Activation of macrophages and the intestinal immune system by an orally administered decoction from cultured mycelia of Cordyceps sinensis.
The effects of an orally administered hot-water extract (HW) from cultured mycelia of Cordyceps sinensis on the activation of macrophages and the intestinal immune system were studied in mice. The general composition of HW was 83.9% carbohydrate, 11.8% protein, 1.9% lipid and 2.4% ash, and the carbohydrates were mainly composed of glucose, mannose, galactose and arabinose (molar ratio of 1.0:0.8:0.5:0.1). HW stimulated the activation (1.7-fold of the saline control) of macrophages and IL-6 production (1.5-fold) at 2.0 g/kg/day. Analyzing the culture supernatant of Peyer's patch cells from C3H/HeJ mice that had been fed with HW at 1.0 g/kg/day for 7 days indicated that the bone marrow cells had significantly proliferated (1.9-fold). In addition, the amounts of GM-CSF and IL-6 in the culture supernatant of Peyer's patch cells at the same dose were significantly increased (1.8-fold and 2.2-fold, respectively). These results indicate that an oral administration of HW may modulate IL-6 production by the activation of macrophages, and also enhance the secretion of hematopoietic growth factors such as GM-CSF and IL-6 from Peyer's patch cells. Since such cytokines as GM-CSF and IL-6 from Peyer's patch cells act on the systemic immune system, it can be assumed that orally administered HW modulated not only the local but also systemic immune system.


Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease.
In mammalians, toll-like receptors (TLR) signal-transduction pathways induce the expression of a variety of immune-response genes, including inflammatory cytokines. It is therefore plausible to assume that TLRs are mediators in glial cells triggering the release of cytokines that ultimately kill DA neurons in the substantia nigra in Parkinson disease (PD). Accordingly, recent data indicate that TLR4 is up-regulated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in a mouse model of PD. Here, we wished to evaluate the role of TLR4 in the acute mouse MPTP model of PD: TLR4-deficient mice and wild-type littermates control mice were used for the acute administration way of MPTP or a corresponding volume of saline. We demonstrate that TLR4-deficient mice are less vulnerable to MPTP intoxication than wild-type mice and display a decreased number of Iba1+ and MHC II+ activated microglial cells after MPTP application, suggesting that the TLR4 pathway is involved in experimental PD.


Complete absorption of topologically protected waves.
Chiral edge states can transmit energy along imperfect interfaces in a topologically robust and unidirectional manner when protected by bulk-boundary correspondence. However, in continuum systems, the number of states at an interface can depend on boundary conditions. Here we design interfaces that host a net flux of the number of modes into a region, trapping incoming energy. As a realization, we present a model system of two topological fluids composed of counter-spinning particles, which are separated by a boundary that transitions from a fluid-fluid interface into a no-slip wall. In these fluids, chiral edge states disappear, which implies non-Hermiticity and leads to an interplay between topology and energy dissipation. Solving the fluid equations of motion, we find explicit expressions for the disappearing modes. We then conclude that energy dissipation is sped up by mode trapping. Instead of making efficient waveguides, our paper shows how topology can be exploited for applications towards acoustic absorption, shielding, and soundproofing.


Effects of antidepressant treatment on total antioxidant capacity and free radical levels in patients with major depressive disorder.
In this prospective study, we investigated the effects of antidepressant therapy on total antioxidant capacity and free radical levels in patients with major depressive disorder (MDD). We recruited thirty-five first-episode patients who met the criteria of the Fourth Edition of Diagnostic and Statistical Manual of Mental Disorders of MDD and 35 age- and sex-matched healthy controls. Superoxide and hydroxyl radicals were measured to investigate oxidative status and the total radical-trapping antioxidant parameter (TRAP) assay was performed to evaluate antioxidant capacity in healthy controls and in patients before and after receiving a 12-week regimen of sertraline. The severity of depression was evaluated using the 17-item Hamilton Depression Rating Scale (HDRS). Before treatment, the mean HDRS score in patients with MDD was 26.11±4.93. Of the 35 patients with MDD, 19 (54.29%) completed the 12-week treatment regimen and all achieved remission. Patients with MDD had significantly lower TRAP baseline values than healthy controls. After adjusting for age, sex, occupation, education and marital status, we found that HDRS score was negatively correlated with TRAP value and level of superoxide radicals. After treatment, the MDD group demonstrated significantly higher TRAP values and significantly lower levels of superoxide and hydroxyl radicals. In conclusion, MDD patients are accompanied by lowered antioxidant capacity than healthy individuals. Antidepressant treatment for 12 weeks results in increased antioxidant capacity and a decrease in circulating free radicals.


Escape of black holes from the brane.
TeV-scale gravity theories allow the possibility of producing small black holes at energies that soon will be explored at the CERN LHC or at the Auger observatory. One of the expected signatures is the detection of Hawking radiation that might eventually terminate if the black hole, once perturbed, leaves the brane. Here, we study how the "black hole plus brane" system evolves once the black hole is given an initial velocity that mimics, for instance, the recoil due to the emission of a graviton. The results of our dynamical analysis show that the brane bends around the black hole, suggesting that the black hole eventually escapes into the extra dimensions once two portions of the brane come in contact and reconnect. This gives a dynamical mechanism for the creation of baby branes.


Expression of DNA-dependent protein kinase catalytic subunit in laryngeal squamous cell carcinoma and its importance.
The aim of the present study was to explore the expression and distribution of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in tumor tissues and adjacent normal mucosa tissues of patients with laryngeal squamous cell carcinoma (LSCC), and further analyze the association between the expression and the clinicopathological parameters of patients with LSCC. Clinical data of tumor tissues and corresponding adjacent normal mucosa tissues of pathologically diagnosed LSCC in 96 cases were collected in the present study. Of these specimens, the mRNA and protein expression levels of DNA-PKcs in LSCC tissues and the adjacent normal mucosa tissues were analyzed via reverse transcription-quantitative polymerase chain reaction and western blot analysis. Immunohistochemistry was used to detect expression and distribution of DNA-PKcs protein in LSCC tissues and corresponding adjacent normal mucosa tissues. The association between DNA-PKcs expression and the specific clinicopathologic features was evaluated by the χ2 test. Kaplan-Meier and Cox proportional hazards regression models were used to analyze the data. It was revealed that the expression of DNA-PKcs mRNA and protein was significantly higher in LSCC tissues than the adjacent normal mucosa tissues (P<0.05). DNA-PKcs was expressed predominantly in the nucleus. DNA-PKcs expression showed significant correlation with the differentiation degree of LSCC (P<0.05), and changes of DNA-PKcs expression gradually increased with the decrease of the differentiation degree. However, DNA-PKcs expression was not significantly associated with sex, age, lymph node metastasis or TMN stage (P>0.05). Patients with LSCC exhibited higher DNA-PKcs expression had markedly shorter survival than those with lower DNA-PKcs expression. In conclusion, the present results suggested that the expression levels of DNA-PKcs were significantly increased in LSCC tumor tissues than in adjacent normal mucosa. DNA-PKcs expression was correlated with differentiation of LSCC, and may become a novel prognostic marker for patients with LSCC.


Adopting evidence-based practice in clinical decision making: nurses' perceptions, knowledge, and barriers.
Evidence-based practice (EBP) provides nurses with a method to use critically appraised and scientifically proven evidence for delivering quality health care to a specific population. The objective of this study was to explore nurses' awareness of, knowledge of, and attitude toward EBP and factors likely to encourage or create barriers to adoption. In addition, information sources used by nurses and their literature searching skills were also investigated. A total of 2,100 copies of the questionnaire were distributed to registered nurses in 2 public hospitals in Singapore, and 1,486 completed forms were returned, resulting in a response rate of 70.8%. More than 64% of the nurses expressed a positive attitude toward EBP. However, they pointed out that due to heavy workload, they cannot keep up to date with new evidence. Regarding self-efficacy of EBP-related abilities, the nurses perceived themselves to possess moderate levels of skills. The nurses also felt that EBP training, time availability, and mentoring by nurses with EBP experience would encourage them to implement EBP. The top three barriers to adopting EBP were lack of time, inability to understand statistical terms, and inadequate understanding of the jargon used in research articles. For literature searching, nurses were using basic search features and less than one-quarter of them were familiar with Boolean and proximity operators. Although nurses showed a positive attitude toward EBP, certain barriers were hindering their smooth adoption. It is, therefore, desirable that hospital management in Southeast Asia, particularly in Singapore, develop a comprehensive strategy for building EBP competencies through proper training. Moreover, hospital libraries should also play an active role in developing adequate information literacy skills among the nurses.


Patagonian wines: implantation of an indigenous strain of Saccharomyces cerevisiae in fermentations conducted in traditional and modern cellars.
In this work we evaluate the implantation capacity of the selected S. cerevisiae indigenous strain MMf9 and the quality of the produced wines in a traditional (T) and a modern (M) cellar with different ecological and technological characteristics in North Patagonia (Argentina). Red musts were fermented in 10,000 l vats using the indigenous strain MMf9 as well as the respective controls: a fermentation conducted with a foreign starter culture (BC strain) in M cellar and a natural fermentation in T cellar. Since commercial S. cerevisiae starters are always used for winemaking in M cellar and in order to compare the results, natural fermentations and fermentations conducted by the indigenous strain MMf9 were performed at pilot (200 l) scale in this cellar, concomitantly. Thirty indigenous yeasts were isolated at three stages of fermentation: initial, middle and end. The identification of the yeast biota associated to vinifications was carried out using ITS1-5.8S-ITS2 PCR-RFLP. The intra-specific variability of the S. cerevisiae populations was evaluated using mtDNA-RFLP analysis. Wines obtained from all fermentations were evaluated for their chemical and volatile composition and for their sensory characteristics. A higher capacity of implantation of the indigenous MMf9 strain was evidenced in the fermentation carried out in M cellar (80% at end stage) than the one carried out in T cellar (40%). This behaviour could indicate that each cellar differs in the diversity of S. cerevisiae strains associated to wine fermentations. Moreover a higher capacity of implantation of the native starter MMf9 with regard to the foreign (BC) one was also found in M cellar. The selected indigenous strain MMf9 was able to compete with the yeast biota naturally present in the must. Additionally, a higher rate of sugar consumption and a lower fermentation temperature were observed in vinifications conducted by MMf9 strain with regard to control fermentations, producing wines with favourable characteristics. Even when its implantation in T fermentation was lower than that observed in M one, we can conclude that the wine features from MMf9 fermentations were better than those from their respective controls. Therefore, MMf9 selected indigenous strain could be an interesting yeast starter culture in North Patagonian wines.


