Cell proliferation control by Notch signaling in Drosophila development.
The Notch receptor mediates cell interactions controlling the developmental fate of a broad spectrum of undifferentiated cells. By modulating Notch signaling in specific precursor cells during Drosophila imaginal disc development, we demonstrate that Notch activity can influence cell proliferation. The activation of the Notch receptor in the wing disc induces the expression of the wing margin patterning genes vestigial and wingless, and strong mitotic activity. However, the effect of Notch signaling on cell proliferation is not the simple consequence of the upregulation of either vestigial or wingless. Vestigial and Wingless, on the contrary, display synergistic effects with Notch signaling, resulting in the stimulation of cell proliferation in imaginal discs.


Personality correlates of pro-environmental attitudes.
There is considerable scientific interest in the psychological correlates of pro-environmental attitudes and concerns. While much research has focused on demographic and social-psychological characteristics of individuals with pro-environmental attitudes, our study explores the relations between personality traits and pro-environmental behaviours. The study found that Honesty, Agreeableness, Openness, Proactive personality and Pro-environmental attitude predict environmental behaviour. The main implication of the study is the fact that responsible environmental behaviour could be enhanced through programmes focused on the increase of the environmental awareness and the development of a more pro-ecological view.


High-impedance wire grid method to study spatiotemporal behavior of hot electron clump generated in a plasma.
High-impedance Wire Grid (HIWG) detector has been developed to study spatiotemporal behavior of a hot electron clump generated in an electron cyclotron resonance (ECR) plasma. By measuring the floating potentials of the wire electrodes, and generating structure matrix made of geometrical means of the floating potentials, the HIWG detector reconstructs the spatial distribution of high-temperature electron clump at an arbitrary instant of time. Time slices of the spike event in floating potential revealed the growth and decay process of a hot spot occurs in an ECR plasma.


Antioxidant Status before and after Dietary Intervention in Cardiovascular Disease (CVD) Patients.
There is some evidence showing an inverse correlation between dietary sources including natural antioxidant vitamins and the risk of cardiovascular disease (CVD). The aim of this study was to evaluate the effect of dietary antioxidants on oxidative stress in CVD patients. This study was carried out on 31 CVD patients and 63 healthy individuals. Nutritional status and dietary antioxidant vitamins were assessed by 48-hour recall. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities as well as the levels of vitamins A, E, C, total antioxidant capacity (TAC) and malondialdehyde (MDA) were determined before and after serving fresh fruits and vegetables for 3 months. Before intervention intake, levels of vitamins A, E and C were significantly lower in patients than in normal individuals (P<0.001). The serum levels of vitamins A, E and C were significantly lower in the cases than in the control subjects. After intervention, the serum levels of vitamins A, E and C were increased significantly (P<0.0001). Similarly, the levels of TAC as well as the activities of SOD and GPx were found to increase by end of 3 months. In addition, a significant increase of TAC and a decrease in MDA levels were observed. In conclusion, the findings show that dietary supplementation improves the antioxidant defense system in CVD patients.


Specific interactions between the viral coreceptor CXCR4 and the biguanide-based compound NB325 mediate inhibition of human immunodeficiency virus type 1 infection.
The present studies were conducted to better define the mechanism of action of polyethylene hexamethylene biguanide (PEHMB) (designated herein as NB325), which was shown in previous studies to inhibit infection by the human immunodeficiency virus type 1 (HIV-1). Fluorescence-activated flow cytometric analyses of activated human CD4(+) T lymphocytes exposed to NB325 demonstrated concentration-dependent reductions in CXCR4 epitope recognition in the absence of altered recognition of selected CD4 or CD3 epitopes. NB325 also inhibited chemotaxis of CD4(+) T lymphocytes induced by the CXCR4 ligand CXCL12. However, NB325 did not cause CXCR4 internalization (unlike CXCL12) and did not interfere with CXCL12 binding. Additional flow cytometric analyses using antibodies with distinct specificities for extracellular domains of CXCR4 demonstrated that NB325 specifically interfered with antibody binding to extracellular loop 2 (ECL2). This interaction was confirmed using competitive binding analyses, in which a peptide derived from CXCR4 ECL2 competitively inhibited NB325-mediated reductions in CXCR4 epitope recognition. Collectively, these results demonstrate that the biguanide-based compound NB325 inhibits HIV-1 infection by specifically interacting with the HIV-1 coreceptor CXCR4.


Prenatal diagnosis of Fukuyama-type congenital muscular dystrophy by microsatellite analysis.
We applied microsatellite analysis to prenatal diagnosis of Fukuyama-type congenital muscular dystrophy (FCMD), an autosomal recessive severe muscular dystrophy associated with brain malformations. Recent identification of the FCMD gene locus at 9q31-q33 provided the basis for prenatal diagnosis and carrier detection. We recently developed new microsatellite markers which are closer to the FCMD gene and improved the phenotype probability. Nine fetuses in eight unrelated FCMD families, including a twin pregnancy, were analysed using the newly developed markers. Four fetuses showed over 99% probability of being healthy either as normal homozygote (n = 1) or heterozygote carrier (n = 3) and were born without signs of FCMD. The other five fetuses were diagnosed with a probability of FCMD of 99% or greater; all of the latter parents decided to terminate the pregnancies. Brain malformations characteristic of FCMD in one of the aborted fetuses confirmed the diagnosis of FCMD at 19 weeks of gestation.


Demographic differences in substance use problems among juvenile delinquents.
This article presents two studies that used community-based, national samples of adolescents to compare demographic differences between delinquent and nondelinquent respondents. Results indicated that ethnic differences in alcohol problems were similar in the delinquent and nondelinquent groups, with whites reporting higher levels of alcohol problems. In contrast, age differences were smaller among delinquents than nondelinquents, which pointed to a heightened risk for both alcohol and marijuana problems among younger delinquents. Future research can explore biological and psychosocial factors that increase risk for substance problems among younger delinquents.


Geographical network model for COVID-19 spread among dynamic epidemic regions.
Pandemic due to SARS-CoV-2 (COVID-19) has affected to world in several aspects: high number of confirmed cases, high number of deaths, low economic growth, among others. Understanding of spatio-temporal dynamics of the virus is helpful and necessary for decision making, for instance to decide where, whether and how, non-pharmaceutical intervention policies are to be applied. This point has not been properly addressed in literature since typical strategies do not consider marked differences on the epidemic spread across country or large territory. Those strategies assume similarities and apply similar interventions instead. This work is focused on posing a methodology where spatio-temporal epidemic dynamics is captured by means of dividing a territory in time-varying epidemic regions, according to geographical closeness and infection level. In addition, a novel Lagrangian-SEIR-based model is posed for describing the dynamic within and between those regions. The capabilities of this methodology for identifying local outbreaks and reproducing the epidemic curve are discussed for the case of COVID-19 epidemic in Jalisco state (Mexico). The contagions from July 31, 2020 to March 31, 2021 are analyzed, with monthly adjustments, and the estimates obtained at the level of the epidemic regions present satisfactory results since Relative Root Mean Squared Error RRMSE is below 15% in most of regions, and at the level of the whole state outstanding with RRMSE below 5%.


Randomised controlled trial of a livestock productive asset transfer programme to improve economic and health outcomes and reduce intimate partner violence in a postconflict setting.
Diverse economic empowerment programmes (eg, microcredit, village-led savings and loan, cash and productive asset transfers) for the poor have demonstrated mixed results as vehicles for improved economic stability, health and women's empowerment. However, limited rigorous evaluations exist on the impact of financial and non-financial outcomes of these programmes, especially in conflict-affected areas. The team evaluated the effectiveness of an innovative livestock productive asset transfer intervention-Pigs for Peace (PFP)-on economic, health and women's empowerment outcomes with participants in households in 10 villages in Eastern Democratic Republic of Congo. Residual change analysis was used to examine the amount of change from baseline to 18 months between the intervention and delayed control groups, controlling for baseline scores. The majority of the 833 household participants were women (84%), 25 years of age or older, married, had on average 3 children and had never attended school. At 18 months postbaseline, the number of participants in the PFP households having outstanding credit/loans was 24.7% lower than households in the control group (p=0.028), and they had an 8.2% greater improvement in subjective health (p=0.026), a 57.1% greater reduction in symptoms of anxiety (p=0.020) and a 5.7% greater improvement in symptoms of post-traumatic stress disorder (p<-0.001). At 18 months postbaseline, partnered women and men reported a reduction in experience and perpetration of all forms of intimate partner violence, although not statistically significant between groups. The findings support scalability of a livestock productive asset transfer programme in rural and conflict-affected settings where residents have extremely limited access to financial institutions or credit programmes, health or social services and where social norms that sustain gender inequality are strong. NCT02008708.


Uptake and Persistence of Homologous and Heterologous Zooxanthellae in the Temperate Sea Anemone Cereus pedunculatus (Pennant).
The uptake and persistence of symbiotic dinoflagellates (zooxanthellae) were measured in the temperate sea anemone Cereus pedunculatus (Pennant). Aposymbiotic specimens of C. pedunculatus were inoculated with zooxanthellae freshly isolated from a range of temperate and subtropical Anthozoa. Each inoculate consisted of zooxanthellae from a single host species and was either homologous (zooxanthellae from a host of the same species as the one being inoculated) or heterologous (from a host of a different species than the one being inoculated). The densities of zooxanthellae in host tissues were determined at regular intervals. C. pedunculatus took up homologous and heterologous zooxanthellae to similar degrees, except for zooxanthellae from the temperate Anthopleura ballii, which were taken up to a lesser extent. The densities of all zooxanthellae declined between 4 hours and 4 days after uptake, indicating that zooxanthellae were expelled, digested, or both during this period. The densities of all zooxanthellae increased between 2 and 8 weeks after inoculation, indicating zooxanthella growth. Over the entire 8-week period after uptake, densities of homologous zooxanthellae were always greater than those of heterologous zooxanthellae. Between 8 and 36 weeks after infection, densities of homologous zooxanthellae declined markedly and densities of some heterologous zooxanthellae increased further, resulting in homologous and heterologous zooxanthella densities being the same at 36 weeks. These densities were the same as those in naturally infected C. pedunculatus of similar size. The results suggest that zooxanthellae from a range of host species and environments can establish symbioses with C. pedunculatus and that, over long periods under laboratory conditions, heterologous zooxanthellae may populate C. pedunculatus to the same extent as homologous zooxanthellae.


