus (HPV) E6 proteins inhibit apoptosis in both p53-dependent and p53-independent manners. A key point in apoptosis is the regulation provided by the Bcl-2 family; and in differentiating keratinocytes, in which HPV replicates, the Bak protein is highly expressed. We show that HPV-18 E6 will inhibit Bak-induced apoptosis and this is mediated by an interaction between the E6 and Bak proteins resulting in degradation of the Bak protein in vivo. We also show that Bak protein interacts with the ubiquitin ligase, E6AP, and that a mutant of Bak defective in E6AP binding is overexpressed in comparison with wild type. These studies suggest that Bak is probably the first naturally occurring target of E6AP to be identified.


Loss of neurofibromin results in neurotrophin-independent survival of embryonic sensory and sympathetic neurons.
Mutations at the neurofibromatosis 1 (NF1) locus in humans and mice result in abnormal growth of neural crest-derived cells, including melanocytes and Schwann cells. We have exploited a targeted disruption of the NF1 gene in mice to examine the role of neurofibromin in the acquisition of neurotrophin dependence in embryonic neurons. We show that both neural crest- and placode-derived sensory neurons isolated from NF1(-/-) embryos develop, extend neurites, and survive in the absence of neurotrophins, whereas their wild-type counterparts die rapidly unless nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) is added to the culture medium. Moreover, NF1 (-/-) sympathetic neurons survive for extended periods and acquire mature morphology in the presence of NGF-blocking antibodies. Our results are consistent with a model wherein neurofibromin acts as a negative regulator of neurotrophin-mediated signaling for survival of embryonic peripheral neurons.


Wegener's granulomatosis presenting as a renal mass.
Wegener's granulomatosis is a systemic necrotizing vasculitis that usually involves the kidneys, typically causing segmental necrotizing glomerulonephritis. An association between Wegener's granulomatosis and renal cell carcinoma was recently reported. We describe a case of Wegener's granulomatosis presenting as a renal mass in a 72-year-old woman. Histologic examination of the mass revealed granulomatous inflammation, an extremely rare manifestation of this disease. We also review the incidence of renal mass in Wegener's granulomatosis and highlight the importance of excluding the coexistence of renal cell carcinoma.


Understanding neurocognitive developmental disorders can improve education for all.
Specific learning disabilities (SLDs) are estimated to affect up to 10% of the population, and they co-occur far more often than would be expected, given their prevalences. We need to understand the complex etiology of SLDs and their co-occurrences in order to underpin the training of teachers, school psychologists, and clinicians, so that they can reliably recognize SLDs and optimize the learning contexts for individual learners.


Responses of Chinese Merino Sheep (Junken Type) on Copper-Deprived Natural Pasture.
To research responses of Chinese Merino Sheep (Junken type) to copper-deprived natural pasture, we analyzed mineral contents in soil, forage, and sheep tissues. Physiological and biochemical parameters were also determined. Results showed that copper concentrations in soil and forage from affected pastures were significantly lower than those in healthy ranges (P < 0.01). Copper contents in animal tissues (blood, liver, and wool) from affected Chinese Merino Sheep were also significantly lower than those in healthy sheep (P < 0.01). Hemoglobin levels, packed cell volume, mean corpuscular volume, and mean corpuscular hemoglobin from affected Chinese Merino Sheep were significantly lower than those in healthy animals (P < 0.01). Serum ceruloplasmin was significantly lower in affected Chinese Merino Sheep than that in healthy animals, while activities of lactate dehydrogenase, alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase in serum were significantly higher in affected compared with healthy animals (P < 0.01). The levels of superoxide dismutase, glutathione peroxidase, total antioxidant capacity, and catalase in serum were significantly lower, and the malondialdehyde content was significantly higher in affected compared with healthy sheep (P < 0.01). The levels of interleukin-2, interleukin 6, interleukin-1β, immunoglobulin A, immunoglobulin M, and immunoglobulin G in copper-deprived sheep were significantly lower than those in healthy animals (P < 0.01). Copper deprivation in forage not only influenced the mineral content in blood but also severely disrupted blood parameters (physiology, biochemistry, immunity, and antioxidant) in Chinese Merino Sheep.