CREB1-driven expression of miR-320a promotes mitophagy by down-regulating VDAC1 expression during serum starvation in cervical cancer cells.
The altered expression of miRNAs in response to stresses contributes to cancer pathogenesis. However, little is known regarding the mechanism by which cellular stresses drive alterations in miRNA expression. Here, we found that serum starvation enhanced mitophagy by downregulating the mitophagy-associated protein voltage-dependent anion channel 1 (VDAC1) and by inducing the expression of miR-320a and the transcription factor cAMP responsive element binding protein 1(CREB1). Furthermore, we cloned the promoter of miR-320a and identified the core promoter of miR-320a in the upstream -16 to -130 region of pre-miR-320a. Moreover, CREB1 was found to bind to the promoter of miR-320a to activate its expression and to induce mitophagy during serum starvation. Collectively, our results reveal a new mechanism underlying serum starvation-induced mitophagy in which serum starvation induces CREB1 expression, in turn activating miR-320a expression, which then down-regulates VDAC1 expression to facilitate mitophagy. These findings may provide new insights into cancer cell survival in response to environmental stresses.


Dissolution kinetics of nanodispersed gamma-alumina in aqueous solution at different pH: unusual kinetic size effect and formation of a new phase.
The dissolution of a technical, nanodispersed gamma-alumina in water was studied at 25 degrees C in the pH range 3.0 < or = pH < or = 11.0. The obtained kinetic dissolution curves showed a distinct pH dependency, whereas only for pH > or = 4.5 the typical behavior of nanodispersed materials could be observed. X-ray powder diffraction analysis and nitrogen adsorption, as well as IR and UV-Raman spectroscopy, were used to characterize the solid material collected during and at the end of each dissolution experiment. As a result the formation of a new aluminum phase-bayerite-could be proven. The analysis of the equilibrium concentration enabled us to determine the solubility constant of the corresponding phase assuming a pH-dependent species distribution. The rate constants of the dissolution process were evaluated using the model of Gibbs free energy of cluster formation, which considers the size effect, among other things. As a result, we could show that the observed maxima in the concentration profiles are due to a size effect of the starting material having a primary particle radius of 10.1 nm.


Intensified seed spices-based cropping systems for higher productivity, resource-use efficiency, soil fertility and profitability in arid and semi-arid regions of India.
Coriander, fenugreek, nigella etc. are collectively known as seed spices. They are "High value and low volume crops" and considered cash crops for the growers of arid and semi-arid regions of India. Coriander, fenugreek and nigella are grown during the rabi season and take hardly 130-140 days to attain full maturity. In this context, farmers are not able to develop income from available arable land round the year, even though they have sufficient resources as well as manpower. Therefore, coriander, fenugreek and nigella-based cropping systems, four of each (total 12) were evaluated during 3 consecutive years (2019-20 to 2021-22) for their productivity, resource-use efficiency, economics and soil fertility. The results showed that among the seed spices-based cropping systems, maximum system productivity (5193 kg ha-1), production efficiency (18.81 kg ha-1 day-1), water-use efficiency (2.31 kg ha-1 mm-1), economic efficiency (11.85 US $ ha-1 day-1), net return (3270 US $ ha-1), benefit:cost ratio (3.27) and available N (165.6 kg ha-1) were observed under nigella-green coriander-mungbean cropping system. Hence, seed spices growers are recommended to adopt nigella-green coriander-mungbean cropping system in order to realize better productivity, resource-use efficiency, soil fertility and profitability.


Improving Drug Delivery for Alzheimer's Disease Through Nose-to-Brain Delivery Using Nanoemulsions, Nanostructured Lipid Carriers (NLC) and in situ Hydrogels.
Current treatments for Alzheimer's disease (AD) attenuate the progression of symptoms and aim to improve the patient's quality of life. Licensed medicines are mostly for oral administration and are limited by the difficulty in crossing the blood-brain barrier (BBB). Here in, the nasal route has been explored as an alternative pathway that allows drugs to be directly delivered to the brain via the nasal cavity. However, clearance mechanisms in the nasal cavity impair the delivery of drugs to the brain and limit their bioavailability. To optimize nose-to-brain delivery, formulations of lipid-based nanosystems, namely nanoemulsions and nanostructured lipid carriers (NLC), formulated in situ gelling hydrogels have been proposed as approaches for nose-to-brain delivery. These formulations possess characteristics that facilitate drug transport directly to the brain, minimizing side effects and maximizing therapeutic benefits. It has been recommended that the manufacture of these drug delivery systems follows the quality by design (QbD) approach based on nasal administration requirements. This review provides an insight into the current knowledge of the AD, highlighting the need for an effective drug delivery to the brain. Considering the mounting interest in the use of nanoemulsions and NLC for nose-to-brain delivery, a description of drug transport pathways in the nasal cavity and the application of these nanosystems and their in situ hydrogels through the intranasal route are presented. Relevant preclinical studies are summarised, and the future prospects for the use of lipid-based nanosystems in the treatment of AD are emphasized.


A probe in the connection between inflammation, cognition and suicide.
Increased inflammation is linked to suicide risk. However, it is unclear whether increased inflammation drives suicidal crises or is a trait associated with lifetime suicidal behavior. Limited data exist on the sources of increased inflammation observed in suicidal patients and on its downstream effects. To examine factors associated with inflammation and with suicidal ideation severity in acutely suicidal depressed patients. Fifty-two adult depressed patients of both sexes hospitalized for severe suicidal ideation were characterized for suicidality, depression, anxiety, medical comorbidity, psychological and physical pain, impulsivity, verbal fluency, C-reactive protein (CRP) and interleukin (IL) 6. Two generalized linear models were performed with either CRP or suicidal ideation severity as dependent variables. CRP levels were positively associated with age, body mass index (BMI), IL6, current physical pain and number of lifetime suicide attempts. Suicidal ideation severity was not significantly correlated with either CRP or IL6. Suicidal ideation severity was positively associated with female sex, presence of an anxiety disorder, current physical pain, number of lifetime suicide attempts and with delay discounting for medium and large losses. Increased inflammation is not associated with acute suicidal risk, but seems to represent a trait associated with lifetime suicidal behavior.


ApoD mediates binding of HDL to LDL and to growing T24 carcinoma.
Apolipoprotein (Apo) D is an important protein produced in many parts of the body. It is necessary for the development and repair of the brain and protection from oxidative stress. The purpose of this study was to investigate the extent to which apoD interacts with lipoproteins in human plasma. By using detergent-free ELISA, we show that immobilized monoclonal antibodies against apoD very efficiently bind to low density lipoprotein (LDL) from plasma; this binding is as equally efficient as binding to an anti-apoB monoclonal antibody. Adding detergent to the plasma inhibited the binding, suggesting that the binding is dependent on the presence of intact lipoprotein particles. Reversing the system by using immobilized anti-apoB revealed that the affinity of apoD for LDL is rather low, suggesting that multiple bindings are needed for a durable connection. Biosensor experiments using purified lipoproteins also showed that purified apoD and high density lipoprotein 3 (HDL3), a lipoprotein fraction rich in apoD, were both able to bind LDL very efficiently, indicating that the HDL3-LDL interaction may be a physiological consequence of the affinity of apoD for LDL. Furthermore, we found that apoD increases the binding of HDL to actively growing T24 bladder carcinoma cells but not to quiescent, contact-inhibited, confluent T24 cells. This result is especially intriguing given that the T24 supernatant only contained detectable levels of apoD after growth inhibition, raising the possibility that alternating the expression of apoD and a putative apoD-receptor could give direction to the flow of lipids. In the current paper, we conclude that apoD mediates binding of HDL to LDL and to growing T24 carcinomas, thereby highlighting the importance of apoD in lipid metabolism.


Acquired prosopagnosia: structural basis and processing impairments.
Cognitive models propose a hierarchy of parallel processing stages in face perception, and functional neuroimaging shows a network of regions involved in face processing. Reflecting this, acquired prosopagnosia is not a single entity but a family of disorders with different anatomic lesions and different functional deficits. One classic distinction is between an apperceptive variant, in which there is impaired perception of facial structure, and an associative/amnestic variant, in which perception is relatively intact, with subsequent problems matching perception to facial memories, because of either disconnection or loss of those memories. These disorders also have to be distinguished from people-specific amnesia, a multimodal impairment, and prosop-anomia, in which familiarity with faces is preserved but access to names is disrupted. These different disorders can be conceived as specific deficits at different processing stages in cognitive models, and suggests that these functional stages may have distinct neuroanatomic substrates. It remains to be seen whether a similar anatomic and functional variability is present in developmental prosopagnosia.


Knowledge, attitudes and practices and fear of COVID-19 among medical students in Serbia.
The outbreak of the disease caused by the novel coronavirus, SARS-CoV-2 named COVID-19 has spread throughout the world. The number of registered cases is increasing and almost no country or territory worldwide has been without any COVID-19 patient. The aim of this study was to examine the level of knowledge on the SARS-COv-2 and COVID-19 among medical students and to explore the differences in attitudes, practices and fear of COVID-19 among students with sufficient and students with insufficient knowledge. The cross-sectional study among the 1,722 medical students was conducted through an online platform of the Faculty of Medicine, University of Belgrade. The instrument used was a questionnaire with sections on socio-demographic characteristics, knowledge, attitudes and practices towards COVID-19 and the Fear of COVID-19 scale. Total of 1576 (91.50%) students were in the sufficient knowledge group. The multivariate logistic regression analysis showed that there was a significant association between the sufficient knowledge on COVID-19 and female sex (OR = 1.70, 95% CI = 1.18-2.45), age (OR = 1.10, 95% CI = 1.02-1.18), considering the preventive measures enforced in Serbia as good (OR = 2.57, 95% CI = 1.18-5.56), wearing the surgical mask outside of the household in the past 14 days (OR = 1.87, 95% CI = 1.22-2.87) and score on Fear of COVID-19 scale (OR = 0.94, 95% CI = 0.91-0.98). Medical students showed good knowledge of COVID-19 and could be a part of the promotion of health education messages as a part of preventive measures.