Family conflict, chaos, and negative life events predict cortisol activity in low-income children.
Childhood poverty is hypothesized to increase risk for mental and physical health problems at least in part through dysregulation of the hypothalamic-pituitary-adrenal axis. However, less is known about the specific psychosocial stressors associated with cortisol reactivity and regulation for children living in poverty. The current study investigates negative life events, household chaos, and family conflict in preschool and middle childhood as potential predictors of cortisol regulation in low-income 7-10 year olds (N = 242; M age = 7.9 years). Participants were assessed in preschool and participated in a follow-up assessment in middle childhood, during which diurnal free cortisol and free cortisol reactivity to the Trier Social Stress Test for Children (TSST-C) were assessed. Household chaos during preschool predicted a more blunted diurnal cortisol slope in middle childhood. Greater negative life events during preschool and greater concurrent family conflict were associated with increased free cortisol reactivity in middle childhood.


Endoscopic MRI.
We used a new magnetic resonance endoscope with a small radiofrequent (RF) coil attached to the tip. After insertion of the instrument into the second portion of the duodenum, patients were placed in a magnetic resonance imaging (MRI) scanner. Fast spoiled gradient-recalled acquisition (SPGR) pulse sequences were used for this method. After plain scans, six axial scans were performed after intravenous injection of 20 ml of gadolinium-diethylenetriaminepentaacetic acid (DTPA) contrast medium. We performed endo-MRI on 22 patients, 13 with pancreatic carcinoma, four with pancreatic cystoadenoma, and five with other diseases. In the patients with pancreatic carcinoma, tumors were delineated as low-intensity masses after injection of contrast medium. Dilated main pancreatic ducts were clearly defined. In eight patients with carcinoma of the head of the pancreas, tumors were clearly defined in seven (87.5%) cases. In the eighth case, motion artifact prevented acquisition of a clear image of the pancreas. For diagnosis of invasion of the portal vein, the sensitivity of endo-MRI was 80%, the specificity was 100%, and overall accuracy was 87.5%. The new technique of endo-MRI allows the precise diagnosis of pancreatic tumors.


A theoretical study of Favorskii reaction stereochemistry. Lessons in torquoselectivity.
The mechanisms of the chloroenolate-->cyclopropanone step of the "normal" Favorskii rearrangement have been investigated in detail using high-level ab initio calculations. A series of simple alpha-chloroenolates, based on chloroacetone (6), all monomethyl derivatives (7-9), a dimethyl analogue (10), and 1-acetyl-1-chlorocyclohexane (11) was first used to explore and define the basic features of the mechanism, which include the finding of both an "inversion" and a "retention" transition state and that in most cases these arise from separate ground-state conformations of the chloroenolate. These theoretical studies were then extended to an isomeric pair of chloroenolates 1 and 2, the cis- and trans-2-methyl derivatives of 11, which are the reactive intermediates involved in a well-known experimental study carried out by Stork and Borowitz (S-B). Finally, three alpha-chlorocyclohexanone enolate systems 12-14 were studied, since these intermediates have a more restricted enolate geometry. The "inversion" mechanism has been described as an SN2 process but the present results, while supporting a concerted process, is better described as an oxyallyl structure undergoing concerted ring closure. The "retention" mechanism has been described as SN1-like, but the calculations show that this process is also concerted, although much less so, and again involves oxyallyl-like transition-states. The model systems 6-8, 10, and 11 with a potential plane of symmetry have two enantiomeric transition states for inversion and another two for retention of configuration (at the C-Cl center). With 9 and the S-B models 1 and 2, with no symmetry plane, there are a calculated total of four diastereomeric transition states for cyclopropanone ring closure in each case, two for inversion and two for retention. While the transition-state energies calculated for simple chloroenolates favor the inversion process, the S-B models 1 and 2 have almost equal inversion-retention transition-state energies. Solvation simulation calculations of ground states and transition states suggest that the retention mechanism becomes relatively more favored in polar solvents, in agreement with some experimental results. In the chloroenolates 12-14, both inversion and retention mechanisms were also located, these arising from two different ground-state ring conformations of the enolate. In these models, one also finds similar inversion and retention transition-state energies, but again with a small preference for the inversion process.


Inhibition of alloresponsive naive and memory T cells by CD7 and CD25 antibodies and by cyclosporine.
Human naive and memory T cells can be isolated from each other by their CD45RA and CD45RO expression, respectively. This enables the assessment of their differential sensitivities to immunosuppressive agents for the first time. We have investigated the ability of cyclosporine or CD7 and CD25 antibodies to selectively block alloantigen stimulated naive and memory T cells in vitro. CD7 antibodies blocked the proliferation of naive (P less than 0.025) but not memory T cells in a primary MLR. CD25 antibody inhibited both naive and memory subsets but a significantly greater effect was found on the memory T cells (P less than 0.005). The constitutive CD7 and CD25 antigen expression on resting naive or memory T cells was related to the inhibitory activities of these antibodies on both subsets. Accordingly, naive T cells expressed more CD7 antigen than memory cells while memory T cells displayed low levels of CD25 antigen that was absent from naive populations before activation. Cyclosporine, like CD25 antibody, inhibited both subsets in a primary MLR but had a greater effect on memory cells (P less than 0.02). Memory T cells, therefore, are more dependent than naive cells on IL-2 for proliferation. There was great individual variation in the ability of CsA to block the MLR. The simultaneous addition of CD25 or CD7 antibody together with CsA, however, enhanced the MLR inhibition as the effects of all three were additive. This suggested interference by these agents at different points during T cell activation. Thus, in CsA sensitive individuals, one-tenth of the optimal CsA concentration together with CD25 antibody maintained maximum immunosuppression in vitro. These results demonstrate the possibility of using CD7 and CD25 antibodies for selective inhibition of naive or memory T cells and also the possibility of augmenting the inhibition of and reducing the CsA concentration required for clinically effective immunosuppression.


[Bacteriostatic - bactericidal].
Action of chemotherapeutics on bacteria can be described as "bacteriostatic" or "bactericidal". In vitro, "bactericidal" agents are able to kill >or= 99.9% bacteria of the inoculum within 18-24 h. However, "bactericidal" or "bacteriostatic" effects are dependent on several variables, e.g., inoculum, species, or medium. The number of bacteria found in an infectious process amounts to 10(8)-10(10) CFU/ml (colony-forming units per milliliter) and is far beyond the in vitro test inoculum of 5 x 10(5) CU/ml. Contrary to the term "bactericidal", in vivo a significant number of bacteria will survive. These bacteria are able to regrow, to mutate and to support infection. It is thought that a special advantage of "bactericidal" agents is the rapid killing of bacteria, thus avoiding or at least slowing down development of resistance. Contrary to this assumption, there is now an alarming increase in resistance including third-generation cephalosporins, quinolones and even carbapenems.Recent randomized clinical studies comparing "bacteriostatic" and "bactericidal" regimens revealed an equivalent clinical success. It became obvious that therapy with certain "bacteriostatic" agents even in severe infections is not harmful to patients. In addition, e.g. tetracyclines are able not only to fight bacteria but also to modulate immune response of the host. This property may offer possibilities to develop new strategies in treating infections.


Detection of obstructive apnea events in sleeping infants from thoracoabdominal movements.
The aim of the study was to determine whether in infants, the evaluation of thoracoabdominal movements alone, with no measurement of airflow, could be used to identify obstructive sleep apnea events (OA). Two different methods were used: first, we initially quantified thoracoabdominal asynchrony. Although 79.3% of OAs showed a significant increase of thoracoabdominal asynchrony, only 10.9% of the events scored by the identification of phase opposition were true OAs. Next, we developed two artificial neural networks (ANNs) as classifiers for the study of the thoracoabdominal signals. The first network was trained to locate obstructive and central apnea events. It correctly detected 75% of the OAs; however, only 6.2% of the detected events were true OAs. When a second network was used, OAs could not be discriminated from other portions of the signals showing similar phase characteristics. It was concluded that the information available in uncalibrated signals of thoracic and abdominal respiratory movements was insufficient to unambiguously detect OA events in sleeping infants.


Absence of TGFβ signaling in retinal microglia induces retinal degeneration and exacerbates choroidal neovascularization.
Constitutive TGFβ signaling is important in maintaining retinal neurons and blood vessels and is a factor contributing to the risk for age-related macular degeneration (AMD), a retinal disease involving neurodegeneration and microglial activation. How TGFβ signaling to microglia influences pathological retinal neuroinflammation is unclear. We discovered that ablation of the TGFβ receptor, TGFBR2, in retinal microglia of adult mice induced abnormal microglial numbers, distribution, morphology, and activation status, and promoted a pathological microglial gene expression profile. TGFBR2-deficient retinal microglia induced secondary gliotic changes in Müller cells, neuronal apoptosis, and decreased light-evoked retinal function reflecting abnormal synaptic transmission. While retinal vasculature was unaffected, TGFBR2-deficient microglia demonstrated exaggerated responses to laser-induced injury that was associated with increased choroidal neovascularization, a hallmark of advanced exudative AMD. These findings demonstrate that deficiencies in TGFβ-mediated microglial regulation can drive neuroinflammatory contributions to AMD-related neurodegeneration and neovascularization, highlighting TGFβ signaling as a potential therapeutic target.


Mitochondrial genome of the Neotropical catfish Ageneiosus pardalis, Lütken 1874 (Siluriformes, Auchenipteridae).
Ageneiosus pardalis is a trans-Andean member of the Neotropical freshwater fish family Auchenipteridae (Siluriformes). In this work, the complete mitochondrial genome of A. pardalis was pyrosequenced by FLX 454 technology. The mitochondrial genome is 16,484 bp in length and encodes 13 proteins, 22 tRNAs and 2 ribosomal RNAs. Additionally, the synteny is conserved with others species of the Auchenipteridae family as well as other Siluriformes.