Intermale social aggression: reinstatement in castrated rats by implants of testosterone propionate in the medial hypothalamus.
Male hooded rats were castrated, subcutaneously implanted with testosterone-filled silastic tubes, and individually housed with an intact adult female rat. An unfamiliar male intruder was introduced into each colony on a weekly basis and the aggressive behavior of the resident male was recorded. When the intermale social aggressive behavior of the resident male toward the intruder reached a high level in terms of a composite aggression score, the subcutaneous testosterone tubes were removed. Weekly tests of aggression toward unfamiliar intruders continued until the aggression of the resident male dropped to a low level for two successive weeks in terms of our composite aggression score. Bilateral implants of pellets of testosterone propionate were then made into the medial hypothalamus or adjacent tissue. A control group was implanted with cholesterol pellets into the medial hypothalamus. During four weekly tests following the implant, rats with testosterone propionate implants in the medial hypothalamus showed increases in lateral attacks, lateral attack duration, bites, and piloerection. The increase in aggression was not consistently displayed by animals with testosterone propionate implants dorsal or anterior to the medial hypothalamus or by animals with cholesterol implants in the medial hypothalamus. These results suggest that the medial hypothalamus or closely adjacent tissue contains testosterone-sensitive neural circuitry modulating intermale social aggression.


Comparison between E-test and CLSI broth microdilution method for antifungal susceptibility testing of Candida albicans oral isolates.
Thirty Candida albicans isolated from oral candidosis patients and 30 C. albicans isolated from control individuals were studied. In vitro susceptibility tests were performed for amphotericin B, fluconazole, 5-flucytosine and itraconazole through the Clinical and Laboratorial Standards Institute (CLSI) reference method and E test system. The results obtained were analyzed and compared. MIC values were similar for the strains isolated from oral candidosis patients and control individuals. The agreement rate for the two methods was 66.67% for amphotericin B, 53.33% for fluconazole, 65% for flucytosine and 45% for itraconazole. According to our data, E test method could be an alternative to trial routine susceptibility testing due to its simplicity. However, it can not be considered a substitute for the CLSI reference method.


The role of colonic microbiota in lactose intolerance.
In a previous study we observed a clear difference in lactose intolerance symptoms after a 25-g lactose load in two groups of persons with lactase nonpersistence and similar small intestinal lactase activity. From this observation we hypothesized a colon resistance factor. To identify this factor, the microbial composition of fecal samples of the two lactose intolerant groups (one with mild symptoms, n = 16, and one with diarrhea-predominant symptoms, n = 11) was compared using the fluorescent in situ hybridization technique. Large interindividual differences were found in the numbers of total bacteria and main groups of bacteria (CV: 0.65 and 0.64-0.82 respectively). The bacterial numbers were not significantly different between the two groups. A significant negative correlation, however, was found between the individual symptom scores of the intolerant persons and the numbers of total hybridizable bacteria (r(s) = -0.42, P = 0.03). The results suggest that an increased number of bacteria might contribute--by means of a higher fermentative capacity--to the reduction of lactose intolerance symptoms.


Transglutaminase 2 expression is associated with increased risk of lymph node metastasis and recurrence in papillary thyroid cancer.
Transglutaminase 2 (TG2) is associated with mobilization, invasion, and chemoresistance of tumor cells. We aimed to determine whether the immunohistochemical staining with TG2 antibody differs between metastatic and non-metastatic papillary thyroid cancer patients. We included 76 patients with papillary thyroid cancer (72% female, median age 52 (24-81) years, follow-up time 107 (60-216) months). Thirty of them with no metastasis, 30 of them with only lymph node metastasis and 16 patients with distant ± lymph node metastasis. Immunohistochemical staining of TG2 antibody was evaluated in the primary tumor and extra-tumoral tissue. We also divided subjects into two groups according to their primary tumor TG2 staining score (group A, high risk group: ≥3, n = 43; group B, low risk group: <3, n = 33). Vascular invasion (p < 0.001), thyroid capsule invasion (p < 0.001), extrathyroidal extension (p < 0.001), intrathyroidal dissemination (p = 0.001), lymph node metastasis (p < 0.001), presence of aggressive histology (p < 0.001) were significantly higher in group A. No significant difference was found between the groups in terms of distant metastasis. Based on ATA risk classification 95.5% of patients with low risk were in group B but 86.8% of intermediate risk and 56.3% of high risk were in group A. In regression analysis, lymph node metastasis increased by 1.9 times with each one point increase in TG2 staining score. TG2 staining score of the primary tumor may be a predictive factor for lymph node metastasis. High or low TG2 scores may effect the frequency of follow-up and decision of treatment regimens.