Suppression of retinoic acid receptor beta in non-small-cell lung cancer in vivo: implications for lung cancer development.
Retinoids, analogues of vitamin A, are required for the normal growth and differentiation of human bronchial epithelium. They are also able to reverse premalignant lesions and prevent second primary tumors in some patients with non-small-cell lung cancer (NSCLC). These effects are thought to result from modulation of cell growth, differentiation, or apoptosis (programmed cell death). When certain retinoid receptors in the cell nucleus (i.e., retinoic acid receptors [RARs] and retinoid X receptors [RXRs]), which mediate most retinoid actions, are suppressed, abnormal activity may result that could enhance cancer development. This study was designed to determine whether there are abnormalities in the expression of retinoid receptors in surgical specimens from patients with NSCLC. Transcripts of nuclear retinoid receptors were detected in formalin-fixed, paraffin-embedded specimens by use of digoxigenin-labeled riboprobes specific for RAR alpha, RAR beta, RAR gamma, RXR alpha, RXR beta, and RXR gamma for in situ hybridization to histologic specimens from 79 patients with NSCLC and as control from 17 patients with non-lung cancer. The quality and specificity of the digoxigenin-labeled probes were determined by northern blotting, and the specificity of the binding of antisense riboprobes was verified by use of sense probes as controls. All receptors were expressed in at least 89% of control normal bronchial tissue specimens from 17 patients without a primary lung cancer and in distant normal bronchus specimens from patients with NSCLC. RAR alpha, RXR alpha, and RXR gamma were expressed in more than 95% of the NSCLC specimens. In contrast, RAR beta, RAR gamma, and RXR beta expression was detected in only 42%, 72%, and 76% of NSCLC, respectively. These data suggest that the expression of RAR alpha, RXR alpha, and RXR gamma is not altered in NSCLC; however, expression of RAR beta and possibly also of RAR gamma and RXR beta is suppressed in a large percentage of patients with lung cancer. The loss of expression of one or more of these nuclear retinoid receptors may be associated with lung carcinogenesis.


Feasibility and accuracy of a robotic guidance system for navigated spine surgery in a hybrid operating room: a cadaver study.
The combination of navigation and robotics in spine surgery has the potential to accurately identify and maintain bone entry position and planned trajectory. The goal of this study was to examine the feasibility, accuracy and efficacy of a new robot-guided system for semi-automated, minimally invasive, pedicle screw placement. A custom robotic arm was integrated into a hybrid operating room (OR) equipped with an augmented reality surgical navigation system (ARSN). The robot was mounted on the OR-table and used to assist in placing Jamshidi needles in 113 pedicles in four cadavers. The ARSN system was used for planning screw paths and directing the robot. The robot arm autonomously aligned with the planned screw trajectory, and the surgeon inserted the Jamshidi needle into the pedicle. Accuracy measurements were performed on verification cone beam computed tomographies with the planned paths superimposed. To provide a clinical grading according to the Gertzbein scale, pedicle screw diameters were simulated on the placed Jamshidi needles. A technical accuracy at bone entry point of 0.48 ± 0.44 mm and 0.68 ± 0.58 mm was achieved in the axial and sagittal views, respectively. The corresponding angular errors were 0.94 ± 0.83° and 0.87 ± 0.82°. The accuracy was statistically superior (p < 0.001) to ARSN without robotic assistance. Simulated pedicle screw grading resulted in a clinical accuracy of 100%. This study demonstrates that the use of a semi-automated surgical robot for pedicle screw placement provides an accuracy well above what is clinically acceptable.


The role of two conserved amino acids, glutamine 90 and asparagine 137, in O6-methylguanine-DNA methyltransferase stability, activity and substrate specificity.
To assess the possibility that two conserved amino acids (glutamine 90 and asparagine 137) in O6-methylguanine-DNA methyltransferase (MGMT) are involved in protein-substrate contact and/or discrimination between favored and non-favored substrates, families of proteins mutant at these two sites were expressed in alkyltransferase-deficient bacteria and analyzed for stability, ability to repair O6-methylguanine (MG)-containing DNA, and ability to differentially repair a preferred (MG-containing DNA) versus a non-preferred (free base MG) substrate. All seven proteins mutant at glutamine 90 (except a proline mutant) were stable in bacteria and repaired MG-containing DNA (> 50% of wild-type levels). A representative glutamine 90 mutant protein was not, however, significantly different from the wild-type protein in the preferential repair of MG-containing DNA versus MG free base. Of eight proteins mutant at asparagine 137, only glutamine and serine mutants repaired MG-containing DNA to any degree (8.5% and 0.8% of wild-type respectively) and only the glutamine mutant protein was detectable in bacterial sonicates by Western blot analysis. Alanine and leucine mutant alkyltransferases, inactive and unstable as non-fusion proteins, could, however, be stably expressed in bacteria as glutathione S-transferase fusion proteins, although the proteins were still inactive in repair. These results suggest that while glutamine 90 has no direct role in MG-DNA methyltransferase-mediated repair or free base/lesioned DNA substrate specificity, asparagine 137 is important in both the stability and activity of the protein and may contribute to the formation or function of the active site of the protein.


Metal free TBHP-promoted intramolecular carbonylation of arenes via radical cross-dehydrogenative coupling: synthesis of indenoquinolinones, 4-azafluorenones and fluorenones.
A metal-free, TBHP-promoted economical route is developed via the sp(2) C-H bond functionalization strategy for the synthesis of indenoquinolinones, 4-azafluorenones and fluorenones. Reactions provided excellent yield of the products under mild conditions. We have successfully synthesized 11H-indeno[1,2-b]quinolin-11-one, an antibacterial agent, in excellent yields.


Transgenerational programming of maternal behaviour by prenatal stress.
Peripartum events hold the potential to have dramatic effects in the programming of physiology and behaviour of offspring and possibly subsequent generations. Here we have characterized transgenerational changes in rat maternal behaviour as a function of gestational and prenatal stress. Pregnant dams of the parental generation were exposed to stress from days 12-18 (F0-S). Their daughters and grand-daughters were either stressed (F1-SS, F2-SSS) or non-stressed (F1-SN, F2-SNN). Maternal antepartum behaviours were analyzed at a time when pregnant dams usually show a high frequency of tail chasing behaviours. F1-SS, F2-SNN and F2-SSS groups showed a significant reduction in tail chasing behaviours when compared with controls. The effects of multigenerational stress (SSS) slightly exceeded those of transgenerational stress (SNN) and resulted in absence of tail chasing behaviour. These findings suggest that antepartum maternal behaviour in rats is programmed by transgenerational inheritance of stress responses. Thus, altered antepartum maternal behaviour may serve as an indicator of an activated stress response during gestation.


Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed): in older adults.
Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed) [PCV13] is approved for protection against pneumococcal disease in children aged 6 weeks to 5 years and adults aged ≥50 years. In randomized trials in adults aged 60-64 years (not previously vaccinated with 23-valent pneumococcal polysaccharide vaccine [PPV23]) and ≥70 years (previously vaccinated with PPV23), PCV13 was noninferior to PPV23 in opsonophagocytic assay (OPA) geometric mean titres (GMTs) for all 12 serotypes common to the two vaccines. More PCV13 than PPV23 recipients had ≥4-fold increases in serotype 6A OPA GMTs (serotype 6A is not included in PPV23). PCV13 recipients also had higher OPA GMTs and met superiority criteria for most serotypes. Adults aged 50-59 years had antibody responses to PCV13 that were noninferior to those in adults aged 60-64 years for all included serotypes. PCV13 administered concomitantly with trivalent inactivated influenza vaccine in adults aged 50-59 or ≥65 years produced antibody responses that were noninferior to those following sequential administration, except for influenza strain A/H3N2 and pneumococcal serotype 19F in those aged ≥65 years. Antibody responses were numerically higher with sequential administration, although the clinical significance of this is unknown. Adverse events within 14 days of vaccination were mostly of mild-to-moderate severity, with serious events occurring in 0.2-1.4% of PCV13 and 0.4-1.7% of PPV23 recipients.


Out Come Of Trial Of Scar In Patients With Previous Caesarean Section.
Patients who had one caesarean section were previously not given a trial of scar due to fear of increased morbidity. However, recently there has been a trend to give a trial of labour to patients with a previous caesarean section for a non-recurrent cause. Medical evidence indicates that 60-80% of women can achieve vaginal delivery after a previous lower segment caesarean section. Proper selection of patients for trial of scar and vigilant monitoring during labour will achieve successful maternal and perinatal outcome. The objective of our study is to establish the fact that vaginal delivery after one caesarean section has a high success rate in patients with previous one caesarean section for non-recurrent cause. The study was conducted in Ayub Teaching Abbottabad, Gynae-B Unit. All labouring patients, during the study period of five years, with previous one caesarean section and between 37 weeks to 41 weeks of gestation for a non-recurrent cause were included in the study. Data was recorded on special pro forma designed for the purpose. Patients who had previous classical caesarean section, more than one caesarean section, and previous caesarean section with severe wound infection, transverse lie and placenta previa in present pregnancy were excluded. Foetal macrosomia (wt>4 kg) and severe IUGR with compromised blood flow on Doppler in present pregnancy were also not considered suitable for the study. Patients who had any absolute contraindication for vaginal delivery were also excluded. There were 12505 deliveries during the study period. Total vaginal deliveries were 8790 and total caesarean sections were 3715. Caesarean section rate was 29.7%. Out of these 8790 patients, 764 patients were given a trial of scar and 535 patients delivered successfully vaginally (70%). Women who presented with spontaneous onset of labour were more likely to deliver vaginally (74.8%) as compared to induction group (27.1%). Trial of vaginal birth after caesarean (VBAC) in selected cases has great importance in the present era of the rising rate of primary caesarean section.


Dietary patterns and their associations with glycemic control among type 2 diabetic patients in Jazan, Saudi Arabia: A cross-sectional study.
Diabetes is an important global health concern. According to the World Health Organization, the Kingdom of Saudi Arabia (KSA) has 2.8 to 4.3 million diabetic patients between the ages of 27 to 60 in the year 2022. Medical nutrition therapy an essential component of diabetes management, helps improve diabetes outcomes by assisting patients in achieving a target glycated hemoglobin (HbA1c) level of <7. This study aimed to describe the pattern of food consumption in the study population and determine its association with glycemic control. This was a cross-sectional study among health facility attendees at the Endocrinology and Diabetes Center (EDC) in Jazan, KSA. A total of 315 patients with type 2 diabetes (T2D) were enrolled using a systematic random sampling technique. Sociodemographic and dietary habit information gathered through face-to-face interviews, anthropometric measurements, and HbA1c were collected from medical records. Participants were mostly females (55.6%), and more than half of them were above 50 years of age. More than 90% of the patients had poor HbA1c levels, and 2-thirds of the patients were overweight and obese (43.8% and 37.1%, respectively). The most consumed foods were bread (8 times/week) and coffee/tea and vegetables (7 times per week), and the least consumed was soda beverages (once/week). Multivariate logistic regression revealed that the consumption of fruits (consumed 5 times/week) significantly decreased HbA1c, while the consumption of pastries/pizza (consumed twice/week) significantly increased it. The pattern of consumption of fruits and vegetables in the study population conformed to the recommended levels, and that of fruits showed a statistically significant association with the control of HbA1c. Another food item that has a significant negative effect on HbA1c is pastries/pizza. Further studies that include more potentially confounding variables, such as treatment type, are needed.