Effects of pregnancy on the toxicity and metabolism of acetaminophen in mice.
Although acetaminophen is widely used in pregnant women, the effects of pregnancy on its hepatotoxicity remain unknown. We assessed these effects in pregnant mice (17-18 days of gestation). The hepatotoxicity of acetaminophen (300-400 mg X kg-1 i.p.) was increased markedly in pregnant mice, as judged by increased serum glutamic-pyruvic transaminase activity, higher incidence of liver necrosis and greater mortality. In vitro, acetaminophen sulfotransferase activity was increased by 47% in pregnant mice, but acetaminophen glucuronosyltransferase activity was decreased by 54%; the metabolic activation of acetaminophen to covalently bound metabolites was unchanged. Glutathione S-transferase activities were decreased slightly. In vivo, after administration of acetaminophen (300 mg X kg-1 i.p.), the 24-hr urinary excretion of the sulfate conjugate was increased (from 12% of the recovered dose in nonpregnant mice to 21% in pregnant mice), that of the glucuronide was decreased (from 61 to 52%), whereas those of the cysteine and mercapturic acid conjugates and that of acetaminophen were unchanged. Finally, the plasma clearance and the apparent volume of distribution of acetaminophen (both expressed per body weight) remained unchanged. Similarly, in vivo covalent binding to hepatic proteins 4 hr after administration of acetaminophen (300 and 400 mg X kg-1 i.p.) remained unchanged as were in vivo indexes of lipid peroxidation. In contrast, liver glutathione concentration, albeit initially normal, fell to much lower levels after administration of acetaminophen (200-400 mg X kg-1 i.p.) or diethylmaleate (0.5 ml X kg-1 i.p.) in pregnant mice, and recovered more slowly thereafter.(ABSTRACT TRUNCATED AT 250 WORDS)


Intergenerational impact of maternal overnutrition and obesity throughout pregnancy in sheep on metabolic syndrome in grandsons and granddaughters.
We previously reported that maternal overnutrition and obesity (MO) throughout pregnancy and lactation in sheep (MOF0) decreases term fetal pancreatic β-cell numbers and increases perirenal adiposity producing hyperphagia, increased adiposity and insulin resistance in adult female offspring (MOF1) fed ad libitum. Pregnant female MOF1 exhibited increased blood glucose from mid to late gestation vs control F1 (CTRF1) though both groups ate only to NRC recommendations. MOF1 ewes delivered female offspring (F2) who like their MOF1 mothers exhibited increased abdominal adiposity and absent neonatal leptin surge. In the current work, we determined if adult MOF2 exhibited metabolic syndrome components when fed ad libitum. After weaning, MOF2 males (n = 5), MOF2 females (n = 6), CTRF2 males (n = 5), and CTRF2 females (n = 6) were fed to NRC requirements until 19 mo followed by 12-wk ad libitum feeding. Body weight and % fat increased (P < 0.01) in all F2 during this feeding trial. MOF2 males were heavier (P < 0.01) than CTRF2 males and females, and MOF2 females throughout the trial. By wk 8, baseline blood glucose concentrations increased (P < 0.001) in MOF2 females, but not other groups, remaining elevated throughout the trial. Baseline insulin was similar through wk 6, increasing (P < 0.05) at wk 8 in MOF2 females only. MOF2 female insulin returned to CTRF2 female levels during wk 10 and 12. The progressive increase of plasma glucose on wk 8 in association with increased insulin in MOF2 females but not other groups demonstrated a diet-induced increase (P < 0.001) in MOF2 female insulin resistance. The subsequent decline in insulin during wk 10 and 12 despite elevated glucose in MOF2 females is consistent with a decrease in glucose-stimulated pancreatic β-cell function. These data indicate that ad libitum feeding exceeds the pancreatic secretory response predisposing MOF2 females to hyperglycemia. Furthermore, there was a sex difference where MOF2 males increased body mass and MOF2 females displayed insulin/glucose dysregulation.


Selecting a medical therapy for overactive bladder.
Immediate-release oxybutynin was the gold standard for pharmacologic treatment of overactive bladder for nearly 30 years. Intolerable systemic side effects, in particular dry mouth, limited its clinical utility, resulting in poor patient compliance with dosing regimens. Multiple studies have demonstrated the vastly superior tolerability of tolterodine, extended-release tolterodine, and extended-release oxybutynin over that of immediate-release oxybutynin at equivalent doses, and in the case of extended-release oxybutynin even to twice the dose of the original immediate-release form. With different drug delivery systems and, perhaps, with better bladder selectivity, these new oral agents have favorable side effect profiles, which translate into higher patient compliance and fewer treatment withdrawals or dosage reductions.


A mesoscopic reaction rate model for shock initiation of multi-component PBX explosives.
The primary goal of this research is to develop a three-term mesoscopic reaction rate model that consists of a hot-spot ignition, a low-pressure slow burning and a high-pressure fast reaction terms for shock initiation of multi-component Plastic Bonded Explosives (PBX). Thereinto, based on the DZK hot-spot model for a single-component PBX explosive, the hot-spot ignition term as well as its reaction rate is obtained through a "mixing rule" of the explosive components; new expressions for both the low-pressure slow burning term and the high-pressure fast reaction term are also obtained by establishing the relationships between the reaction rate of the multi-component PBX explosive and that of its explosive components, based on the low-pressure slow burning term and the high-pressure fast reaction term of a mesoscopic reaction rate model. Furthermore, for verification, the new reaction rate model is incorporated into the DYNA2D code to simulate numerically the shock initiation process of the PBXC03 and the PBXC10 multi-component PBX explosives, and the numerical results of the pressure histories at different Lagrange locations in explosive are found to be in good agreements with previous experimental data.


Antibiotics use, knowledge and practices on antibiotic resistance among breastfeeding mothers in Kaduna state (Nigeria).
This project explores the relationship between sociodemographic status and antibiotic use, practices and knowledge about the concept of antibiotic resistance among breastfeeding mothers. A pre-tested questionnaire was administered to breastfeeding mothers in six public hospitals in Kaduna state of Nigeria. Socio-demographic characteristics using univariate analysis were compared with antibiotic use, knowledge and practices. Multivariable logistic regression models were performed to know the potential predictors of a better knowledge and understanding about antibiotics resistance. A total of 321 breastfeeding mothers took part in the survey with 25.27% believing that antibiotics are used to treat fever, common cold, bacterial and viral infections and 43.7% declaring not having heard of the term before, 45.7% do not believe that antibiotics taken by the mother could affect the baby and 74.58% believe that antibiotics resistance is when their body becomes resistant to antibiotics. Multivariable models showed that the unemployed and those with lower levels of education are more prone to antibiotics misuse. This study demonstrates that breastfeeding mothers have a lack of adequate knowledge and understanding regarding the use of antibiotics and antibiotic resistance. Maternal misuse while breastfeeding could contribute to the development of antibiotic resistance, mainly in the intestinal microbiota in children.


Effects of prone trunk extension exercise using different fixations and with and without abdominal drawing-in maneuver in healthy individuals.
[Purpose] The purpose of this study was to investigate the differential effects of fixation of the thoracolumbar junction on the activity of the thoracic and lumbar muscle groups with and without the abdominal drawing-in maneuver (ADIM). [Subjects and Methods] The participants were 40 healthy adults. During trunk extension, thoracic and lumbar muscle activities were assessed using surface electromyography when fixing the pelvic and popliteal areas and the thoracolumbar junction, with and without the ADIM. [Results] The activity of the thoracic extensors at the T9 level applying thoracolumbar fixation with ADIM was significantly higher than with only pelvic fixation or pelvic fixation with ADIM during prone trunk extension. However, the activity of the lumbar extensors at the L3 level with pelvic fixation alone, without ADIM, was significantly higher than pelvic fixation with ADIM or additional thoracolumbar fixation with ADIM during prone trunk extension [Conclusion] This study demonstrated that fixation of the thoracolumbar junction with ADIM during trunk extension was more effective at eliciting thoracic extensor and minimising lumbar extensor activity than other conventional fixation methods.


Assessment of mineral elements and heavy metals in leaves of indigenous cypress of High Atlas Mountains.
An inductively coupled plasma mass spectrometry was developed to determine 20 mineral elements and heavy metals in leaves of Cupressus atlantica Gaussen, a traditional Moroccan medicinal herb from five environmentally different sites in N'Fis valley (High Atlas Mountains). The results showed in the leaves that Ca, K, P, Mg, Na and Fe were the most abundant of the elements in all samples of the studied locality. The concentrations of trace metals from the leaves of this plant were in the order Ca>K > P > Mg>Na>Fe. The results of the mineral composition were analysed by hierarchical cluster and principal component analysis that established three statistically significant clusters.


Role of Glutathione in the Accumulation of Potassium Ions in Escherichia coli under Osmotic Stress.
When Escherichia coli cells were stressed by NaCl, cellular levels of glutathione (GSH) increased, and potassium ions (K(+)) accumulated. To identify the role of the stress-induced synthesis of GSH in the accumulation of K(+), a GSH-deficient mutant of E. coli was used. The mutant grew even in a medium with a low concentration of K(+) after a lag of about 32 hr. In such cells grown under osmotic stress in this medium, K(+) did not accumulate in the lag phase. In the logarithmic phase, however, intracellular levels of K(+) increased in spite of the lack of intracellular GSH. In a medium with the usual K(+) concentration, K(+) accumulated in a pattern similar to that of the parent strain in both phases. These results showed that GSH participates in the accumulation of K(+) in cells under osmotic stress only in the lag phase in medium with little K(+).


Employability Paradox: The Effect of Development Idiosyncratic Deals on Recipient Employees' Turnover Intention.
Applied social cognitive theory, this study built a moderated mediation model to explain how and when development idiosyncratic deals (i-deals) affect recipients' turnover intention. Specifically, this study proposed two paths that linked development i-deals with the recipients' turnover intention. One path was a retention path via perceived internal employability and another path was a turnover path via perceived external employability. This study tested the hypotheses with a sample of 337 employees from three companies in China. The results showed that development i-deals improved recipients' perception of internal and external employability both. Perceived internal employability predicted low risk of turnover, but perceived external employability predicted high risk of turnover. And perceived internal and external employability played mediating roles in the relationship between development i-deals and turnover intention. Furthermore, the recipients' perception of opportunity to perform in current organization strengthened the relationship between perceived internal employability and turnover intention, but weakened the relationship between perceived external employability and turnover intention. Theoretical and practical implications of these findings were discussed.


How does area-level deprivation depress an individual's self-rated health and life satisfaction? Evidence from a nationwide population-based survey in Japan.
Area-level deprivation is well known to have an adverse impact on mortality, morbidity, or other specific health outcomes. This study examined how area-level deprivation may affect self-rated health (SRH) and life satisfaction (LS), an issue that is largely understudied. We used individual-level data obtained from a nationwide population-based internet survey conducted between 2019 and 2020, as well as municipality-level data obtained from a Japanese government database (N = 12,461 living in 366 municipalities). We developed multilevel regression models to explain an individual's SRH and LS scores using four alternative measures of municipality-level deprivation, controlling for individual-level deprivation and covariates. We also examined how health behavior and interactions with others mediated the impact of area-level deprivation on SRH and LS. Participants in highly deprived municipalities tended to report poorer SRH and lower LS. For example, when living in municipalities falling in the highest tertile of municipality-level deprivation as measured by the z-scoring method, SRH and LS scores worsened by a standard deviation of 0.05 (p < 0.05) when compared with those living in municipalities falling in the lowest tertile of deprivation. In addition, health behavior mediated between 17.6 and 33.1% of the impact of municipality-level deprivation on SRH and LS, depending on model specifications. Results showed that area-level deprivation modestly decreased an individual's general health conditions and subjective well-being, underscoring the need for public health policies to improve area-level socioeconomic conditions.