Counterimmunoelectrophoresis compared with complement fixation and passive haemagglutination tests in the evaluation of the immune response in Campylobacter infections.
The immune response was studied in 238 human patients with Campylobacter jejuni/coli (CJC)-infections in Rotterdam by the counterimmunoelectrophoresis (CIE) test, a commercial complement fixation test (CFT) and the passive haemagglutination test (HA). Antibodies became detectable in the three tests around 4 days after the onset of complaints. Between the 7th and the 20th days after onset of illness 79%, 80% and 53% of the patients demonstrated antibodies by the CIE, the CFT and the HA, respectively. The HA took 30 days to reach 60% positive serum samples and this percentage declined to 35 by the 50th day. Antibody titres demonstrated in the CIE and the CFT declined more slowly. CIE and CFT performed with antigens from a limited number of heat-stable serotypes can be used in the evaluation of the humoral immune response in CJC-infections.


In vitro immunization of Epstein-Barr virus-immortalized B cells augments antigen-specific antibody production.
The current method for in vitro immunization (IVI) uses several antigens including toxins, food allergens, pathogenic bacteria, and self-antigen-derived peptides that induce an antigen-specific immune response in peripheral blood mononuclear cells (PBMCs). This protocol, however, requires donor blood collection and preparation of PBMCs before every IVI. In the present study, we aimed to design a more efficient system utilizing B cells immortalized with Epstein-Barr virus (EBV-B) as host cells for IVI to make antigen-specific antibodies. Results showed that previously antigen-sensitized, EBV-B cells exposed to the antigen along with IL-6, CpG oligonucleotides, and CD40 ligand signal produced antigen-specific antibodies. These results provide evidence for a novel and easy method to expand memory-type B cells and produce antigen-specific antibodies.


Yield of molecular and clinical testing for arrhythmia syndromes: report of 15 years' experience.
Sudden cardiac death is often caused by inherited arrhythmia syndromes, particularly if it occurs at a young age. In 1996, we started a cardiogenetics clinic aimed at diagnosing such syndromes and providing timely (often presymptomatic) treatment to families in which such syndromes or sudden cardiac death existed. We studied the yield of DNA testing for these syndromes using a candidate-gene approach over our 15 years of experience. We analyzed the yield of DNA testing. In subanalyses, we studied differences in the yield of DNA testing over time, between probands with isolated or familial cases and between probands with or without clear disease-specific clinical characteristics. In cases of sudden unexplained death (antemortem or postmortem analysis of the deceased not performed or providing no diagnosis), we analyzed the yield of cardiological investigations. Among 7021 individuals who were counseled, 6944 from 2298 different families (aged 41 ± 19 years; 49% male) were analyzed. In 702 families (31%), a possible disease-causing mutation was detected. Most mutations were found in families with long-QT syndrome (47%) or hypertrophic cardiomyopathy (46%). Cascade screening revealed 1539 mutation-positive subjects. The mutation detection rate decreased over time, in part because probands with a less severe phenotype were studied, and was significantly higher in familial than in isolated cases. We counseled 372 families after sudden unexplained death; in 29% of them (n=108), an inherited arrhythmia syndrome was diagnosed. The proportion of disease-causing mutations found decreased over time, in part because probands with a less severe phenotype were studied. Systematic screening of families identified many (often presymptomatic) mutation-positive subjects.


Three-dimensional forces beyond actomyosin contraction: lessons from fly epithelial deformation.
Epithelium undergoes complex deformations during morphogenesis. Many of these deformations rely on the remodelling of apical cell junctions by actomyosin-based contractile force and this has been a major research interest for many years. Recent studies have shown that cells can use additional mechanisms that are not directly driven by actomyosin contractility to alter cell shape and movement, in three-dimensional (3D) space and time. In this review, we focus on a number of these mechanisms, including basolateral cellular protrusion, lateral shift of cell polarity, cytoplasmic flow, regulation of cell volume, and force transmission between cell-cell adhesion and cell-extracellular matrix adhesion, and describe how they underlie Drosophila epithelia deformations.