[Topping-off surgery versus double-segment fusion for treatment of lumbar degenerative disease with mid-long term follow-up].
Objective: To compare the mid-long term clinical effect of Topping-off surgery and lumbar fusion surgery for two-segmental lumbar degenerative disease. Methods: From March 2009 to March 2012, one hundred and twenty-six consecutive patients (Topping-off surgery and two-segment PLIF surgery) were studied in Orthopedics Department, Beijing Chao-Yang Hospital, Capital Medical University.The VAS and ODI were used to assess clinical symptoms.All patients underwent flexion/extension radiographs examinations before surgery, 1, 2 years and last follow-up postoperatively.Lumbar lordosis, sacral slop, data of Coflex segment and adjacent segment (disc height index, range of motion, foraminal height, foraminal width and Pfirrmann classification of intervertebral disc in MRI) were recorded.The paired double-tailed t test was used to analyze the differences in the results from baseline to each postoperative time point.The paired double-tailed t test was used in both groups to analyze the differences in the results from baseline to each postoperative time point.The Chi-square test was used to evaluate the differences between the incidences of adjacent segment degeneration(ASD) in the groups. Logistic regression analysis was used to analyze risk factors for developing radiographic ASD. Results: In topping-off group, 60 patients, average operation time was (134.5±10.2) min. The average blood loss was (301.5±64.6) ml.In fusion group, 68 patients, average age (58.3±4.6) years.The average follow-up time was (47.5±5.1) months.The average operation time was (158.6±19.3) min (P=0.000). The average blood loss was (413.6±131.3) ml (P=0.000). Sex, age, body mass index and intervertebral disc grading were matched between the two groups.Better improvement in VAS back pain score was noted in the topping-off group over the fusion group (P=0.030). Both groups achieved good recovery in ODI and improvement in VAS leg pain and back pain scores at last follow-up postoperatively.In the Topping-off group, FH increased from 10.5 mm at baseline to 11.8 mm at 1 year after surgery (P=0.000) and then decreased mildly in the third postoperative year, while in the fusion group, showed no significant change at all postoperative time points.In the fusion group, the disc height and FW at the same segment were no significant change after first year follow-up, while ROM was significantly decreased after surgery (P=0.000). Foraminal height, foraminal width and intervertebral disc height of adjacent segment of Coflex implant level were found decreased at the end of the postoperative follow-up, while compared with preoperative data no significant difference (P>0.05). At last follow-up, eight patients (13.3%) in the Topping-off group and eighteen patients (26.5%) in the fusion group developed ASD (P=0.033). Conclusions: Topping-off surgery compared with two-segment lumbar fusion surgery can achieve a good result in cases with pre-existing mild or moderate adjacent segment degeneration, restrict the adjacent segment's range of motion and reduce the adjacent segment degeneration. Under strict indications, Topping-off surgery is an acceptable alternative to fusion surgery for the treatment of two-segment lumbar disease.


Clinical microscopy of the cornea utilizing optical sectioning and a high-numerical-aperture objective.
A doublet contact element was added to a long-working-distance objective to increase the numerical aperture to 0.75 and to maintain the focus during in vivo examination of the eye. Optical sectioning by use of confocal slits permits visualization of weakly scattering structures within the cornea. With photographic film and a 1/60-s exposure time to limit the effect of eye movement, an effective optical section half-thickness of approximately 20 microns was realized. Structures observed in the cornea include epithelial cells (surface, wing, and basal cells), nerve-fiber bundles in the subepithelial region, keratocytes and inflammatory cells in the stroma, and endothelial cells.


Voluntary movement controlled by the surface EMG signal for tissue-engineered skeletal muscle on a gripping tool.
We have developed a living prosthesis consisting of a living muscle-powered device, which is controlled by neuronal signals to recover some of the functions of a lost extremity. A tissue-engineered skeletal muscle was fabricated with two anchorage points from a primary rat myoblast cultured in a collagen Matrigel mixed gel. Differentiation to the skeletal muscle was confirmed in the tissue-engineered skeletal muscle, and the contraction force increased with increasing frequency of electric stimulation. Then, the tissue-engineered skeletal muscle was assembled into a gripper-type microhand. The tissue-engineered skeletal muscle of the microhand was stimulated electrically, which was then followed by the voluntary movement of the subject's hand. The signal of the surface electromyogram from a subject was processed to mimic the firing spikes of a neuromuscular junction to control the contraction of the tissue-engineered skeletal muscle. The tele-operation of the microhand was demonstrated by optical microscope observations.


Does early PET/CT assesment of response to chemotherapy predicts survival in patients with advanced stage non-small-cell lung cancer?
The aim of this study is to determine the prognostic role and the timing of metabolic response to chemotherapy, based on F-fluorodeoxyglucose positron emission tomography (F-FDG-PET), in patients with metastatic non-small-cell lung cancer (NSCLC). The study included 55 patients with metastatic NSCLC that were analyzed in terms of prognostic factors and survival. F-FDG-PET/CT findings were evaluated in patients separated into 3 groups, before and after 1st, 2nd, 3rd cycle of the first line chemotherapy. Metabolic response was assessed according to PET Response Criteria in Solid Tumors (PERCIST 1.0). Among the 55 patients, 34 (62%) died, and 21 (38%) remained alive during a mean follow-up of 13.5 months. Median overall survival (OS) was 11.69 months (range 2-26.80 months) and median progression-free survival (PFS) was 6.27 months (range 1.37-20.43 months). Univariate analysis showed that the only favorable prognostic factor for OS in all the patients was the achievement of metabolic response. Metabolic response according to PERCIST, and weight lose ≤ 5% were also independent favorable prognostic factors predictive of survival in all patients based on multivariet analysis (metabolic response: P=0.002, OR; 1.90, 95% CI 1.26-2.89, and weight lose ≤5%: P=0.022, OR; 2.24, 95% CI 1.12-4.47). Median OS in all patients with partial response (PR)-according to the PERCIST 1.0- was significantly longer than in those with progressive disease (PD) (16.36 months vs 8.14 months, P=0.008). Median OS in the patients with PR was significantly longer than in those with PD based on PET/CT performed after 2nd and 3rd cycles of chemotherapy (18.35 months vs 7.54 months, P=0.012 and 18.04 months vs 7.43 months, P<0.001, respectively), whereas, median OS did not differ significantly between patients with PR and those with PD based on PET/CT performed after the 1st cycle of chemotherapy (8.01 months vs 5.08 months, P=0.290). Metabolic response according to PERCIST and weight loss are independent factors predictive of OS. PET/CT performed after second cycle of chemotherapy may be the earliest predictor of treatment response in patients with advanced stage NSCLC.


Immunogenicity of umbilical cord tissue derived cells.
Umbilical cord tissue provides a unique source of cells with potential for tissue repair. Umbilical cord tissue-derived cells (UTCs) are MHC class I (MHCI) dull and negative for MHC class II (MHCII), but can be activated to increase MHCI and to express MHCII with IFN-gamma stimulation. Mesenchymal stem cells with similar characteristics have been inferred to be nonimmunogenic; however, in most cases, immunogenicity was not directly assessed. Using UTC from Massachusetts General Hospital MHC-defined miniature swine, we assessed immunogenicity across a full MHC barrier. Immunogenicity was assessed by in vitro assays including mixed lymphocyte reaction (MLR) and flow cytometry to detect serum alloantibody. A single injection of MHC-mismatched unactivated UTCs did not induce a detectable immune response. When injected in an inflamed region, injected repeatedly in the same region or stimulated with IFN-gamma prior to injection, UTCs were immunogenic. As clinical cellular repair strategies may involve injection of allogeneic cells into inflamed regions of damaged tissue or repeated doses of cells to achieve the desired benefit, our results on the immunogenicity of these cells in these circumstances may have important implications for optimal success and functional improvement for this cellular treatment strategy for diseased tissues.


Congenital Grouped Albinotic Spots: New Insights on the Pathophysiology Based on Multimodal Retinal Imaging.
The terms "congenital grouped albinotic spots" (CGAS) and "polar bear tracks" refer to a rare, benign retinal disorder of unknown etiology characterized by multiple, predominantly unilateral, variably sized, well-circumscribed, flat white retinal spots organized in groups. To date, very few cases of CGAS have been reported. The authors describe a case of CGAS thoroughly characterized by multimodal imaging over an 8-year follow-up, aiming to provide new insights on the pathophysiology of this entity. This is the first report where a long follow-up combined with up-to-date imaging technology is used to characterize CGAS. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:236-238.].


Effect of dextran on fibrinolysis inhibition activity in the blood after major surgery.
Patients undergoing total hip replacement surgery were given 500 ml of 6% dextran 70 or 5% albumin by intravenous infusion on the third postoperative day when the post-traumatic fibrinolysis inhibition has reached its maximum. The large increase in the fibrinolysis inhibition activity measured by a clot-lysis system was counteracted by the infusion of dextran, whereas the albumin infusion had no such effect. The plasma concentration of antiplasmin (chromogenic substrate assay) and the immunologically determined plasma levels of the primary fibrinolysis inhibitor (alpha2-antiplasmin), alpha2-macroglobulin, alpha2-antitrypsin and plasminogen were not changed after the infusion of dextran. It is hypothesized that dextran exerts its effects partly by interfering with the interaction between the primary fibrinolysis inhibitor, fibrin and plasmin(ogen) and by enhancing the activation rate of plasminogen. This observed effect of dextran may be of importance in the prevention of deep venous thrombosis and pulmonary embolic complications, as well as pulmonary microembolism.


The vascular anatomy of the rat cochlea.
The vascular pattern of the rat cochlea was demonstrated by the aid of Berlin Blue (Prussian Blue) contrast. The vascular anatomy is similar to other mammals. The infrequent occurrence of the vessel of the basilar membrane under the organ of Corti is interesting in respect to its presumed importance for the oxygen supply to the hair cells. In the place where the vessel of the basilar membrane usually lies when present, a large uninjected channel was often seen throughout the cochlea. In the external wall, radiating arterioles supply and collecting venules drain all capillary areas. The vascular pattern of the external wall is well maintained at the basal end but is more sparse in apical parts of the cochlea as in other mammals. The rat cochlea is somewhat more difficult to manipulate than the cochlea in other mammals due to its small size, but the dissection of different parts of the cochlea was achieved without major problems.