New Raman-peak at 1850 cm(-1) observed in multiwalled carbon nanotubes produced by hydrogen arc discharge.
The new peak (near 1850 cm(-1)) assigned to carbon linear chain included in the centre of very thin innermost multiwalled carbon nanotubes (MWNTs) has been verified by Raman spectroscopy. These MWNTs were produced by dc arc discharge of pure graphite rods in pure hydrogen gas and existed in the cathode deposit. In this paper, we clarified that the new Raman-peaks could also be observed in the cathode deposit including MWNTs produced by hydrogen dc arc discharge using graphite electrode with added Y or La. By changing the quantity of addition (Y or La), dc arc current and pressure of ambient hydrogen gas, the optimum condition to get maximum intensity of the new Raman-peaks was obtained. For the case of 1 wt% La, dc 50 A, H2 pressure of 50 Torr was found to be optimum, and the intensity of new Raman-peak was even higher than the G-band peak. For the case of 1 wt% Y, dc 50 A, H2 pressure of 50 Torr was optimum, but the intensity of new Raman-peak was weaker than the G-band peak. Transmission electron microscopy observation revealed that the crystallinity of MWNTs produced with pure graphite rod was better than those produced with added Y or La.


Extraction of metastatic lymph nodes from MR images using two deformable model-based approaches.
We presented and evaluated two deformable model-based approaches, region plus contour deformation (RPCD), and level sets to extract metastatic cervical nodal lesions from pretreatment T2-weighted magnetic resonance images. The RPCD method first uses a region deformation to achieve a rough boundary of the target node from a manually drawn initial contour, based on signal statistics. After that, an active contour deformation is employed to drive the rough boundary to the real node-normal tissue interface. Differently, the level sets move a manually drawn initial contour toward the desired nodal boundary under the control of the evolvement speed function, which is influenced by image gradient force. The two methods were tested by extracting 33 metastatic cervical nodes from 18 nasopharyngeal carcinoma patients. Experiments on a basis of pixel matching to reference standard showed that RPCD and level sets achieved averaged percentage matching at 82-84% and 87-88%, respectively. In addition, both methods had significantly lower interoperator variances than the manual tracing method. It was suggested these two methods could be useful tools for the evaluation of metastatic nodal volume as an indicator of classification and treatment response, or be alternatives for the delineation of metastatic nodal lesions in radiation treatment planning.


Perceptual integration of head and eye cues to gaze direction in schizophrenia.
The perceptual mechanisms that underlie social experience in schizophrenia are increasingly becoming a target of empirical research. In the context of low-level vision, there is evidence for a reduction in the integration of sensory features in schizophrenia (e.g. increased thresholds for contour detection and motion coherence). In the context of higher-level vision, comparable differences in the integration of sensory features of the face could in theory impair the recognition of important social cues. Here we examine how the sense of where other people are looking relies upon the integration of eye-region cues and head-region cues. Adults with schizophrenia viewed face images designed to elicit the 'Wollaston illusion', a perceptual phenomenon in which the perceived gaze direction associated with a given pair of eyes is modulated by the surrounding sensory context. We performed computational modelling of these psychophysical data to quantify individual differences in the use of facial cues to gaze direction. We find that adults with schizophrenia exhibit a robust perceptual effect whereby their sense of other people's direction of gaze is strongly biased by sensory cues relating to head orientation in addition to eye region information. These results indicate that the visual integration of facial cues to gaze direction in schizophrenia is intact, helping to constrain theories of reduced integrative processing in higher-level and lower-level vision. In addition, robust gaze processing was evident in the tested participants despite reduced performance on a theory of mind task designed to assess higher-level social cognition.


Intensive combination chemotherapy and autologous bone marrow transplantation leads to the reappearance of Philadelphia chromosome-negative cells in chronic myelogenous leukemia.
Fifteen patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) who were ineligible for allogeneic bone marrow transplantation (BMT) or alpha-interferon therapy were included in this study. Eight patients were in the first late chronic phase, five were in the second chronic phase, one was in the accelerated phase, and one was in the blastic phase. Autologous bone marrow cells (median, 2.5 x 10(8) nucleated cells/kg) were stored at a median of 30 months after diagnosis. Patients were treated with cyclophosphamide (1.5 g/m2 daily for 4 days), carmustine (BCNU) (300 mg/m2), and etoposide (VP-16) (250 mg/m2 daily for 3 days) (CBV), followed by reinfusion of autologous bone marrow. Hematopoietic recovery was rapid, and toxicity was mild to moderate in 14 patients. One patient died of cytomegalovirus pneumonitis. Eight of 15 patients showed Ph suppression to less than 90% Ph-positive metaphases after autologous BMT. Major cytogenetic responses (Ph suppression to less than 35% Ph-positive metaphases) developed in four patients. Cytogenetic responses were observed in 4 of 11 patients infused with 100% Ph-positive marrows, and in all 4 patients infused with Ph-mosaic marrows (mixture of diploid and Ph-positive cells). Better results were observed when autologous BMT was performed in the chronic phase compared with the advanced phases. The major cytogenetic responses have lasted for 3, 4, 12, and 15+ months, whereas minor cytogenetic responses lasted for only a short time (less than 2 months). Three of seven patients (43%) in the chronic phase with previous resistance to alpha-interferon therapy became sensitive to alpha-interferon therapy after autologous BMT. The authors concluded that intensive chemotherapy followed by autologous BMT produced cytogenetic remissions in patients with Ph-positive CML and reinduced disease sensitivity to alpha-interferon therapy in patients previously resistant to it. This is particularly useful when treatment is given during the chronic phase and stem cells are collected at a time of previous cytogenetic remission.


Modulation of cytochrome-P450 inhibition (CYP) in drug discovery: a medicinal chemistry perspective.
Cytochrome P450 (CYP450) has widely been implicated for drug-drug interactions (DDI) in the pharmaceutical industry. Inhibition or induction of this enzyme family has led to withdrawal of multiple drugs from the market leading to major time and financial losses for the pharmaceutical industry. CYP450 plays a prevailing role in the biotransformation of a large number of structurally diverse drugs. Few isoenzymes of the CYP enzyme family (CYP3A4, 2D6 and 2C9 family) are mainly involved in metabolism of most of the drugs. To avoid such interactions and potentially minimize DDI, major pharmaceutical organizations prefer to incorporate CYP enzyme screening at an early stage of their discovery program. While this has been a prevalent practice in the pharmaceutical industry lately, there is very limited literature available reviewing the relationship between chemotypes and CYP isoforms. This review will collate literature pertaining to CYP-inhibition modulation through physicochemical parameters and chemical modification and thus bring to focus commonly used trends by medicinal chemists world-wide.


Target specific virtual screening: optimization of an estrogen receptor screening platform.
In this work, we introduce a four-step scoring and filtering procedure, furnishing target specific virtual screening (TS-VS), which serves to minimize false positives resulting from conformational artifacts of the docking process and is optimized to converge on novel chemotypes of estrogen receptor alpha (ERalpha). As a proof of concept, VS of a commercial compound database was undertaken (SPECs database release: Aug 2005, 202 054 compounds in total), resulting in the identification of both previously known and novel putative ER scaffolds. Application of distance constraints within TS-VS allowed facile identification of three novel active ligands with ERalpha binding affinities (IC50) of 1.4 microM, 57 nM, and 53 nM. Importantly, they all exhibited ERalpha over ERbeta selectivity, with the most selective being 17-fold. The ligands also displayed low micomolar antiproliferative activity (7-15 microM) in the human MCF-7 breast cancer cell line.


Trachea stabilisation with autologous costal cartilage in acquired tracheomalacia: report of two cases.
Post-operative tracheomalacia is a life threatening condition whose management is challenging. Surgical procedures which have been suggested in the literature to manage the condition include tracheostomy, staged thyroid reductions and the use of artificial stents either within the lumen of the tracheobronchial tree or as external support. We report the successful management of two patients using autologous costal cartilage to support the tracheal wall.


Regulated Polarization of Tumor-Associated Macrophages by miR-145 via Colorectal Cancer-Derived Extracellular Vesicles.
Macrophages are polarized into functional classically activated and alternatively activated (M2) phenotypes depending on their microenvironment, and these cells play an important role in the immune system. M2-like polarization of tumor-associated macrophages (TAMs) is activated by various secretions from cancer cells; however, the interaction between cancer cells and TAMs is not well understood. Recent studies showed that cancer cell-derived extracellular vesicles (EVs) contribute to tumor development and modulation of the tumor microenvironment. In the current study, we investigated colorectal cancer-derived EVs containing miR-145 with respect to the polarization of TAMs. Colorectal cancer cells positively secreted miR-145 via EVs, which were taken up by macrophage-like cells. Interestingly, colorectal cancer-derived EVs polarized macrophage-like cells into the M2-like phenotype through the downregulation of histone deacetylase 11 An in vivo study showed that EV-treated macrophages caused significant enlargement of the tumor volumes. These findings suggest that colorectal cancer cells use miR-145 within EVs to efficiently modulate M2-like macrophage polarization and tumor progression.


The cloning and expression of a human creatine transporter.
A human creatine transporter (hCRT-BS2M) cDNA clone was isolated from a human brainstem/spinal cord using a PCR and phage plaque hybridization based technique. This clone included an open reading frame of 1,905 base pairs(bp) within a 2,283bp cDNA. Northern blot hybridization detected the expression of corresponding mRNAs most prominently in the skeletal muscle, heart and kidney. Peptide sequence analysis of the hCRT-BS2M protein product revealed 12 putative transmembrane domains. The predicted protein sequence further demonstrates that the hCRT-BS2M has highly conserved amino acid identity with the other members of the sodium dependent plasma membrane transporter family. Transient expression of the hCRT-BS2M in COS-7 cells demonstrates sodium dependent [14C]creatine uptake with a KM value of 14.9 +/- 3.0 microM (n = 5) that is attenuated by creatine and selective structural analogues of creatine.