N-acetyl-D-glucosamine induces germination in Candida albicans through a mechanism sensitive to inhibitors of cAMP-dependent protein kinase.
The present study examines the involvement of cAMP-dependent protein kinase (PKA) in the dimorphic transition of Candida albicans by assessing the in vivo effect of two permeable PKA inhibitors on N-acetyl-D-glucosamine (GlcNAc)- and serum-induced differentiation. The permeable myristoylated derivative of the heat-stable PKA inhibitor (MyrPKI), which inhibited C. albicans PKA in vitro, caused a concentration-dependent inhibition of germ-tube formation in cultures induced to germinate by GlcNAc; germination halted irrespective of the time of addition of the inhibitor. MyrPKI also blocked dibutyryl-cAMP (dbcAMP)- and glucagon-stimulated germination but did not affect serum-induced germination. H-89, another highly specific PKA inhibitor, displayed the same effect on germination. Neither MyrPKI nor H-89 had any effect on budding of yeast cells. In conclusion, our results indicate that cAMP-mediated activation of PKA plays a pivotal role in the biochemical mechanism underlying morphogenesis.


Moderate substrate stiffness induces vascular smooth muscle cell differentiation through cellular morphological and tensional changes.
Vascular smooth muscle cells (VSMCs) are one of the main components of arterial walls and actively remodel the arterial walls in which they reside through biomechanical signals applied to themselves. Contractile or differentiated VSMCs have been observed in normal blood vessels. In pathological vascular conditions, they become dedifferentiated from contractile to non-contractile or synthetic cells, and a similar change is observed when VSMCs are placed in culture conditions. The mechanisms regulating VSMC differentiation remain unclear at this stage. In this paper we investigated the effects of substrate stiffness on the morphology, intercellular tension, and differentiation of VSMCs. Rat VSMCs were cultured on polyacrylamide (PA) gels, with elastic moduli of 15 kPa, 40 kPa, and 85 kPa, and PDMS substrate with elastic modulus of 1 MPa, and their morphology, intercellular tension, and contractile differentiation were assessed. Using fluorescence microscope image-based analysis and nano-indentation imaging with atomic force microscopy, we found that cell spreading and stiffening were induced by substrate stiffening in VSMCs. Interestingly, VSMCs on PA gel substrates with medium stiffness (40 kPa) showed significant elongation and shape polarization, and their 𝛼-SMA with F-actin cytoskeleton expression ratio was significantly higher than those of cells on other substrates. The results indicate an existing optimal substrate stiffness for promoting VSMC differentiation, and also indicate that cell shape polarization might be a key factor for VSMC differentiation.


Alexithymia and depression in a chronic pain patient sample.
The aim of the present study was to assess the prevalence of alexithymia in a sample of general chronic pain patients, to explore possible differences in depression and pain variables between alexithymic and nonalexithymic chronic pain patients and to analyze if depression is a mediator between alexithymia and pain disability. Two hundred and seventy-one patients making their first visit to a pain clinic completed the study questionnaire including various pain measures, the Beck Depression Inventory-II (BDI-II) and the 20-item Toronto Alexithymia Scale (TAS-20). The sample was dichotomized to alexithymic and nonalexithymic groups. The means of the study variables were compared between the groups. The correlation analysis of the variables was carried out separately in both groups. Path analysis was done to ascertain the mediation effect of BDI-II between the TAS-20 and pain disability. Every fifth chronic pain patient was alexithymic. The BDI-II and pain variable scores were significantly higher in the alexithymic group than in the nonalexithymic group. Pain variables were not associated with alexithymia when BDI-II was controlled for. BDI-II worked as a full mediator between TAS-20 and pain disability. The alexithymic patient group was more morbid than the nonalexithymic group. The results suggest that depression is the main factor in pain conditions of alexithymic chronic pain patients. The authors recommend screening and treatment of depression in alexithymic chronic pain patients.