Ambient neutron dose equivalent outside concrete vault rooms for 15 and 18 MV radiotherapy accelerators.
In this work, the ambient dose equivalent, H*(10), due to neutrons outside three bunkers that house a 15- and a 18-MV Varian Clinac 2100C/D and a 15-MV Elekta Inor clinical linacs, has been calculated. The Monte Carlo code MCNPX (v. 2.5) has been used to simulate the neutron production and transport. The complete geometries including linacs and full installations have been built up according to the specifications of the manufacturers and the planes provided by the corresponding medical physical services of the hospitals where the three linacs operate. Two of these installations, those lodging the Varian linacs, have an entrance door to the bunker while the other one does not, although it has a maze with two bends. Various treatment orientations were simulated in order to establish plausible annual equivalent doses. Specifically anterior-posterior, posterior-anterior, left lateral, right lateral orientations and an additional one with the gantry rotated 30° have been studied. Significant dose rates have been found only behind the walls and the door of the bunker, near the entrance and the console, with a maximum of 12 µSv h(-1). Dose rates per year have been calculated assuming a conservative workload for the three facilities. The higher dose rates in the corresponding control areas were 799 µSv y(-1), in the case of the facility which operates the 15-MV Clinac, 159 µSv y(-1), for that with the 15-MV Elekta, and 21 µSv y(-1) for the facility housing the 18-MV Varian. A comparison with measurements performed in similar installations has been carried out and a reasonable agreement has been found. The results obtained indicate that the neutron contamination does not increase the doses above the legal limits and does not produce a significant enhancement of the dose equivalent calculated. When doses are below the detection limits provided by the measuring devices available today, MCNPX simulation provides an useful method to evaluate neutron dose equivalents based on a detailed description of linac, patient and bunker.


Ischaemic stroke subtypes and their genetic basis: a comprehensive meta-analysis of small and large vessel stroke.
The extent to which genetic effects on the different subtypes of small (SVD) and large vessel disease (LVD) ischaemic stroke differ remains controversial. A comprehensive genetic meta-analysis of all genes investigated by ischaemic stroke subtype was conducted. Odds ratio (OR) and 95% confidence intervals (CI) were determined for each gene disease association. From the initial search of 526 manuscripts, 5 candidate genes were studied comprising 7,533 cases (LVD 4,181, SVD 3,352) and 9,835 control subjects. There was a preferential association for SVD compared to LVD with ACE/DD (SVD: OR 1.31, 95% CI 0.96-1.79; LVD: OR 1.02, 95% CI 0.82-1.26) and eNOS intron 4 ab polymorphism (SVD: OR 1.41, 95% CI 0.94-2.11; LVD: OR 1.07, 95% CI 0.77-1.49), although statistical significance was not reached. No such preference was observed for MTHFR C677T, ApoE/epsilon4 or PAI-1 4G/5G polymorphism. The overall number of studies and the number of subjects recruited per study in whom stroke subtype was classified were small when compared to previous published work without such phenotype classification. Our findings suggest that genetic effects may differ between small and large vessel subtypes, although the evidence base is small.


Ogmocotyle ailuri (Price, 1954) (Digenea: Notocotylidae) found in the Japanese monkey, Macaca fuscata.
Several dozens of small trematodes were found in the small intestine of a Japanese monkey, Macaca fuscata, that was captured in Sendai City, Miyagi Prefecture, Japan. The trematode was identified as Ogmocotyle ailuri. This is the first case of a Japanese monkey infected with Ogmocotyle trematodes, and a new host record for O. ailuri.


Incorporation, oxidation and pyrolysis of ferrocene into porous silica glass: a route to different silica/carbon and silica/iron oxide nanocomposites.
This work reports the incorporation of ferrocene into a porous silica glass under ambient temperature and atmosphere. After or during the ferrocene incorporation, the spontaneous formation of ferricinium ions was observed by electron paramagnetic resonance (EPR), UV-visible, X-ray absorption near-edge structure (XANES), and 57Fe Mössbauer measurements. It was shown that the oxidation of ferrocene molecules to ferricinium ions was promoted by air and that the Si-O- groups on the surface of the pores act as counteranions. Pyrolysis of the porous glass/ferricinium material under argon atmosphere and variable temperature yields different glass/carbon nanocomposites, which were subsequently treated with an HF solution in order to remove the glassy fraction. The resulting insoluble carbon materials were characterized by transmission electron microscopy (TEM), Raman, and EPR spectroscopy and consisted of amorphous carbon when the pyrolysis was carried out at 900 or 1000 degrees C and of a mixture of carbon nanotubes and carbonaceous materials at a pyrolysis temperature of 1100 degrees C. When the pyrolysis was conducted under air, the incorporated ferricinium forms alpha-Fe2O3, and the resulting material is a transparent and highly homogeneous glass/iron oxide nanocomposite.


Risk stratification personalised model for prediction of life-threatening ventricular tachyarrhythmias in patients with chronic heart failure.
The development of prognostic factors of life-threatening ventricular tachyarrhythmias (VTA) and sudden cardiac death (SCD) continues to maintain its priority and relevance in cardiology. The development of a method of personalised prognosis based on multifactorial analysis of the risk factors associated with life-threatening heart rhythm disturbances is considered a key research and clinical task. To design a prognostic and mathematical model to define personalised risk for life-threatening VTA in patients with chronic heart failure (CHF). The study included 240 patients with CHF (mean-age of 50.5 ± 12.1 years; left ventricular ejection fraction 32.8 ± 10.9%; follow-up period 36.8 ± 5.7 months). The participants received basic therapy for heart failure. The elec-trocardiogram (ECG) markers of myocardial electrical instability were assessed including microvolt T-wave alternans, heart rate turbulence, heart rate deceleration, and QT dispersion. Additionally, echocardiography and Holter monitoring (HM) were performed. The cardiovascular events were considered as primary endpoints, including SCD, paroxysmal ventricular tachycardia/ventricular fibrillation (VT/VF) based on HM-ECG data, and data obtained from implantable device interrogation (CRT-D, ICD) as well as appropriated shocks. During the follow-up period, 66 (27.5%) subjects with CHF showed adverse arrhythmic events, including nine SCD events and 57 VTAs. Data from a stepwise discriminant analysis of cumulative ECG-markers of myocardial electrical instability were used to make a mathematical model of preliminary VTA risk stratification. Uni- and multivariate Cox logistic regression analysis were performed to define an individualised risk stratification model of SCD/VTA. A binary logistic regression model demonstrated a high prognostic significance of discriminant function with a classification sensitivity of 80.8% and specificity of 99.1% (F = 31.2; c2 = 143.2; p < 0.0001). The method of personalised risk stratification using Cox logistic regression allows correct classification of more than 93.9% of CHF cases. A robust body of evidence concerning logistic regression prognostic significance to define VTA risk allows inclusion of this method into the algorithm of subsequent control and selection of the optimal treatment modality to treat patients with CHF.


Semi-synthetic diet versus diet using natural ingredients-Comparative study in female Golden Syrian hamsters.
Semi-synthetic diets (SSD) are recommended and are widely used to carry out experiments in rodents. However, in our experiments planned to carry out generation studies in female Golden Syrian hamsters using semi-synthetic diets, it was observed that the hamsters did not conceive as a result of decreased food intake. In this paper, we present the effects of both semi-synthetic diets and natural source diets (NSD) on food intake, body weight and reproductive performance of this species. Four-week-old female hamsters were equally divided into 3 groups and initially acclimatized for 2 weeks on natural chow diet (NCD). Thereafter, they were fed either control diet, high fat diet (HFD) or low protein diet (LPD) based on semi-synthetic/natural source ingredients until 12 weeks. Daily food intake and weekly body weights were monitored. Hamsters were kept for mating for about 2 weeks from 10th week onwards, during which the pregnancy confirmation test was done using standard vaginal smear examination. In all the groups fed SSD, the food intake was very poor, hamsters lost body weight and did not conceive, thus preventing us from carrying out further experiments. Hamsters fed NCD/NSD ingested more than twice as much as hamsters fed SSD (7-8 g/day/hamster against 3 g/day/hamster on average respectively). Based on the results of the current research, we conclude that the routinely used semi-synthetic diet is not suitable for carrying out studies in female hamsters. We suggest that scientists must also consider the unusual biological characteristics of a given species besides other biological factors. It is therefore critical to select appropriate biological models and diets that provide optimal sensitivity and specificity to accomplish the research objectives.


A novel pressure-driven piezodispenser for nanoliter volumes.
A successful dispensing device has been built for use in biotechnology applications requiring nanoliter volume liquid transfer. Air pressure is used as the primary driving force and is controlled via a high speed miniature solenoid valve as opposed to many existing systems that use a valve in line with constantly pressurized fluid to start and stop the dispensing action. This automated pressure-driven system is used to improve a typical piezodriven microdispenser. The resulting system is much less prone to failures resulting from air entrainment and can dispense much higher viscosity fluids than the microdispenser alone.


Quantitative analysis of basal and interim PET/CT images for predicting tumor recurrence in patients with Hodgkin's lymphoma.
The qualitative analysis of interim PET has been reported to be useful for predicting the outcome of Hodgkin's lymphoma (HL) after chemotherapy. As the next step, our study aims to present a quantitative analysis on the basis of both a basal (PET/CT0) and an interim (PET/CT2) scan to improve the prognostic value of imaging in HL patients. A cohort of 68 patients undergoing a basal and an interim scan with F-fluorodeoxyglucose after two cycles of chemotherapy consisting of adriamycin, bleomycin, vinblastine, and dacarbazine were examined. Two subsets of patients with a positive and a negative interim scan were selected. In patients with a negative scan, a total of 108 lymph node lesions showing a good response to chemotherapy were contoured, whereas in the remaining patients with positive scans, six responder and 12 relapsing lymph node lesions were contoured. Standardized uptake value (SUV) and Hounsfield unit (HU) values were included in the volumes contoured on coregistered basal and interim scans and included in a database. A linear regression model was used to identify the predictor of relapse at the lesion level. The support vector machine analysis and bootstrap approach were used to determine the model capability. The predictive models were presented as nomograms on the basis of basal or both basal and interim studies. SUV at the basal/interim study and basal HU values were predictors of a poor prognosis. In particular, the higher points were associated with lower values of SUV and HU at baseline and the higher values of SUV at the interim study. Using the bootstrap and support vector machine approach, the cut-off of the model increased up to 89%. The novel tool enables estimation of the risk of tumor relapse after chemotherapy in HL patients on the basis of basal and interim PET/CT scans including SUV and densitometric information.