Hematologic changes associated with half-body irradiation in dogs with lymphoma.
Reports describe the technique and efficacy of half-body irradiation (HBI) of dogs with lymphoma, but few describe the distinctive toxicoses associated with the combination of HBI and chemotherapy. HBI would transiently affect myelocytic and erythroid variables as assessed by serial analysis of complete blood counts. Twenty-nine dogs with lymphoma treated with HBI during 2002 and 2003. A retrospective study of medical records of 29 dogs was performed. Two HBI protocols were used, resulting in delivery of either 6 Gy or 8 Gy to each half of the body, 1 month apart. Dogs received chemotherapy before, during, or after irradiation, or at multiple times. Serial hematology was available for all dogs. Data were analyzed between collection periods by analysis of variance (ANOVA) RESULTS: The mean granulocyte count significantly (P < .01) decreased from 10,017 cells/microL (data range 3,001-20,170 cells/ microL) before the first radiation treatment to 3,250 cells/microL (820-4,400 cells/microL) at week 5 (P < .01). Three weeks after this nadir, the mean increased to 10,150 cells/microL (900-26,700 cells/microL). The hematocrit did not change (36-38%). Thrombocytopenia (<100,000/microL) occurred in 10 dogs. Two dogs died because of complications associated with thrombocytopenia. No significant difference in toxicity was found between the 6 Gy and 8 Gy group. HBI was myelosuppressive but effects were short term and resolved in 22 of 24 dogs. Further studies are needed to elucidate the safety and role of HBI in the treatment of dogs with lymphoma.


Ultrasonication-assisted one-step self-assembly preparation of biocompatible fluorescent-magnetic nanobeads for rare cancer cell detection.
Multifunctional nanomaterials simultaneously possessing attractive properties, such as strong fluorescent intensity, excellent superparamagnetic behavior, easy modification and good biocompatibility, are always desired in a wide range of applications. In this work, we present a facile ultrasonication-assisted one-step self-assembly strategy for the fabrication of smart fluorescent-magnetic nanobeads (FMNBs) without using a matrix. Via one-step ultrasonication, organic-soluble superparamagnetic nanoparticles (MNPs) and quantum dots (QDs) were automatically encapsulated by amphiphilic (2-hydroxyl-3-dodecanoxyl) propylcarboxymethylchitosans (HDP-CMCHSs) through hydrophobic interaction to form hydrophilic FMNBs, presenting a good QD fluorescent property and a strong MNP magnetic response. The outer surface of the FMNBs was derived from natural biopolymer chitosans, enabling FMNBs with good biocompatibility and convenience for biological modification. As-prepared FMNBs can be easily modified with streptavidin, facilitating bioconjugation with biotin-labeled human epidermal growth factor (hEGF). hEGF-functionalized FMNBs are able to specifically recognize and capture rare target cells spiked in white blood cells, and the recovered cells can be further cultured for a long time. All of these excellent properties make nanobeads promising for circulating tumor cell (CTC) detection.


Innate immune responses to endosymbiotic Wolbachia bacteria in Brugia malayi and Onchocerca volvulus are dependent on TLR2, TLR6, MyD88, and Mal, but not TLR4, TRIF, or TRAM.
The discovery that endosymbiotic Wolbachia bacteria play an important role in the pathophysiology of diseases caused by filarial nematodes, including lymphatic filariasis and onchocerciasis (river blindness) has transformed our approach to these disabling diseases. Because these parasites infect hundreds of millions of individuals worldwide, understanding host factors involved in the pathogenesis of filarial-induced diseases is paramount. However, the role of early innate responses to filarial and Wolbachia ligands in the development of filarial diseases has not been fully elucidated. To determine the role of TLRs, we used cell lines transfected with human TLRs and macrophages from TLR and adaptor molecule-deficient mice and evaluated macrophage recruitment in vivo. Extracts of Brugia malayi and Onchocerca volvulus, which contain Wolbachia, directly stimulated human embryonic kidney cells expressing TLR2, but not TLR3 or TLR4. Wolbachia containing filarial extracts stimulated cytokine production in macrophages from C57BL/6 and TLR4(-/-) mice, but not from TLR2(-/-) or TLR6(-/-) mice. Similarly, macrophages from mice deficient in adaptor molecules Toll/IL-1R domain-containing adaptor-inducing IFN-beta and Toll/IL-1R domain-containing adaptor-inducing IFN-beta-related adaptor molecule produced equivalent cytokines as wild-type cells, whereas responses were absent in macrophages from MyD88(-/-) and Toll/IL-1R domain-containing adaptor protein (TIRAP)/MyD88 adaptor-like (Mal) deficient mice. Isolated Wolbachia bacteria demonstrated similar TLR and adaptor molecule requirements. In vivo, macrophage migration to the cornea in response to filarial extracts containing Wolbachia was dependent on TLR2 but not TLR4. These results establish that the innate inflammatory pathways activated by endosymbiotic Wolbachia in B. malayi and O. volvulus filaria are dependent on TLR2-TLR6 interactions and are mediated by adaptor molecules MyD88 and TIRAP/Mal.


Familial cryoglobulinemia and C4 deficiency.
The coexistence of cryoglobulinemia and C4 deficiency was found in one family. Twelve subjects were examined, most of them being asymptomatic. Cryoglobulins were found in 9 members and its type was defined in 6 of them, 3 having mixed IgM-IgG and 3 having monoclonal IgM cryoglobulins. The concentration of the third component of the complement system was normal in 10 subjects, while the concentration of the fourth one was found to be below the lower limit of normal in 9 subjects. Only C4 deficiency--and not cryoglobulinemia--was HLA-linked. There was no evidence of HBs antigenemia. The results of this study are discussed in the light of the pertinent literature.


Experimental Evidence for Branch-to-Bird Transfer as a Mechanism for Avian Dispersal of the Hemlock Woolly Adelgid (Hemiptera: Adelgidae).
Birds have long been hypothesized as primary dispersal agents of the hemlock woolly adelgid (Adelges tsugae Annand). Although A. tsugae eggs and mobile first instars (crawlers) have been collected from wild birds, key mechanistic elements necessary for avian dispersal have never been examined. To evaluate the mechanisms of bird-mediated A. tsugae dispersal, we conducted both stationary (i.e., where crawlers must actively disperse) and disturbance (i.e., where crawlers may transfer from substrates due to mechanical abrasion) dispersal trials. For stationary trials, we tested the role of perching duration, ovisac density, and seasonal timing on the rate of crawler transfer to immobile preserved bird mounts at a single site in Connecticut. For disturbance trials, we explored if transfer rates were different when branches were actively brushed against birds. Both stationary and disturbance trials resulted in successful transfers of A. tsugae to bird mounts, with disturbance trials having significantly higher rates of transfers. Crawler counts from stationary trials increased significantly with local ovisac density. Additionally, we found a nonlinear relationship between crawler transfer and experimental week, with crawler transfer highest at the beginning of sampling in May, coinciding with avian spring migration in Connecticut and the emergence of progrediens crawlers, and spiking again near 14 June, when sistens generation crawlers began to emerge. While many aspects of potential avian dispersal of A. tsugae remain unknown, these results suggest that crawler transfer to birds may occur most often when peak crawler emergence coincides with the northward migration of many small passerine bird species.


[Hysteroscopic evaluation of female infertility].
Three-hundred-seventy-one infertile patients underwent hysteroscopic evaluation. The test was performed in an outpatient setting without any form of anesthesia. A comparison has been made among this technique, the hysterosalpingography and ultrasounds: hysteroscopy showed to be more accurate in the evaluation of intracavitary pathology, because of its capability to obtain a direct view of the uterine cavity. We can evaluate hysteroscopically nature, dimension and localization of the lesions. However HSG remains the best technique for the study of tubal factors of infertility. We think that hysteroscopy should be used besides other diagnostic methods, in order to obtain a better evaluation of the infertile patients.


DNA (cytosine-5) methyltransferase inhibitors: a potential therapeutic agent for schizophrenia.
In this issue of Molecular Pharmacology, Kundakovic et al. (p. 644) present compelling evidence suggesting that the promoters for reelin and GAD67 are coordinately regulated. The regulation occurs at the level of DNA (cytosine-5) methylation. Moreover, the authors present evidence suggesting that pharmacologic inhibition of DNA methyltransferase results in reversal of methylation, loss of methyl-DNA binding proteins and relief of repression. Repression of both reelin and GAD67 has been implicated in the pathogenesis of schizophrenia. Therefore, these results suggest that the reelin and GAD67 promoters are subject to continuous repression by DNA methyltransferase and that inhibitors of DNA methyltransferase represent a potential treatment for Schizophrenia.


Evolution of prescribing practices and outcomes in the COVID-19 pandemic in metropolitan areas.
We wanted to characterize the evolution of the COVID-19 pandemic in a typical metropolitan area. Data were extracted from the Detroit COVID-19 Consortium database for hospitalized COVID-19 patients treated in Southeast Michigan over the 12-month period from March 2020 to February 2021. Demographic and outcomes data were compared to CDC data. A total of 4,775 patients were enrolled during the study period. We divided the pandemic into three phases: Phase-1 (Spring Surge); Phase-2 (Summer Lull); and Phase-3 (Fall Spike). Changes in hydroxychloroquine, remdesivir, corticosteroid, antibiotic and anticoagulant use closely followed publication of landmark studies. Mortality in critically-ill patients decreased significantly from Phase-1 to Phase-3 (60.3% vs. 47.9%, Chisq p=0.0110). Monthly mortality of all hospitalized patients ranged between 14.8% - 21.5% during Phase-1 and 9.7 to 13.4% during Phase 3 (NS). The COVID-19 pandemic presented in three unique phases in Southeast Michigan. Medical systems rapidly modified treatment plans, often preceding CDC and NIH recommendations. Despite improved treatment regimens, intubation rates and mortality for hospitalized patients remained elevated. Preventive measures aimed at reducing hospitalizations for COVID-19 should be emphasized.


Incomplete right bundle branch block: a novel electrocardiographic marker for lone atrial fibrillation.
P-wave morphology and PR interval have both been previously associated with atrial fibrillation (AF). We hypothesized that incomplete right bundle branch block (IRBBB) would be associated with early-onset lone AF. We conducted a case-control study comparing electrocardiographic (ECG) markers from patients with early-onset lone AF and from a healthy control population. We included 187 patients with early-onset lone AF and 383 healthy controls. Sixty-two lone AF patients were excluded from the study because of AF at the time of enrolment or because of the use of antiarrhythmic drugs. For the remaining 125 patients with paroxysmal or persistent lone AF (84% males, mean age 37), controls were matched on a 1:1 basis on the parameters gender and age. A significantly higher proportion of the lone AF population had an IRBBB compared with the subjects in the control group (33.6 vs. 10.4%; P<0.001). In multivariable analysis adjusted for conventional risk factors, IRBBB was strongly associated with lone AF [odds ratio (OR) 5.43; 95% confidence interval (CI) 2.30-13.02; P<0.001]. Lone AF patients had a significantly longer PR interval than the control group (175.1 vs. 160.9 ms; P<0.001), but in multivariable analysis, every 10 ms increase in the PR interval was only borderline significantly associated with an OR of 1.15 (95% CI 0.99-1.32; P=0.060) for lone AF. We are the first to report that IRBBB is strongly and independently associated with early-onset lone AF.