Unexpected heterogeneity of multifunctional T cells in response to superantigen stimulation in humans.
Toxic shock syndrome (TSS) is a potentially life threatening condition characterized by fever, rash, shock, and multi-organ failure. Staphylococcal enterotoxin B (SEB) is a well characterized superantigen that has been shown to play an important role in TSS. Although the precise mechanisms by which SEB and other superantigens cause TSS are unknown, induction of a pro-inflammatory cytokine cascade appears central to this phenomenon. We show that CD4+ and CD8+ Teffector/memory (T(EM)) and other subsets produce IL-17A following SEB stimulation. We also show that IL-17A is co-produced with other pro-inflammatory cytokines (i.e., IL-2, IFN-γ and TNF-α). These responses are significantly different than those elicited by mitogenic stimulation. Multifunctional IL-17A producing cells possess markers typical of the T(H)17/T(C)17 and T(H)1 subsets, including CCR6, IL-22, and transcription factors retinoic acid receptor-related orphan nuclear receptor (ROR)-γt and T-bet. These results suggest a possible role for IL-17A-producing multifunctional T cells in the pathogenesis of TSS.


Intentional Modulation of Ibrutinib Pharmacokinetics through CYP3A Inhibition.
Ibrutinib (Imbruvica; PCI-32765) is an orally administered inhibitor of Bruton's tyrosine kinase that has transformed the treatment of B-cell malignancies. However, ibrutinib has very low oral bioavailability that contributes to significant variability in systemic exposure between patients, and this has the potential to affect both efficacy and toxicity. We hypothesized that the oral bioavailability of ibrutinib is limited by CYP3A isoform-mediated metabolism, and that this pathway can be inhibited to improve the pharmacokinetic properties of ibrutinib. Pharmacokinetic studies were performed in wild-type mice and mice genetically engineered to lack all CYP3A isoforms [CYP3A(-/-)] that received ibrutinib alone or in combination with CYP3A inhibitors cobicistat or ketoconazole. Computational modeling was performed to derive doses of ibrutinib that, when given after a CYP3A inhibitor, results in therapeutically-relevant drug levels. Deficiency of CYP3A in mice was associated with a ~10-fold increase in the area under the curve of ibrutinib. This result could be phenocopied by administration of cobicistat before ibrutinib in wild-type mice, but cobicistat did not influence levels of ibrutinib in CYP3A(-/-) mice. Population pharmacokinetic and prospectively validated physiologically-based pharmacokinetic models established preclinical and clinical doses of ibrutinib that could be given safely in combination with cobicistat without negatively affecting anti-leukemic properties. These findings signify a dominant role for CYP3A-mediated metabolism in the elimination of ibrutinib, and suggest a role for pharmacological inhibitors of this pathway to intentionally modulate the plasma levels and improve the therapeutic use of this clinically important agent.


Ammonia is endogenously generated in the brain in the presence of presumed and verified dementia of Alzheimer type.
The healthy, mature, non-starved brain was found to take up a small amount of ammonia on average 7.22 +/- 0.72 micrograms/100 g x min. In contrast, in patients thought to be suffering from incipient early-onset dementia of the Alzheimer type (DAT) the brain released a larger amount of ammonia on average 25.59 +/- 16.17 micrograms/100 g x min. In advanced DAT states, an average of 2.73 +/- 0.32 micrograms/100 g x min was released indicating the temporary nature of the severe loss of amino-N during the early stages of presumed DAT. Detrimental effects of endogenously formed ammonia on brain metabolism may affect the membrane potential, the excitability of neurons, and the energy metabolism. Ammonia may be assumed to be involved in the morphological changes in astrocytes and in the gliosis observed in early degeneration related to DAT. Endogenously generated brain ammonia thus may have a role in the cascade of cell damaging events in presumed incipient DAT.