[Personalised antibiotic therapy in a surgical intensive care unit overview of current knowledge and the results of an observational kinetic study].
The current efforts of intensivists focused on individual antibiotic treatment in patients suffering from sepsis has inspired us to conduct an open prospective clinical study to assess the relationship between body fluid retention (>10 L/24 hours) and the efficiency of hydrophilic time-dependent antibiotics used in critically ill patients. Polytrauma and abdominal catastrophes are the most frequent causes of systemic inflammatory response syndrome (SIRS). Consequent body liquid retention is taken for a pathophysiological covariate modifying the pharmacokinetics (PK) and pharmacodynamics (PD) of hydrophilic time-dependent antibiotics (betalactams and carbapenems). Not only body fluid retention but also changes in renal clearance are thought to be responsible for failure in PK/PD target attainment necessary for effective antimicrobial activity. To describe the importance of the pathophysiological covariates for the individual kinetic variables of a representative antibiotic (piperacillin) is the primary goal of this kinetic observational study. Three patients with polytrauma and SIRS admitted at the ICU of the Surgical Department, Teaching Hospital Hradec Králové, whose condition was characterized by cumulative body fluid retention (>10 L), were eligible for enrolment. As per standard hospital protocol, the patients were administered with 4 g of piperacillin in combination with tazobactam 0.5 g intravenously by 1-hour (h) infusion every 8 h. A series of blood samples were taken 1, 2.5, and 5 h after the termination of the infusion. Urine was collected over each dosing interval and for 24 h. Piperacillin was detected using a previously validated HPLC method. Individual pharmacokinetic variables were estimated using non-compartmental pharmacokinetic analysis. Cumulative body fluid retention was calculated as the difference between fluid intake and output. Creatinine clearance (Cl) was used for renal function evaluation. PK/PD target attainment was analysed according to Carlier (2013). In three patients with polytrauma and SIRS, great interindividual and intraindividual differences in extravascular volume expansion, i.e. cumulative body fluid retention 2030 L and changes in renal function, were recorded. In 2/3 patients these pathophysiological changes as well as the clinical interventions administered resulted in augmented piperacillin clearance and an increase in distribution volume (Vd) (>20 L) with a maximum at Day 28 after initiation of therapy. In such patients treated with a standard dose of piperacillin, only minimum PK/PD target attainment (50% Ft >MIC) was obtained. In contrast, a patient suffering from renal dysfunction attained both minimum (50% ft >MIC) and maximum PK/PD target (100% ft >MIC). In three critically ill patients with polytrauma and SIRS, pathophysiological changes (covariates) had a profound effect on the key determinants of the pharmacokinetics (Cl and Vd), resulting in significant intraindividual variability in pharmacodynamic /pharmacokinetic target attainment necessary for therapeutic time-dependent antibacterial activity of piperacillin. Consequently, patients with augmented clearance of piperacillin may be at risk for treatment failure, and/or bacterial resistance without dose up-titration. A subsequent clinical study will be conducted to describe personalised kinetically guided antibiotic therapy.


Phenylephrine suppresses the pain modulation of diffuse noxious inhibitory control in rats.
Diffuse noxious inhibitory control (DNIC) is a phenomenon whereby wide dynamic range neurons are selectively and powerfully inhibited through the central nervous system by noxious stimuli heterotopically applied to a body area distant from their excitatory receptive fields. Previous work has shown that systemic administration of an alpha1-adrenoceptor agonist, phenylephrine (PE), blocked the DNIC. We hypothesized that descending inhibitory pathways mediate the DNIC mechanism and that the neural network of the DNIC loop exists in the middle brainstem, likely in a more rostral part than formerly assumed, possibly the nucleus raphe magnus (RMg). The aim of this study was to determine whether DNIC is directly modulated by PE when administered close to the RMg. The experiments were performed on anesthetized male Sprague-Dawley rats. For administration of different drugs close to the RMg, the tip of a 33-gauge cannula was placed into an area close to the RMg as determined using the atlas of Paxinos and Watson. Single square-wave electrical stimuli were applied to the digits of the left hindpaw. The C-fiber reflex response elicited by electrical stimulation within the receptive field of the ipsilateral sural nerve was recorded from the biceps femoris muscle in the absence and presence of noxious tail immersion in warm water at 50 degrees C. The DNIC effect was calculated from a recorded electromyogram as the "inhibition rate." Saline (0.05 microL) or PE (0.05 microg/0.05 microL) was microinjected close to the RMg through the cannula. The C-fiber reflex evoked by electromyographic activity was recorded the same way. The inhibition rate of the C-fiber reflex was compared before and after administration of drugs. A paired t test was used for statistical comparison between same drug administration groups, and 1-way analysis of variance and Bonferroni multiple comparison were used for statistical analysis between different drugs. At the end of all experiments, the tissue-contacting end of the cannula tip was cauterized with an electric current to localize the drug administration site. The brain was removed, sliced in coronal sections, and stained with hematoxylin and eosin. The C-fiber reflex inhibited by noxious thermal stimuli (DNIC) was significantly blocked after the injection of PE close to the RMg. Direct administration of PE close to the RMg inhibited DNIC, thereby affecting and modulating the intrinsic pain inhibition system. These findings suggest that the RMg may be involved in the regulation of DNIC.


The serine/threonine kinase Nek6 is required for cell cycle progression through mitosis.
The Aspergillus nidulans protein NIMA (never in mitosis, gene A) is a protein kinase required for the initiation of mitosis, whereas its inactivation is necessary for mitotic exit. Here, we demonstrate that human NIMA-related kinase 6 (Nek6) is required for mitotic progression of human cells. Nek6 is phosphorylated and activated during M phase. Inhibition of Nek6 function by either overexpression of an inactive Nek6 mutant or elimination of endogenous Nek6 by siRNA arrests cells in M phase and triggers apoptosis. Time-lapse recording of the cell cycle progression of cells expressing kinase-inactive Nek6 reveals mitotic arrest at the metaphase stage prior to cells entering apoptosis. In contrast to NIMA and the closely related mammalian Nek2 kinase, which regulate centrosome function and separation, our data demonstrate an important function for Nek6 during mitosis and suggest that Nek6 kinase is required for metaphase-anaphase transition.


(11)C-CUMI-101, a PET radioligand, behaves as a serotonin 1A receptor antagonist and also binds to α(1) adrenoceptors in brain.
The PET radioligand (11)C-CUMI-101 was previously suggested as a putative agonist radioligand for the serotonin 1A (5-hydroxytryptamine 1A [5-HT1A]) receptor in recombinant cells expressing human 5-HT1A receptor. However, a recent study showed that CUMI-101 behaved as a potent 5-HT1A receptor antagonist in rat brain. CUMI-101 also has moderate affinity (Ki = 6.75 nM) for α1 adrenoceptors measured in vitro. The current study examined the functional properties and selectivity of CUMI-101, both in vitro and in vivo. The functional assay was performed using (35)S-GTPγS (GTP is guanosine triphosphate) in primate brains. The cross-reactivity of CUMI-101 with α1 adrenoceptors was performed using in vitro radioligand binding studies in rat, monkey, and human brains as well as in vivo PET imaging in mouse, rat, and monkey brains. CUMI-101 did not stimulate (35)S-GTPγS binding in primate brain, in contrast to 8-OH-DPAT, a potent 5-HT1A receptor agonist. Instead, CUMI-101 behaved as a potent 5-HT1A receptor antagonist by dose-dependently inhibiting 8-OH-DPAT-stimulated (35)S-GTPγS binding. Both in vitro and in vivo studies showed that CUMI-101 had significant α1 adrenoceptor cross-reactivity. On average, across all 3 species examined, cross-reactivity was highest in the thalamus (>45%) and lowest in the neocortex and cerebellum (<10%). PET imaging further confirmed that only preblocking with WAY-100635 plus prazosin decreased (11)C-CUMI-101 brain uptake to that of self-block. CUMI-101 behaves as a 5-HT1A receptor antagonist in primate brain, with significant, regional-dependent α1 adrenoceptor cross-reactivity, limiting its potential use as a PET radioligand in humans.


Vancomycin pharmacokinetics in preterm infants.
[corrected] The objective of the present study was to evaluate the kinetic disposition of vancomycin in preterm infants with emphasis on the apparent volume of distribution, biological half-life, and total body clearance as well as whether their variations cause significant modification of the trough plasma concentration of the drug, depending on the postconceptional age (PCA) and the postnatal age (PNA). Twenty-five selected patients were distributed into 2 groups which differed significantly in terms of mean PCA (31.2-32.3 weeks in group 1, n = 13; 33.5-34.1 weeks in group 2, n = 12: CI95%, P < .001) and PNA (group 1, 12.0-18.5 days; group 2, 18.0-34.0 days, CI95%, P < .05). The parents were informed and signed a written consent for participation of the infants in the protocol that had been previously approved by the Ethics Committee of the hospital. Apparent volume of distribution was significantly increased in group 1 compared with patients of group 2 (0.85 vs. 0.56 L/kg, respectively; P = .01,). Additionally multiple linear regression revealed a good linear correlation (r = 0.85) of trough plasma concentration of vancomycin with the apparent volume of distribution and also with the biological half-life in patients of group 1, while a good correlation (r = 0.91) was obtained for the trough plasma concentration with total body clearance in infants of group 2. The influence of these kinetic parameters on the trough concentration of vancomycin in preterm infants seems to vary according to PCA and PNA. In conclusion, the trough plasma concentration of vancomycin depends on the pharmacokinetics, and multiple linear correlation indicates that it varies according to the postconceptional and postnatal age of preterm infants.