Semiautomatic quantification of carotid plaque volume with three-dimensional ultrasound imaging.
Vessel wall volume (VWV) assessed by three-dimensional duplex ultrasound (3DUS) imaging provides a more comprehensive measure of plaque burden than conventional two-dimensional measures of diameter stenosis. We previously demonstrated that manual outlining of the arterial lumen-intima boundary and outer wall boundary can be performed reliably on images obtained with a commercially available 3D-DUS transducer. Manual segmentation, however, is time consuming (∼45 minutes), limiting its clinical translation. We have developed a semiautomatic algorithm (manual selection of the carotid bifurcation image with subsequent automatic plaque outlining) to outline carotid plaques on 3DUS data sets. In this study, we investigated the accuracy, reproducibility, reliability, and time taken by this algorithm. 3DUS data sets from 30 patients with asymptomatic ≥50% carotid stenosis underwent manual outlining of lumen-intima boundary and outer wall boundary to measure VWV. Two observers implemented a semiautomatic segmentation algorithm. The algorithm's accuracy was compared with manual outlining using the Pearson correlation coefficient. The Dice similarity coefficient (DSC) and modified-Hausdorff distance (MHD) were used to quantify the geometric similarity of the outlines. We also compared results after an intermediate stage of the algorithm vs the complete algorithm. Reproducibility and the least amount of detectable change in plaque volume were computed for each method. Intraobserver and interobserver metrics for each method were computed using the intraclass correlation coefficient (ICC), coefficient of variability (CV), minimum detectable change (MDC), and standard error of measurement (SEM) of the VWV. Plaque volume estimates obtained from the semiautomatic algorithm were accurate compared with manual outlining. The Pearson correlation coefficient was 0.76 (P < .001), and measurements were geometrically similar (DSC, 0.85; MHD, 0.48 mm). The algorithm was more reproducible and reliable and could detect smaller changes in plaque volume on repeat imaging (low interobserver variability: ICC, 0.9; CV, 8.22%; MDC, 5.57%; SEM, 1.45%; DSC, 0.88; MHD, 0.43 mm). Intraobserver variability was even lower (ICC, 0.9; CV, 8%; MDC, 3.62%; SEM, 1.31%; DSC, 0.89; MHD, 0.37 mm). Plaque volume estimates at the intermediate stage of the algorithm matched results from the full algorithm (Pearson correlation coefficient, 0.76; DSC, 0.84; MHD, 0.52 mm). The intermediate approach, however, was less reliable than the full algorithm (interobserver: ICC, 0.81; CV, 11.7%; MDC, 9.58%; SEM, 3.46%; DSC, 0.88; MHD, 0.42 mm; intraobserver: ICC, 0.87; CV, 8.6%; MDC, 4.55%; SEM, 1.64%; DSC, 0.89; MHD, 0.38 mm). The full algorithm required ∼14 minutes to implement. However, a quick (7 minutes) and accurate assessment of VWV can be obtained by running only the intermediate stage of the algorithm, although with a loss in repeatability and reliability. We present a unique algorithm to perform semiautomatic quantification of carotid plaque volume using 3DUS imaging. It is quick (mean time, 14 minutes), accurate, repeatable, and implementable in a clinical environment and in longitudinal studies tracking plaque progression. It reliably detects plaque volume changes as low as 4% to 6% with 95% confidence.


Food Basket Foundation International: Profile, mission statement and activities.
The Food Basket Foundation International (FBFI) is an indigenous non-governmental organization (NGO) which was set up to assist low income families, especially those from vulnerable groups, achieve nutrition security on a sustainable basis. The Foundation was formed in 1988 by a group of professionals in nutrition, communication, medicine, the social sciences (economics, sociology, psychology), law and agriculture, based on the recognition that governments' efforts at providing basic needs to the poor and guaranteeing them opportunities to adequately feed themselves and their families contained a missing link between program planning and implementation. Food Basket Foundation International was registered in March 1989 under the Land Perpectual Succession Act CAP 98. The fundamental objective of the FBFI is to create appropriate awareness among members of the public in an effort to influence government policies and programs to sustain the development of the grassroots. In addition, the Foundation initiates, and cooperates with, community-based organizations to bring about social and economic changes based on improvement in the traditional systems with which people are familiar for the attainment of food and nutrition security within a sustainable livelihood system.


Using Field Based Data to Model Sprint Track Cycling Performance.
Cycling performance models are used to study rider and sport characteristics to better understand performance determinants and optimise competition outcomes. Performance requirements cover the demands of competition a cyclist may encounter, whilst rider attributes are physical, technical and psychological characteristics contributing to performance. Several current models of endurance-cycling enhance understanding of performance in road cycling and track endurance, relying on a supply and demand perspective. However, they have yet to be developed for sprint-cycling, with current athlete preparation, instead relying on measures of peak-power, speed and strength to assess performance and guide training. Peak-power models do not adequately explain the demands of actual competition in events over 15-60 s, let alone, in World-Championship sprint cycling events comprising several rounds to medal finals. Whilst there are no descriptive studies of track-sprint cycling events, we present data from physiological interventions using track cycling and repeated sprint exercise research in multiple sports, to elucidate the demands of performance requiring several maximal sprints over a competition. This review will show physiological and power meter data, illustrating the role of all energy pathways in sprint performance. This understanding highlights the need to focus on the capacity required for a given race and over an event, and therefore the recovery needed for each subsequent race, within and between races, and how optimal pacing can be used to enhance performance. We propose a shift in sprint-cyclist preparation away from training just for peak power, to a more comprehensive model of the actual event demands.


Chylous ascites in cats: nine cases (1978-1993).
Medical records of 9 cats with chylous ascites that underwent exploratory celiotomy were reviewed. In 7 cats, chylous ascites was associated with intra-abdominal neoplasia: 4 cats had an unresectable tumor (hemangiosarcoma, 3 cats; paraganglioma, 1 cat) within the mesenteric root; 2 had malignant lymphoma of the small intestine and mesenteric lymph nodes; and 1 had lymphangiosarcoma of the abdominal wall. In 2 cats, chylous ascites was associated with nonneoplastic diseases: 1 cat had severe biliary cirrhosis and an extrahepatic portosystemic shunt; the other had steatitis caused by vitamin E deficiency. Three cats were euthanatized or died at the time of surgery, and 5 cats were euthanatized within 3 months of surgery. One cat with malignant lymphoma responded well to chemotherapy and lived for 14 months after surgery.


Postoperative desogestrel for pelvic endometriosis-related pain: a randomized controlled trial.
To determine the effectiveness of desogestrel for relieving endometriosis-related pain. A double-blinded randomized placebo-controlled trial was conducted in 40 patients who had endometriosis with moderate-to-severe dysmenorrhea or chronic pelvic pain undergoing laparoscopic conservative surgery. After surgery, patients were randomized to desogestrel or placebo group. Outcomes included changes in visual analog scale (VAS) of dysmenorrhea, pelvic pain and dyspareunia, patient satisfaction, and adverse effects. Forty patients were randomized to desogestrel group (n = 20) and placebo group (n = 20). At month 6, the desogestrel group had significantly lower median VAS of overall pelvic pain, dysmenorrhea and noncyclic pelvic pain. Comparing with the placebo group, the desogestrel group had greater reduction in VAS of overall pain, dysmenorrhea and pelvic pain, but comparable reduction in VAS of dyspareunia. No patient in the desogestrel group but 4 patients in the placebo group still had moderate-to-severe pelvic pain at 6 months postoperatively. The proportion of patients who rated the treatment as very satisfied was higher in the desogestrel group than in the placebo group. There was no serious adverse event during the study period. Desogestrel is effective and acceptable for postoperative therapy for patients with moderate-to-severe pain related to endometriosis.


Upconversion NaYF4:Yb3+/Er3+@silica-TPGS Bio-Nano Complexes: Synthesis, Characterization, and In Vitro Tests for Labeling Cancer Cells.
Fluorescence imaging is an important technique used for early diagnosis and effective treatment of some incurable diseases including cancer. Herein, we report novel NaYF4:Yb3+/Er3+@silica-TPGS bio-nano complexes for labeling cancer cells. The NaYF4:Yb3+/Er3+ nanoparticles have been successfully synthesized via a hydrothermal route, further coated with a silica shell, and functionalized with d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). The experimental results indicate that NaYF4:Yb3+/Er3+@silica-TPGS emits stronger upconversion luminescence than NaYF4:Yb3+/Er3+ under an excitation of 980 nm. More significantly, the NaYF4:Yb3+/Er3+@silica-TPGS bio-nano complexes could strongly label MCF-7 breast cancer cells for in vitro experiments detected by a fluorescence microscope. On the other hand, the complex could not typically probe healthy cells, which are HEK-293A human embryonic kidney cells, under the same experimental conditions. Because of their strong upconversion luminescence, good dispersibility, and biocompatibility, NaYF4:Yb3+/Er3+@silica-TPGS bio-nano complexes can be a promising candidate/probe for biomedical labeling and diagnostics.


[Influence factors of carotid endarterectomy improving vascular cognitive impairment].
Objective: To investigate the influence factors of carotid endarterectomy(CEA) improving cognitive function in patients with carotid stenosis. Methods: The clinical data of carotid stenosis patients with cognitive impairment who underwent CEA in Nanjing Drum Tower Hospital and the First People's Hospital of Lianyungang from December 2011 to July 2017 were retrospectively analyzed. One week before operation, carotid CT angiography and cranial magnetic resonance imaging were performed, and the cognitive function of patients was evaluated with Montreal Cognitive Scale (MoCA). The magnetic resonance imaging and MoCA were reexamined 4 weeks after the procedure. The patients were divided into improved group (COI+) and un-improved group (COI-) according to whether the cognitive function score was improved or not after operation. The general data, carotid artery occlusiontime, surgical site, preoperative carotid calcification score (CS) and the Fazekas score, pre-operative and post-operative cerebral perfusion parameters, like mean transit time(MTT), time to peak(TTP) and arrivetime (T0), and any new infarcts after operation between the two groups were compared. Results: A total of 70 patients were selected, including 50 patients in group COI+ and 20 patients in group COI-. There were no significant differences in age, gender, hypertension, diabetes mellitus, smoking and drinking habits, as well as in carotid artery occlusiontime and preoperative Fazekas score between the two groups (all P>0.05). The preoperative carotid artery calcification scores of the two groups were 469.75±50.86 and 393.51±77.41, respectively. The changes of pre-and post-operation perfusion parameters between the two groups were statistically significant, with ΔMTT were 7.79±9.51 and 3.03±6.40, ΔTTP were 5.83±8.98 and 1.17±4.77, T0 were 5.89±8.08 and 3.05±5.95, respectively(t=4.844, 2.053, 2.192 and 1.423, respectively, all P<0.05). Proportion of cases with new infarcts after operation(0.38 vs 0.65) or undergoing left CEA (0.66 vs 0.40)between the two groups was statistically different (χ(2)=4.197 and 9.677, respectively, both P<0.05). Conclusion: Higher preoperative CS score, undergoing left CEA, significantly improved cerebral perfusion and without new infarct postoperatively, are independent factors contributing to improving cognitive function through CEA operation.