Interactome analysis reveals that lncRNA HULC promotes aerobic glycolysis through LDHA and PKM2.
Interacting with proteins is a crucial way for long noncoding RNAs (lncRNAs) to exert their biological responses. Here we report a high throughput strategy to characterize lncRNA interacting proteins in vivo by combining tobramycin affinity purification and mass spectrometric analysis (TOBAP-MS). Using this method, we identify 140 candidate binding proteins for lncRNA highly upregulated in liver cancer (HULC). Intriguingly, HULC directly binds to two glycolytic enzymes, lactate dehydrogenase A (LDHA) and pyruvate kinase M2 (PKM2). Mechanistic study suggests that HULC functions as an adaptor molecule that enhances the binding of LDHA and PKM2 to fibroblast growth factor receptor type 1 (FGFR1), leading to elevated phosphorylation of these two enzymes and consequently promoting glycolysis. This study provides a convenient method to study lncRNA interactome in vivo and reveals a unique mechanism by which HULC promotes Warburg effect by orchestrating the enzymatic activities of glycolytic enzymes.


Chitosan-polyvinyl alcohol nanoscale liquid film-forming system facilitates MRSA-infected wound healing by enhancing antibacterial and antibiofilm properties.
Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most predominant and fatal pathogens at wound infection sites. MRSA is difficult to treat because of its antibiotic resistance and ability to form biofilms at the wound site. In this study, a novel nanoscale liquid film-forming system (LFFS) loaded with benzalkonium bromide was produced based on polyvinyl alcohol and chitosan. This LFFS showed a faster and more potent effect against MRSA252 than benzalkonium bromide aqueous solution both in vitro and in vivo. Additionally, the LFFS had a stronger ability to destroy biofilms (5 mg/mL) and inhibit their formation (1.33 μg/mL). The LFFS inflicted obvious damage to the structure and integrity of MRSA cell membranes and caused increases in the release of alkaline phosphate and lactate dehydrogenase in the relative electrical conductivity and in K+ and Mg2+ concentrations due to changes in the MRSA cell membrane permeability. The novel LFFS is promising as an effective system for disinfectant delivery and for application in the treatment of MRSA wound infections.


APM/CD13 and FOS in the hypothalamus of monosodium glutamate obese and food deprived rats.
Protein (western blotting) and gene (PCR) expressions, catalytic activity of puromycin-insensitive membrane-bound neutral aminopeptidase (APM/CD13) and in situ regional distribution of CD13 and FOS immunoreactivity (ir) were evaluated in the hypothalamus of monosodium glutamate obese (MSG) and/or food deprived (FD) rats in order to investigate their possible interplay with metabolic functions. Variations in protein and gene expressions of CD13 relative to controls coincided in the hypothalamus of MSG and MSG-FD (decreased 2- to 17-fold). Compared with controls, the reduction of hypothalamic CD13 content reflected a negative balance in its regional distribution in the supraoptic, paraventricular, periventricular and arcuate nuclei. CD13-ir increased in the supraoptic nucleus in MSG (2.5-fold) and decreased in the paraventricular nucleus (2-fold) together with FOS-ir (1.5-fold) in FD. In MSG-FD, FOS-ir decreased (7-fold) in the paraventricular nucleus, while CD13-ir decreased in the periventricular (5.6-fold) and the arcuate (3.7-fold) nuclei. It was noteworthy that all these changes of CD13 were not related to catalytic activity of APM. Data suggested that hypothalamic CD13 plays a role in the regulation of energy metabolism not by means of APM enzyme activity.


Longitudinal changes in ferritin during chronic transfusion: a report from the Stroke Prevention Trial in Sickle Cell Anemia (STOP).
Chronic red cell transfusion has been used for prevention of recurrent stroke in patients with sickle cell disease for three decades, and its effectiveness in primary prevention was recently shown. Iron overload, the inevitable result of chronic transfusion, is commonly monitored with serum ferritin concentration. Sixty-one patients at high risk for stroke received chronic transfusion in a clinical trial of stroke prevention. A serum ferritin level of less than 500 ng/mL was required for study entry. Ferritin levels were obtained quarterly. Fifty patients who had four or more ferritin measurements were included in this analysis. Transfusions were administered as exchange or simple, with washed, reconstituted, or packed red blood cells, at the discretion of the site investigator. Serum ferritin levels increased linearly with cumulative transfusion volume during the first four ferritin measurements, but the rate of increase varied widely among patients. Rates of increase varied similarly among 23 patients who received exclusively simple transfusion with packed red cells and in five patients who received exchange transfusions. Thirty-two patients received a total transfusion volume of more than 250 mL/kg. Ferritin continued to increase linearly after the first four measurements in 14, but the remaining 18 experienced a plateau before the level reached 3,000 ng/mL. Six of those with a linear increase never reached a ferritin level of 3,000 ng/dL. There was strong intrapatient correlation between serum ferritin levels and volume transfused but wide interpatient variability early during chronic transfusion therapy. Intrapatient correlation declined at transfusion volumes of more than 250 mL/kg. Direct iron store assessment is needed to determine the clinical significance of serum ferritin variability.