Higher Quality, Lower Cost with an Innovative Geriatrics Consultation Service.
To design a value-driven, interprofessional inpatient geriatric consultation program coordinated with systems-level changes and studied outcomes and costs. Propensity-matched case-control study of older adults hospitalized at an academic medical center (AMC) who did or did not receive geriatric consultation. Single tertiary-care AMC in Portland, Oregon. Adults aged 70 and older who received an inpatient geriatric consultation (n=464) and propensity-matched controls admitted before development of the consultation program (n=2,381). Pre- and postintervention controls were also incorporated into cost difference-in-difference analyses. Daily charges, total charges, length of stay (LOS), 30-day readmission, intensive care unit (ICU) days, Foley catheter days, total medication doses per day, high-risk medication doses per day, advance directive and Physician Orders for Life Sustaining Treatment (POLST) documentation, restraint orders, discharge to home, and mortality. On average, individuals who received a geriatric consultation had $611 lower charges per day than those without a consultation (p=.02). They spent on average 0.36 fewer days in the ICU (p<.001). They were less likely to have restraint orders (20.0% vs 27.9%, p<0.001), more likely to have a POLST (58.2% vs 44.6%, p<.001), and more likely to be discharged to home (33.4% vs 28.2%, p=.03). They received fewer doses of antipsychotics, benzodiazepines, and antiemetics (10, 5, and 7 fewer doses per 100 patient-days, respectively) and had lower in-hospital mortality (2.4% vs 4%, p=.01). There was no difference in hospital LOS or 30-day readmission. Our consultation program resulted in significant reductions in daily charges, ICU days, potentially inappropriate medication use, and use of physical restraints and increased end-of-life planning. This model has potential for dissemination to other institutions operating in resource-scarce, value-driven settings.


Molecular genetic approaches to the pathogenesis of bacillary dysentery.
Bacillary dysentery is an invasive infectious disease of the human colon. At least three genetic loci on the chromosome and a huge plasmid have been implicated in its pathogenesis. Results obtained from molecular genetic studies, mainly of the genes, virG, virF and kcpA are discussed.


Heavy alcohol use in lung donors increases the risk for primary graft dysfunction.
Heavy alcohol use is known to increase the risk of acute lung injury and the acute respiratory distress syndrome. This is in part due to increased production of reactive oxygen species. We hypothesized that recipients of lungs from heavy drinkers would be more susceptible to lung injury following transplantation. In this retrospective cohort study, donor histories and transplant outcomes were reviewed in 192 consecutive lung transplant recipients. Donors were classified as No Alcohol Use, Moderate Alcohol Use, or Heavy Alcohol Use based on documented donor histories. Freedom from mechanical ventilation took longer in the lung transplant recipients whose donors had Heavy Alcohol Use, compared with those whose donors had No Alcohol Use or Moderate Alcohol Use (p = 0.01). At admission to the intensive care unit, the Heavy Alcohol Use group had median PaO2 /FiO2 ratio 219 (interquartile range [IQR]: 162 to 382), compared with 305 (IQR: 232 to 400) in the Moderate Alcohol Use group and 314 (IQR: 249 to 418) in the No Alcohol Use group (p = 0.005). The odds of developing severe primary graft dysfunction (PGD) in the Heavy Alcohol Use group versus the No Alcohol Use group were 8.7 times greater (95% confidence interval 1.427 to 53.404, p = 0.019) after controlling for factors known to be associated with PGD. Recipients of donors with a heavy alcohol use history had an over 8 times greater risk of developing severe PGD following lung transplant. The increase in PGD resulted in poorer gas exchange in the recipients of donor lungs from heavy alcohol users, and these recipients subsequently required mechanical ventilation for a longer time following transplant. Further investigation into lung donors with heavy alcohol use histories is necessary to determine those at highest risk for PGD following transplant.


External yeast beta-fructosidase. The role of tryptophyl residues in catalysis.
1. In native invertase at pH 4.6, 23 out of a total of 34 tryptophyl residues are "exposed" to oxidation with N-bromosuccinimide, the other residues being apparently shielded from the oxidant within the molecule. 2. Oxidation of 5-6 tryptophyl residues/molecule with N-bromosuccinimide is proportional to the complete inactivation of the enzyme, and appears to be specific for indole chromophore only. The ligand binding and fluorescence measurements indicate that the oxidation of native enzyme, up to 50% inhibition, apparently does not change the conformation and topography of enzymes surface. 3. Invertase is inhibited by diazonium-1-H-tetrazole. Since tyrosine residues can be excluded by nitration studies as catalytically unimportant, it appears that a mocification of a single histidyl residue/molecule with diazonium-1-H-tetrazole is sufficient to abolish the enzymic activity. However, the absence of inhibition with diethyl pyrocarbonate indicates that the inhibition with diazonium-1-H-tetrazole may be mediated through steric hindrance or other indirect effects. 4. The absence of inhibition with 2,4-dinitrophenylhydrazine, trinitro benzenesulfonic acid and 5,5'-dithiobis-(2-nitrobenzoate) indicates that the carbonyl groups of the carbohydrate moiety, free amino and -SH groups are not essential for activity.


Distribution of Class I Integron and smqnr Resistance Gene Among Stenotrophomonas maltophilia Isolated from Clinical Samples in Iran.
Stenotrophomonas maltophilia (S. maltophilia) is a multiple-antibiotic-resistant opportunistic pathogen that is being isolated with increasing frequency from patients with health-care-associated infections. S. maltophilia is inherently resistant to most of the available antimicrobial agents. Spread of resistant strains has been attributed, in part, to class I integrons. In vitro susceptibility studies have shown trimethoprim-sulfamethoxazole and new floroquinolones as two important agents with activity against these organisms. 150 isolates of S. maltophilia were isolated from clinical samples such as respiratory discharges, sputum, and catheter and hospital environments. These isolates were also subjected to susceptibility testing and polymerase chain reaction for four groups of genes including int encoding integron elements, sulI and sulII encoding trimethoprim-sulfamethoxazole resistance and smqnr encoding quinolone resistance. The rate of resistance to trimethoprim-sulfamethoxazole was up to 27 (18%) and the highest resistance to quinolone family belonged to ofloxacin (20%) and the lowest rate was for gatifloxacin (16%). The results showed that 14% of isolates contained integron elements concomitantly with sulI and sulII genes. Resistance rate of S. maltophilia to co-trimoxazole and fluoroquinolones and detection of integron elements between isolates in this study showed that this rate corresponded to other data obtained from other studies.


Endogenous oestrogens do not regulate endothelial nitric oxide production in early postnatal rats.
Previously we showed that endothelium of 1-2-weeks old rats exerts an anticontractile effect due to spontaneous NO production which correlates with a higher eNOS expression level compared to adult rats. Oestrogens are powerful regulators of eNOS expression and activity in arterial endothelium. This study tested the hypothesis that anticontractile influence of endothelium in young rats is regulated by endogenous oestrogens. Wistar rats were daily treated with ICI 182,780 or letrozole (oestrogen receptor antagonist and aromatase inhibitor, respectively; s.c., 1mg/kg/day) from the second postnatal day, control pups received vehicle injections. At the age of 10-12-days we studied contraction of saphenous arteries using wire myography. ELISA and qPCR were used to evaluate blood sex steroids levels and mRNA expression in arterial tissue, respectively. Ten-12 days old male rats compared to adult male rats demonstrated 78% higher serum 17β-oestradiol concentration and several-fold increase in mRNA contents of oestrogen receptors (ERα and GPER1). However, treatments with ICI 182,780 or letrozole did not affect arterial sensitivity to methoxamine (α1-adrenoceptor agonist) in 10-12-days old males. The blockade of NO-synthase with L-NNA caused tonic contraction and potentiated the response to methoxamine, these effects were similar in control and both treated groups. The sensitivity of endothelium-denuded saphenous arteries to NO-donor DEA/NO did not differ between control and treated groups as well. In addition, treatments with ICI 182,780 or letrozole did not change eNOS expression level in arterial tissue. Our results suggest that endogenous oestrogens do not regulate anticontractile effect of NO during early postnatal development in rats.


Web-based, psychosocial treatment for substance use disorders in community treatment settings.
The purpose of this multisite clinical trial was to evaluate the effectiveness of a web-based version of the Community Reinforcement Approach, plus motivational incentives, within community-based, outpatient substance abuse treatment. This ongoing study is being conducted within the National Drug Abuse Treatment Clinical Trials Network, funded by the National Institute on Drug Abuse. Midway through the enrollment of 500 participants, the study is being implemented in 10 treatment programs across the United States. Information is provided on design, sample, intervention and technology, and preliminary lessons learned.


ABT737 enhances ovarian cancer cells sensitivity to cisplatin through regulation of mitochondrial fission via Sirt3 activation.
The poor prognosis of ovarian cancer is mainly caused by chemotherapy resistance. Studies show that the Bcl-2 inhibitor ABT737 can significantly improve the effect of cisplatin and induce mitochondrial pathway apoptosis. However, the mechanism of ABT737 increases sensitivity to cisplatin by regulating mitochondrial function remains unclear in ovarian cancer cells. Sirt3, as a histone deacetylase, is involved in the regulation of mitochondrial function in cancers. In this study, we intend to explore the mechanistic link between Sirt3 and mitochondrial dysfunction induced by ABT737 and cisplatin in ovarian cancer cells. Apoptosis was examined by flow cytometry following Annexin V and PI staining. Sirt3 activity was assessed using Sirt3 deacetylase fluorometric assay. The mitochondrial membrane potential was examined by flow cytometry following JC-1 staining. Overexpression and knock-down of Sirt3 were confirmed by western blot analysis. Mitochondrial fission/fusion dynamics were detected by immunofluorescence staining or western blot analysis. Cisplatin accompanied with ABT737 promoted apoptosis and decreased mitochondrial membrane potential. ABT737 enhanced the sensitivity of ovarian cancer cells to cisplatin, which was partly achieved by activating Sirt3 to regulate the mitochondrial fission process. This study identified the activation of Sirt3 played an important role in increasing sensitivity of ovarian cancer cells to cisplatin induced by ABT737. Furthermore, Sirt3 might represent a potential therapeutic target for ovarian cancer.


Simple versus complex assessment of white matter hyperintensities in relation to physical performance and cognition: the LADIS study.
White matter hyperintensities (WMH) on MRI are associated with disorders of gait and balance and with cognitive impairment. The most suitable method to assess WMH in relation to the clinical evaluation of disturbances in these areas has not yet been established. To compare a simple visual rating scale, a detailed visual rating scale and volumetric assessment of WMH with respect to their associations with clinical measures of physical performance and cognition. Data were drawn from the multicentre, multinational LADIS study. Data of 574 subjects were available. MRI analysis included assessment of WMH using the simple Fazekas scale, the more complex Scheltens scale and a semi-automated volumetric method. Disturbances of gait and balance and general cognitive function were assessed using the Short Physical Performance Battery (SPPB) and the Mini Mental State Examination (MMSE), respectively. Irrespective of the method of measuring WMH, subjects with disturbances of gait and balance (SPPB < or = 10) had more WMH than subjects with normal physical performance. Subjects with mild cognitive deficits (MMSE < or = 25) had more WMH than subjects with normal cognition. Correlations between clinical measures and WMH were equal across methods of WMH measurement (SPPB: Spearman r = -0.22, -0.25, -0.26, all p < 0.001; MMSE: Spearman r = -0.11, -0.10, -0.09, all p < 0.05, for Fazekas scale, Scheltens scale and volumetry, respectively). These associations remained significant and comparable after correcting for age, gender and education in multivariate linear regression analyses. Simple and complex measures of WMH yield comparable associations with measures of physical performance and cognition. This suggests that a simple visual rating scale may be sufficient, when analyzing relationships between clinical parameters and WMH in a clinical setting.