Antiapoptotic and chemotaxis-stimulating effects of poly (D, L-lactide-co-glycolide)-chitosan and whey proteins against aflatoxicosis-induced splenic and thymic atrophy.
Aflatoxin B (AFB) induces toxicological effects on the liver and immune organs. The whey proteins can modulate the immune response during aflatoxicosis. Our work evaluates the novel polylactic acid-glycolic acid-chitosan-encapsulated bovine and camel whey proteins against AFB-induced thymic and splenic atrophy in rats. Seventy adult male Wister albino rats were divided into a control healthy group (G1) and six AFB1-intoxicated groups (G2-G7). One of the following supplements: distilled water, camel whey proteins (CWP), bovine whey proteins, poly (D, L-lactide-co-glycolide) (PLGA)- chitosan-loaded with camel whey protein microparticles (CMP), PLGA-chitosan loaded with bovine whey protein microparticles (BMP), and PLGA-chitosan nanoparticles were administered as prophylactic supplements to AFB1-intoxicated groups. The AFB-treated group showed significantly higher hepatic levels of oxidative stress and lower levels of antioxidants. In the aflatoxicated group, atrophy of the splenic lymphatic nodules and disfigurement in the organisation with an apparent decrease in the thickness of the cortex in the thymus were observed, as well as a decrease in splenic and thymic CD4+T and CD8+T lymphocytes. Moreover, CXCL12 levels were downregulated, whereas tumour necrosis factor-alpha, nuclear factor kappa B, and cleaved caspase-3 levels were upregulated. CWP, BMP, and CMP supplements markedly decreased oxidative stress, inflammation, and apoptosis, as well as significantly raised CXCL12, CD4+T, and CD8+T cells. The CWP, BMP, and CMP supplements rescue the liver and immune tissues from the toxic effects of AFB through their antioxidant, antiapoptotic, anti-inflammatory, and chemotaxis-enhancing roles.


Safety of endobronchial biopsy in children with cystic fibrosis.
There is little found in the published literature regarding the use of endobronchial biopsy (EBB) in children with cystic fibrosis (CF). One concern over the use of the technique may relate to safety, in particular increased risk of bleeding from a hypertrophied bronchial circulation. The aim of this retrospective study was to compare the safety of EBB in children with CF and those with other conditions, the most frequent of which included primary ciliary dyskinesia and recurrent lower respiratory tract infections. Case notes of all children undergoing EBB in our institution between February 2003 and May 2004 were reviewed. EBB was performed during 45 bronchoscopies in 42 CF patients (19 males, group mean age 7.13 +/- 4.48 years) and in 39 controls (20 males, group mean age 6.59 +/- 4.48 years). There were no significant differences between disease groups in the number, type, or severity of complications occurring during or in the first 12 hr after the procedure. We conclude that EBB performed as part of fibreoptic bronchoscopy (FOB) under general anaesthesia can be performed safely in children with CF, when both bronchoscopist and anaesthetist are suitably experienced. Studies of such samples would allow us to determine the early pathological changes in the CF airway and possibly find new treatments to prevent the progression to bronchiectasis and end stage airway destruction.


The long road to employment: Incivility experienced by job seekers.
This study addresses how job seekers' experiences of rude and discourteous treatment--incivility--can adversely affect self-regulatory processes underlying job searching. Using the social-cognitive model (Zimmerman, 2000), we integrate social-cognitive theory with the goal orientation literature to examine how job search self-efficacy mediates the relationship between incivility and job search behaviors and how individual differences in learning goal orientation and avoid-performance goal orientation moderate that process. We conducted 3 studies with diverse methods and samples. Study 1 employed a mixed-method design to understand the nature of incivility within the job search context and highlight the role of attributions in linking incivility to subsequent job search motivation and behavior. We tested our hypotheses in Study 2 and 3 employing time-lagged research designs with unemployed job seekers and new labor market entrants. Across both Study 2 and 3 we found evidence that the negative effect of incivility on job search self-efficacy and subsequent job search behaviors are stronger for individuals low, rather than high, in avoid-performance goal orientation. Theoretical implications of our findings and practical recommendations for how to address the influence of incivility on job seeking are discussed.


[Sharing information of urological cancer patient in terminal stage using Cybozulive® for home medical care].
It is very important to share patient information because home patient care involves several different specialties of care. We introduced Cybozulive ® , a cloud-based free groupware, for 14 terminal-stage patients with urological cancer to share information among doctors and co-medical staff. This system enables access to patient information regardless of time and place. Of the 14 patients (mean age 74.4 years), 11 died of cancer. The average period in which Cybozulive® was used for the patients was 210 days. The average number of entries to the electronic bulletin board in this period was 88.4. We were able to obtain more information about the patients from the website. There was no difference in the average number of times that the patient consulted the out patient clinic before and after the introduction of Cybozulive® (before 7.0 ; after 6.3). After introduction of this system, eleven patients were hospitalized in our department 21 times. Eighteen of these 21 times, since we had acquired patient information from the website beforehand, there was a quick response for management of the emergency admission. This system could be used to construct a network for home care and may be helpful for sharing patient information in homecare.


Smartphone addiction among university students in Riyadh, Saudi Arabia.
To investigate the prevalence and correlates of smartphone addiction among university students in Saudi Arabia. This cross-sectional study was conducted in King Saud University, Riyadh, Kingdom of Saudi Arabia between September 2014 and March 2015. An electronic self administered questionnaire and the problematic use of mobile phones (PUMP) Scale were used. Out of 2367 study subjects, 27.2% stated that they spent more than 8 hours per day using their smartphones. Seventy-five percent used at least 4 applications per day, primarily for social networking and watching news. As a consequence of using the smartphones, at least 43% had decrease sleeping hours, and experienced a lack of energy the next day, 30% had a more unhealthy lifestyle (ate more fast food, gained weight, and exercised less), and 25% reported that their academic achievement been adversely affected. There are statistically significant positive relationships among the 4 study variables, consequences of smartphone use (negative lifestyle, poor academic achievement), number of hours per day spent using smartphones, years of study, and number of applications used, and the outcome variable score on the PUMP. The mean values of the PUMP scale were 60.8 with a median of 60. University students in Saudi Arabia are at risk of addiction to smartphones; a phenomenon that is associated with negative effects on sleep, levels of energy, eating habits, weight, exercise, and academic performance.


Transellar intercavernous carotid anastomosis with agenesis of internal carotid artery and right-sided descending aorta: case report.
We report a patient with a transellar intercavernous carotid anastomosis associated with right-sided descending aorta and agenesis of the internal carotid artery. To our knowledge, such an association has not been reported previously. Findings at angiography, computed tomography (CT) and dynamic CT are presented. We suggest that dynamic CT is not a reliable method of excluding this anomaly, a fact that has relevance to investigation prior to transphenoidal surgery for pituitary adenoma.


Development of Liposomal Forms of Modified Pyrimidine Nucleosides and Investigation of Their Antibacterial Properties.
Different phosphocholine-cardiolipin-2'-deoxyuridine inclusion complexes were developed, that allowed to compose a water-soluble form of nucleoside analogues with previously defined antituberculosis activity. It was found that the resulting liposomes effectively penetrated to the cells. The increase of cytotoxicity was undoubtedly indicative of accumulation of the nucleoside in the cell culture. The result proved the ability of the liposomes for delivery of the low-soluble compounds to the cells for further investigation of their efficacy. It was shown that treatment of the bacterial cells with the llposomes of the modified nucleosides did not affect the bacterial growth.


Congenital dislocation of the hip--diagnostic screening and treatment. A comparative study of two populations of infants and children.
To understand why congenital dislocated hip (CDH) was diagnosed late (mean age: nine months) in children admitted to the Children's Hospital of Philadelphia (CHOP), 714 consecutive CHOP admissions, aged zero to two years, and 947 consecutive newborns delivered at the Hospital, University of Pennsylvania (HUP) were examined for CDH. The expected frequency of CDH was found at HUP. At CHOP, the children had a higher incidence of CDH, many with associated congenital anomalies, their hips were more difficult to examine, the hospital records contained few references to hip examinations. Had these children's hips been formally examined at birth, the delay in diagnosis might have been eliminated and treatment might have been easier and more successful.


[Search for antiamyloidogenic compounds based on a nucleation-dependent polymerization model].
We have proposed that a nucleation-dependent polymerization model could explain the general mechanisms of amyloid fibril formation in vitro. Based on this model, we systematically demonstrated that several classes of organic compounds (e.g., wine-related polyphenols, non-steroidal anti-inflammatory drugs) not only inhibit the formation of Abeta amyloid fibrils from Abeta and their extension, but also destabilize Abeta amyloid fibrils dose-dependently in vitro. We found significant positive correlations of the effective concentrations (EC(50)) of these compounds ranging from 10 nM to 10 microM, for the formation and destabilization of Abeta amyloid fibrils. We next investigated the anti-amyloidogenic effects of five flavonoids on Abeta amyloid fibrils in vitro. Oxidized flavonoids generally inhibited fibril formation significantly more potently than fresh compounds. By surface plasmon resonance (SPR) analysis, distinct association and dissociation reactions of myricetin (Myr) to Abeta amyloid fibrils were observed, in contrast to the very weak binding to the Abeta monomer. A significant decrease in the rate of fibril extension was observed when>0.5 microM of Myr was injected into the SPR experimental system. These findings suggest that flavonoids, especially Myr exert an anti-amyloidogenic effect in vitro by preferentially and reversibly binding to the amyloid fibril structure of fibrils, rather than to Abeta monomers. This working model should prove useful not only for the rational development of preventive and therapeutics for Alzheimer's disease and other human amyloidosis, but also for understanding the basic mode of action of amyloid imaging compounds.