[Diagnostic standards for extradural tumors and metastases of the spinal column].
Because of the heterogeneous clinical and paraclinical symptoms accompanied by the urgent necessity to rapidly find a diagnosis, the differential diagnostic delineation of spinal tumors from back pain related to other reasons is a special challenge in the orthopedic practice. Employing an algorithm based on anamnesis, clinical, radiological and paraclinical examinations, a guideline-related biopsy as well as histological processing of the biopsy material, tumor lesions can usually be classified regarding entity, dignity and extent. Following this a treatment strategy can be defined. Because of the necessity of an interdisciplinary approach the diagnostic algorithm should be planned during a tumor conference and performed in specialized centers.


Development and Preservation of Avian Sperm.
Terminally differentiated avian sperm consist of a head which male genetic material locates and flagellum that provides the motive force to propel them towards the fertilization site. The apical end of the sperm head accommodates a secretory vesicle, called an acrosome, that undergoes acrosome reaction releasing proteolytic content to penetrate the peri-vitelline membrane of an egg. Transcriptionally and translationally inactive, sperm need to rely on these distinct compartments in which different functions are preassembled, in order to achieve the goal of "fertilization". How are these complex structures with high functionality formed? Spermatogenesis is divided into an early stage in which diploid spermatogonia is proliferated into round spermatids thorough mitotic and meiotic divisions, and a late stage in which round spermatids are transformed into sperm though nuclear condensation and elongation of the sperm head, and formation of accessory structures. Recently, it was reported in aves that morphologically differentiated sperm undergo post-testicular maturation during passage through the male genital tract, suggesting that a similar system to mammals might be involved in the acquisition of fertilizing ability in avian sperm. Investigation for mechanisms underlying how sperm regulate their functions which are necessary to achieve fertilization is important for developing reproductive biotechnology in aves, because cryopreservation of poultry sperm is still not reliable for use in commercial production or for the preservation of genetic resources. In this review, we firstly provide an update on avian spermatogenesis, and then discuss the uniqueness of structure and functions of avian sperm, highlighting differences from mammalian sperm. Lastly, we discuss the molecular mechanism and current techniques of cryopreservation for avian sperm.


Activation of the alternative pathway of complement by grain. I. C3PA conversion and quantification of complement consumption by rye.
Ground whole rye and airborne rye dust of comparable size distribution were tested for their ability to activate the complement cascade via the alternative pathway. Precipitin-negative pooled normal human serum was incubated with increasing amounts of the two rye dusts. Electrophoresis of the resultant supernatant fluids demonstrated the conversion of the proactivator of the third component of complement to the gamma-migrating activator of the third component. This activation was completely prevented by pre-treating the serum with the chelator EDTA, while pre-treatment with EGTA allowed suboptimal arc conversion, strongly implying that complement was activated via the alternative pathway. Quantification of the supernanant fluids showed dose-dependent complement consumption as defined by both CH100 immunodiffusion and CH50 tube haemolytic techniques. Airborne rye dust showed a greater quantitative potential than ground whole rye for activating the alternative pathway. These results indicate the possibility of the direct action of airborne organic dusts on the induction of inflammatory sequelae in the lungs of both sensitized and unsensitized individuals.