Induction of prostaglandin endoperoxide synthase-1 (COX-1) in a human promonocytic cell line by treatment with the differentiating agent TPA.
Prostaglandin endoperoxide synthase (PGH synthase) is responsible for converting arachdonic acid to PGH2, the common precursor of prostaglandins. It has been shown previously that phorbol ester-induced differentiation of human promonocytic leukemia cell lines is accompanied by induction of PGH synthase enzyme and enhanced capacity to produce prostaglandins. However, the identity of the isoform of PGH synthase, i.e., PGH synthase-1 or -2, that is induced under these conditions has not been established. Northern and Western analyses revealed a dramatic increase in levels of PGH synthase-1 mRNA and protein levels within 24 hr after treatment of THP-1 cells with phorbol ester. No significant increase in PGH synthase-2 mRNA or protein was observed. The increases in PGH synthase-1 were accompanied by an enhanced capacity of the cells to produce PGE2. The current findings indicate that expression of PGH synthase-1 is greatly enhanced in a promonocytic cell line by treatment with an agent that induces differentiation.


The role of mammalian foetal membranes in early embryogenesis: Lessons from marsupials.
Across mammals, early embryonic development is supported by uterine secretions taken up through the yolk sac and other foetal membranes (histotrophic nutrition). The marsupial conceptus is enclosed in a shell coat for the first two-thirds of gestation and nutrients pass to the embryo through the shell and the avascular bilaminar yolk sac. At around the time of shell rupture, part of the yolk sac is trilaminar and supplied with blood vessels. It attaches to the uterus and forms a choriovitelline placenta. Rapid growth of the embryo ensues, still supported by histotrophe as well as exchange of oxygen and nutrients between maternal and foetal blood vessels (haemotrophic nutrition). Few marsupials have a chorioallantoic placenta and the highly altricial newborn is delivered after a short gestation. Eutherian embryos pass through a similar sequence before there is a fully functional chorioallantoic placenta. In most orders, there is transient yolk sac placentation, but even before this, nutrients are transferred through an avascular yolk sac. Yolk sac placentation does not occur in rodents or catarrhine primates. Early embryonic development in the mouse is nonetheless dependent on histotrophic nutrition. In the first trimester of human pregnancy, uterine glands open to the intervillous space and secretion products are taken up by the trophoblast. Transfer of nutrients to the early human embryo also involves the yolk sac, which floats free in the exocoelom. Marsupials can therefore inform us about the role of foetal membranes and histotrophic nutrition in early embryogenesis, knowledge that can translate to eutherians.


Contrasting distributions of groundwater arsenic and uranium in the western Hetao basin, Inner Mongolia: Implication for origins and fate controls.
Although As concentrations have been investigated in shallow groundwater from the Hetao basin, China, less is known about U and As distributions in deep groundwater, which would help to better understand their origins and fate controls. Two hundred and ninety-nine groundwater samples, 122 sediment samples, and 14 rock samples were taken from the northwest portion of the Hetao basin, and analyzed for geochemical parameters. Results showed contrasting distributions of groundwater U and As, with high U and low As concentrations in the alluvial fans along the basin margins, and low U and high As concentrations downgradient in the flat plain. The probable sources of both As and U in groundwater were ultimately traced to the bedrocks in the local mountains (the Langshan Mountains). Chemical weathering of U-bearing rocks (schist, phyllite, and carbonate veins) released and mobilized U as UO2(CO3)2(2-) and UO2(CO3)3(4-) species in the alluvial fans under oxic conditions and suboxic conditions where reductions of Mn and NO3(-) were favorable (OSO), resulting in high groundwater U concentrations. Conversely, the recent weathering of As-bearing rocks (schist, phyllite, and sulfides) led to the formation of As-bearing Fe(III) (hydr)oxides in sediments, resulting in low groundwater As concentrations. Arsenic mobilization and U immobilization occurred in suboxic conditions where reduction of Fe(III) oxides was favorable and reducing conditions (SOR). Reduction of As-bearing Fe(III) (hydr)oxides, which were formed during palaeo-weathering and transported and deposited as Quaternary aquifer sediments, was believed to release As into groundwater. Reduction of U(VI) to U(IV) would lead to the formation of uraninite, and therefore remove U from groundwater. We conclude that the contrasting distributions of groundwater As and U present a challenge to ensuring safe drinking water in analogous areas, especially with high background values of U and As.


Vitamin therapy in schizophrenia.
Schizophrenia is a devastating and poorly understood disease for which the only accepted therapy is nonspecific antipsychotic and anti-seizure medication. This article summarizes the evidence that certain vitamin deficiencies likely worsen the symptoms of schizophrenia, and the evidence that large doses of certain vitamins could improve the core metabolic abnormalities that predispose some people to develop it; it recounts the history of a controversial vitamin-based therapy for schizophrenia called orthomolecular psychiatry; and it concludes by advocating a process for discovering promising new schizophrenia therapies that involves small, carefully conducted clinical trials of nutrient combinations in appropriately selected patients.


A survey of PM2.5 preventive behavioral intention and related factors among community elderly in Northern Taiwan.
Population aging and air pollution are global concerns. The purpose of this study is to explore the relationship among particulate matter with a diameter of 2.5 μm or less (PM2.5) knowledge, PM2.5 preventive attitude, and PM2.5 preventive behavioral intention in the elderly.A cross-sectional survey design was applied in this study, including usage intention and snowball sampling. A total of 617 elderly people aged over 65 participated, and the collected data were quantitatively analyzed.The results showed that the mean score of PM2.5 knowledge of the elderly was 10.34 (79.53%) with the standard deviation (SD) of 3.42, the mean score of PM2.5 preventive attitude was 4.58 (91.60%) with SD of 0.49, and the mean score of PM2.5 preventive behavioral intention was 4.72 (94.40%) with SD of 0.40. Elderly people's characteristics regarding PM2.5 knowledge and PM2.5 preventive attitude explained 22% (adjusted R2 = 0.22, F = 30.44, P < .001) of the variance in PM2.5 preventive behavioral intention.It is concluded that we found no difference in PM2.5 knowledge, PM2.5 preventive attitude, or PM2.5 preventive behavioral intention among the elderly with or without chronic diseases. In our opinion, health education regarding the threat of PM2.5 to the health of the elderly should be strengthened, to enhance their knowledge, preventive attitude, and preventive behavioral intention of PM2.5.


Collaborative interaction points in post-discharge stroke care.
Lack of appropriate electronic tools for supporting patient involvement and collaboration with care professionals is a problem in health care. Care and rehabilitation processes of post-discharge stroke patients were analysed using the concept of interaction points where patients, next-of-kin and care professionals interact and exchange information. Thirteen interviews with care professionals and five non-participatory observations were performed. Data were analysed using content analysis and modelling of interaction points in the patient journey. Patient participation and interaction patterns vary; patients requiring home care have a passive role and next-of-kin or nurses become advocates by coordinating care on behalf of the patient, whereas patients who are able to visit primary care coordinate their own care by initiating interactions. Important categories of participation include the following: participation in care planning, in monitoring risk factors and in rehabilitation planning. Designing a supportive electronic tool requires understanding the interactions and patients' activity levels at each interaction point. A tool for patients with higher activity level should support them to coordinate their own care, whereas for a less-active patient group, the tool could focus on supporting next-of-kin and care professionals in motivating, guiding and including passive patients in their care and rehabilitation processes.


Function of GRIM-19, a mitochondrial respiratory chain complex I protein, in innate immunity.
Mitochondria respiratory chain (RC), consisting of five multisubunit complexes, is crucial for cellular energy production, reactive oxygen species generation, and regulation of apoptosis. Recently, a few mitochondrial proteins have been reported to be essential for innate immunity, but the function of mitochondrial RC in innate immunity is largely unknown. By knock-out of GRIM-19, a newly identified subunit protein of mitochondrial complex I, in mice, we found that heterogeneous mice (GRIM-19(+/-)) are prone to spontaneous urinary tract infection, mostly by Staphylococcus saprophyticus. Macrophages derived from these mice have compromised mitochondrial complex I activity and increased reactive oxygen species level. Bacterial infection induces a rapid up-regulation of GRIM-19 and complex I activity in the wild-type macrophages, but both are reduced in the macrophages from GRIM-19(+/-) mice. These cells also have decreased intracellular killing ability against S. saprophyticus. The defects for this probably occur in the fusion of bacteria to lysosome, but not in the bacterial engulfment and macrophage migration. In addition, production of proinflammatory cytokines, such as interleukin (IL)-1, IL-12, IL-6, and interferon (IFN)-γ, induced by both bacterial infection and lipopolysaccharide (LPS) and monodansylcadaverine treatment, is also decreased in the GRIM19(+/-) macrophages. Inhibition of mitochondrial RC activity by inhibitors shows a similar reduction on the cytokine production. Due to low cytokine production, the inflammatory response caused by in vivo bacterial challenge in the bladders of GRIM-19(+/-) mice is compromised. This study provides genetic evidence for a critical role of mitochondrial RC in innate immunity.


On the use of antibiotics to control plant pathogenic bacteria: a genetic and genomic perspective.
Despite growing attention, antibiotics (such as streptomycin, oxytetracycline or kasugamycin) are still used worldwide for the control of major bacterial plant diseases. This raises concerns on their potential, yet unknown impact on antibiotic and multidrug resistances and the spread of their genetic determinants among bacterial pathogens. Antibiotic resistance genes (ARGs) have been identified in plant pathogenic bacteria (PPB), with streptomycin resistance genes being the most commonly reported. Therefore, the contribution of mobile genetic elements (MGEs) to their spread among PPB, as well as their ability to transfer to other bacteria, need to be further explored. The only well-documented example of ARGs vector in PPB, Tn5393 and its highly similar variants (carrying streptomycin resistance genes), is concerning because of its presence outside PPB, in Salmonella enterica and Klebsiella pneumoniae, two major human pathogens. Although its structure among PPB is still relatively simple, in human- and animal-associated bacteria, Tn5393 has evolved into complex associations with other MGEs and ARGs. This review sheds light on ARGs and MGEs associated with PPB, but also investigates the potential role of antibiotic use in resistance selection in plant-associated bacteria.