CuZn superoxide dismutase in the hippocampus and brain cortex of rats exposed to various stress conditions.
The CuZn superoxide dismutase (CuZnSOD) protein expression in hippocampus and brain cortex of Wistar male rats exposed to acute, chronic, or combined stress was followed by Western immunoblotting. The CuZnSOD was significantly induced by acute stressors but not by chronic or combined stress conditions. As CuZnSOD expression is regulated by stress steroids, the lack of SOD upregulation under chronic stress and its moderate upregulation in combined stress may lead to inefficient ROS defense and increased oxidative damage of brain tissues under the stress conditions.


Multiplex serum protein analysis reveals potential mechanisms and markers of response to hyperimmune caprine serum in systemic sclerosis.
Hyperimmune caprine serum (HICS) is a novel biological therapy with potential benefit for skin in established diffuse cutaneous systemic sclerosis. Here we report multiplex protein analysis of blood samples from a placebo-controlled phase II clinical trial and explore mechanisms of action and markers of response. Patients were treated with HICS (n = 10) or placebo (n = 10) over 26 weeks, with follow-up open-label treatment to 52 weeks in 14 patients. Serum or plasma samples at baseline, 26 and 52 weeks were analysed using multiplex or individual immunoassays for 41 proteins. Patterns of change were analysed by clustering using Netwalker 1.0, Pearson coefficient and significance analysis of microarrays (SAM) correction. Cluster analysis, SAM multiplex testing and paired comparison of individual analytes identified proteins that were upregulated or downregulated during treatment with HICS. There was upregulation of the hypothalamo-pituitary-adrenal axis after HICS treatment evidenced by increases in α-MSH and ACTH in cases treated with HICS. Interestingly, significant increase in PIIINP was associated with HICS treatment and improved MRSS suggesting that this may be a marker of extracellular matrix turnover. Other relevant factors reduced in HICS-treated patients compared with controls, although not reaching statistical significance included COMP, CCL2, IL6, TIMP2, Fractalkine and TGFβ1 levels. Our results suggest mechanisms of action for HICS, including upregulation of α-MSH, that has been shown to be anti-fibrotic in preclinical models, and possible markers to be included in future trials targeting skin in diffuse cutaneous systemic sclerosis. Eudract, No. 2007-003122-24. ClinTrials.gov, No. NCT00769028 . Registered 7 October 2008.


Uncharged Components of Single-Stranded DNA Modulate Liquid-Liquid Phase Separation With Cationic Linker Histone H1.
Liquid-liquid phase separation (LLPS) of proteins and DNAs has been recognized as a fundamental mechanism for the formation of intracellular biomolecular condensates. Here, we show the role of the constituent DNA components, i.e., the phosphate groups, deoxyribose sugars, and nucleobases, in LLPS with a polycationic peptide, linker histone H1, a known key regulator of chromatin condensation. A comparison of the phase behavior of mixtures of H1 and single-stranded DNA-based oligomers in which one or more of the constituent moieties of DNA were removed demonstrated that not only the electrostatic interactions between the anionic phosphate groups of the oligomers and the cationic residues of H1, but also the interactions involving nucleobases and deoxyriboses (i) promoted the generation of spherical liquid droplets via LLPS as well as (ii) increased the density of DNA and decreased its fluidity within the droplets under low-salt conditions. Furthermore, we found the formation of non-spherical assemblies with both mobile and immobile fractions at relatively higher concentrations of H1 for all the oligomers. The roles of the DNA components that promote phase separation and modulate droplet characteristics revealed in this study will facilitate our understanding of the formation processes of the various biomolecular condensates containing nucleic acids, such as chromatin organization.


Effects of dispersed fibres in myocardial mechanics, Part II: active response.
This work accompanies the first part of our study "effects of dispersed fibres in myocardial mechanics: Part I passive response" with a focus on myocardial active contraction. Existing studies have suggested that myofibre architecture plays an important role in myocardial active contraction. Following the first part of our study, we firstly study how the general fibre architecture affects ventricular pump function by varying the mean myofibre rotation angles, and then the impact of fibre dispersion along the myofibre direction on myocardial contraction in a left ventricle model. Dispersed active stress is described by a generalised structure tensor method for its computational efficiency. Our results show that both the myofibre rotation angle and its dispersion can significantly affect cardiac pump function by redistributing active tension circumferentially and longitudinally. For example, larger myofibre rotation angle and higher active tension along the sheet-normal direction can lead to much reduced end-systolic volume and higher longitudinal shortening, and thus a larger ejection fraction. In summary, these two studies together have demonstrated that it is necessary and essential to include realistic fibre structures (both fibre rotation angle and fibre dispersion) in personalised cardiac modelling for accurate myocardial dynamics prediction.


Conjugated linoleic acid reduces body fats and cytokine levels of mice.
In order to discover the effect of CLA on the body fat size and serum cytokine levels, four groups of male mice were fed diets containing either 1% linoleic acid (LA) or conjugated linoleic acid (CLA) with or without 0.2% sesamin for 8 weeks. The weight gain and feed efficiency were significantly lower in the CLA groups. CLA significantly reduced relative weights (g/100 g body weight) of epididymal and perirenal adipose tissues, in particular the former. Concentrations of serum TNF-alpha and leptin were significantly reduced by dietary CLA. Sesamin did not show additional effects in all of these parameters. There was a positive correlation between cytokine production and body-fat reducing potential of CLA. These results indicated that mice appeared to be a hyperresponder to dietary CLA insofar as the reduction of body fat size is concerned.


Catha edulis, an international socio-medical problem with considerable pharmacological implications.
It is evident from the mentioned studies that the medical and psychosocial effects of khat chewing are hazardous both to the individual and the community. The habituation of khat chewing seriously effects the psychoeconomic structure of the subject. Being aware of the increasing prevalence of khat chewing (often together with other drugs), it is essential to assess the health and socio-economic problems of khat habituation in order to take further, appropriate medical and social measures.


Synthesis of human fibroblast interferon by E. coli.
A cDNA library was constructed using mRNA from human fibroblasts induced with poly(I):poly(C). A bacterial clone containing fibroblast interferon cDNA sequences was identified by hybridization to a cDNA probe synthesized using deoxyoligonucleotide primers which hybridize to fibroblast interferon mRNA specifically. Expression plasmids were constructed which permitted the synthesis in E. coli of 8 x 10(7) units of human fibroblast interferon per liter of culture. The bacterially produced fibroblast interferon is indistinguishable from authentic human fibroblast interferon by several criteria.


Secondary malignancies following cancer chemotherapy.
Many agents used in cancer chemotherapy are known carcinogens. However, few secondary malignancies have been definitely linked to chemotherapy, since studies on this problem are complicated by methodological problems. A causal relationship has been established between alkylating agents and leukaemia and between cyclophosphamide and bladder cancer. The risk of leukaemia peaks at 5-10 years after beginning of chemotherapy and declines steadily after its end. The interaction between chemotherapy and radiotherapy has not been fully clarified, nor has the leukaemogenic potency of individual drugs, although combinations without nitrogen mustard seem to entail a lower risk. Other tumours reported at increased incidence, in particular among Hodgkin's disease patients, for whom a carcinogenic effect of chemotherapy seems plausible, are non-Hodgkin's lymphoma and lung cancer. Other secondary solid tumors have also been reported, but for none of them an independent effect of chemotherapy has been demonstrated.


Decreased free d-aspartate levels are linked to enhanced d-aspartate oxidase activity in the dorsolateral prefrontal cortex of schizophrenia patients.
It is long acknowledged that the N-methyl d-aspartate receptor co-agonist, d-serine, plays a crucial role in several N-methyl d-aspartate receptor-mediated physiological and pathological processes, including schizophrenia. Besides d-serine, another free d-amino acid, d-aspartate, is involved in the activation of N-methyl d-aspartate receptors acting as an agonist of this receptor subclass, and is abundantly detected in the developing human brain. Based on the hypothesis of N-methyl d-aspartate receptor hypofunction in the pathophysiology of schizophrenia and considering the ability of d-aspartate and d-serine to stimulate N-methyl d-aspartate receptor-dependent transmission, in the present work we assessed the concentration of these two d-amino acids in the post-mortem dorsolateral prefrontal cortex and hippocampus of patients with schizophrenia and healthy subjects. Moreover, in this cohort of post-mortem brain samples we investigated the spatiotemporal variations of d-aspartate and d-serine. Consistent with previous work, we found that d-aspartate content was selectively decreased by around 30% in the dorsolateral prefrontal cortex, but not in the hippocampus, of schizophrenia-affected patients, compared to healthy subjects. Interestingly, such selective reduction was associated to greater (around 25%) cortical activity of the enzyme responsible for d-aspartate catabolism, d-aspartate oxidase. Conversely, no significant changes were found in the methylation state and transcription of DDO gene in patients with schizophrenia, compared to control individuals, as well as in the expression levels of serine racemase, the major enzyme responsible for d-serine biosynthesis, which also catalyzes aspartate racemization. These results reveal the potential involvement of altered d-aspartate metabolism in the dorsolateral prefrontal cortex as a factor contributing to dysfunctional N-methyl d-aspartate receptor-mediated transmission in schizophrenia.


Preparing for the Next Pandemic: Predicting UV Inactivation of Coronaviruses with Machine Learning.
The epidemic of coronaviruses has posed significant public health concerns in the last two decades. An effective disinfection scheme is critical to preventing ambient virus infections and controlling the spread of further outbreaks. Ultraviolet (UV) irradiation has been a widely used approach to inactivating pathogenic viruses. However, no viable framework or model can accurately predict the UV inactivation of coronaviruses in aqueous solutions or on environmental surfaces, where viruses are commonly found and spread in public places. By conducting a systematic literature review to collect data covering a wide range of UV wavelengths and various subtypes of coronaviruses, including severe acute respiratory syndrome 2 (SARS-CoV-2), we developed machine learning models for predicting the UV inactivation effects of coronaviruses in aqueous solutions and on environmental surfaces, for which the optimal test performance was obtained with R2 = 0.927, RMSE = 0.565 and R2 = 0.888, RMSE = 0.439, respectively. Besides, the required UV doses at different wavelengths to inactivate the SARS-CoV-2 to 1 Log TCID50/mL titer from different initial titers were predicted for inactivation in protein-free water, saliva on the environmental surface, or the N95 respirator. Our models are instructive for eliminating the ongoing pandemic and controlling the spread of an emerging and unknown coronavirus outbreak.