[Mobile IT: Possibilities and barriers of mHealth].
The increasing availability of mobile devices and corresponding applications, both for providers and patients, often leads to speculation that mHealth, as the combination of mobile devices and health services is often called, would revolutionize the use of information technology (IT) in healthcare. On the other hand users, providers and operators providing such solutions are often confronted with completely new challenges. This article assesses the options and potential of mHealth and also takes a critical look at potential obstacles. As this field is very broad this critical analysis is illustrated by means of three exemplary application areas: mHealth in radiology, the influence of mHealth on research and mHealth as an enabler of new services, always with examples from other countries.The use of mHealth in radiology currently often develops empirically from existing applications in a relatively unstructured way and benefiting from the dynamic development of mobile technology. The possibilities range from viewing images at the bedside via mobile accessibility of radiologists up to teleradiology. In research there is a huge potential in solutions that actively involve patients with their own mobile devices but the field of data protection is still perceived in Germany as problematic so that only a few research institutions are actively addressing these options. The concept of mHealth allows physicians, hospitals and other service providers to invent entirely new services and a start-up scene is beginning to be established with business models becoming successful particularly with exchanges at the interface with established suppliers.


Exstrophic anomalies: followup of 36 cases.
Since 1950, 36 patients with exstrophic anomalies were seen at the Medical College of Virginia Hospitals. There were several modalities of treatment used, including primary reconstructive procedures in 11 patients, 6 of whom continue to have a functional bladder closure. Our results and current management are discussed.


Circannual transitions in gene expression: lessons from seasonal adaptations.
Circannual timing is important for the coordination of seasonal activities, particularly promoting the survival of individuals in adverse conditions through adaptive physiological and behavioral changes. This includes optimizing the survival of offspring by coordinating reproductive efforts at appropriate times. Thus, timing is very important for overall fitness. In this chapter, we provide several examples of circannually timed events, including mammalian hibernation, discussing the physiological changes that accompany these events, and some of the known genes and pathways underlying these changes. We then describe five candidate systems that are potentially involved in circannual timing. Finally, we discuss several recent advances in molecular biology and animal husbandry that have made the use of nonmodel organisms for research more feasible, which will hopefully promote and encourage further advancement in the knowledge of circannual timing.


Drive and Reinforcement Circuitry in the Brain: Origins, Neurotransmitters, and Projection Fields.
Brain stimulation has identified two central subsets of stimulation sites with motivational relevance. First, there is a large and disperse set of sites where stimulation is reinforcing, increasing the frequency of the responses it follows, and second, a much more restricted set of sites where-along with reinforcement-stimulation also has drive-like effects, instigating feeding, copulation, predation, and other motivated acts in otherwise sated or peaceful animals. From this work a dispersed but synaptically interconnected network of reinforcement circuitry is emerging: it includes afferents to the ventral tegmental area and substantia nigra; the dopamine systems themselves; glutamatergic afferents to the striatum; and one of two dopamine-receptor-expressing efferent pathways of the striatum. Stimulation of a limited subset of these sites, including descending inhibitory medial forebrain bundle fibers, induces both feeding and reinforcement, and suggests the possibility of a subset of fibers where stimulation has both drive-like and reinforcing effects. This review stresses the common findings of sites and connectivity between electrical and optogenetic studies of core drive and reinforcement sites. By doing so, it suggests the biological importance of optogenetic follow-up of less-publicized electrical stimulation findings. Such studies promise not only information about origins, neurotransmitters, and connectivity of related networks, by covering more sensory and at least one putative motor component they also promote a much deeper understanding of the breadth of motivational function.


Use of neutrons reveals the dynamics of cell surface glycosaminoglycans.
Cell surface glycosaminoglycans (GAG), such as heparan sulfate (HS) and heparin, are key multifunctional cell regulators, which are involved in numerous molecular events associated with tumor growth, metastasis, pathogen attachment, and immune response. GAG dynamically bind and regulate the activities of many signaling proteins such as growth factors, chemokines, and cytokines. GAG-binding interactions with proteins rely on the coupling between the geometry, flexibility, and rigidity of the polysaccharide chain. Understanding GAG dynamics at the molecular level can therefore provide fundamental insights into GAG function in a cellular context. Elastic incoherent neutron scattering is a powerful tool for the exploration of fast molecular motions in biological macromolecules. Recently, the technique was used to evaluate HS flexibility and rigidity on different timescales between the picosecond (ps) and the nanosecond (ns). Here, neutron spectroscopy experimental procedures are presented, with emphasis on the practical details necessary to prepare samples, run neutron scattering experiments, and extract the dynamics parameters from the data.