Factors affecting the use of antibiotics and antiseptics to prevent maternal infection at birth: A global mixed-methods systematic review.
Over 10% of maternal deaths annually are due to sepsis. Prophylactic antibiotics and antiseptic agents are critical interventions to prevent maternal peripartum infections. We conducted a mixed-method systematic review to better understand factors affecting the use of prophylactic antibiotics and antiseptic agents to prevent peripartum infections. We searched MEDLINE, EMBASE, Emcare, CINAHL, Global Health, Global Index Medicus, and Maternity and Infant Care for studies published between 1 January 1990 and 27 May 2022. We included primary qualitative, quantitative, and mixed-methods studies that focused on women, families, and healthcare providers' perceptions and experiences of prophylactic antibiotic and antiseptics during labour and birth in health facilities. There were no language restrictions. We used a thematic synthesis approach for qualitative evidence and GRADE-CERQual approach for assessing confidence in these review findings. Quantitative study results were mapped to the qualitative findings and reported narratively. We included 19 studies (5 qualitative, 12 quantitative and 2 mixed-methods studies), 16 relating to antibiotics, 2 to antiseptic use, and 1 study to both antibiotic and antiseptic use. Most related to providers' perspectives and were conducted in high-income countries. Key themes on factors affecting antibiotic use were providers' beliefs about benefits and harms, perceptions of women's risk of infection, regimen preferences and clinical decision-making processes. Studies on antiseptic use explored women's perceptions of vaginal cleansing, and provider's beliefs about benefits and the usefulness of guidelines. We identified a range of factors affecting how providers use prophylactic antibiotics at birth, which can undermine implementation of clinical guidelines. There were insufficient data for low-resource settings, women's perspectives, and regarding use of antiseptics, highlighting the need for further research in these areas. Implications for practice include that interventions to improve prophylactic antibiotic use should take account of local environments and perceived infection risk and ensure contextually relevant guidance.


Connexin26 deafness associated mutations show altered permeability to large cationic molecules.
Intercellular communication is important for cochlear homeostasis because connexin26 (Cx26) mutations are the leading cause of hereditary deafness. Gap junctions formed by different connexins have unique selectivity to large molecules, so compensating for the loss of one isoform can be challenging in the case of disease causing mutations. We compared the properties of Cx26 mutants T8M and N206S with wild-type channels in transfected cells using dual whole cell voltage clamp and dye flux experiments. Wild-type and mutant channels demonstrated comparable ionic coupling, and their average unitary conductance was approximately 106 and approximately 60 pS in 120 mM K(+)-aspartate(-) and TEA(+)-aspartate(-) solution, respectively, documenting their equivalent permeability to K(+) and TEA(+). Comparison of cAMP, Lucifer Yellow (LY), and ethidium bromide (EtBr) transfer revealed differences in selectivity for larger anionic and cationic tracers. cAMP and LY permeability to wild-type and mutant channels was similar, whereas the transfer of EtBr through mutant channels was greatly reduced compared with wild-type junctions. Altered permeability of Cx26 to large cationic molecules suggests an essential role for biochemical coupling in cochlear homeostasis.


Potential Roles of Extracellular Vesicles as Diagnosis Biomarkers and Therapeutic Approaches for Cognitive Impairment in Alzheimer's Disease.
Cognitive dysfunction, the major clinical manifestation of Alzheimer's disease (AD), is caused by irreversible progressive neurological dysfunction. With the aging of the population, the incidence of AD is increasing year by year. However, there is neither a simple and accurate early diagnosis method, nor an effective method to alleviate or prevent the occurrence and progression of AD. Extracellular vesicles (EVs) are a number of heterogeneous membrane structures that arise from the endosome system or shed from the plasma membrane. In the brain, almost every kind of cell may have EVs, which are related to cell-cell communication and regulate cellular function. At present, an increasing body of evidence suggests that EVs play a crucial role in the pathogenesis of AD, and it is of great significance to use them as specific biomarkers and novel therapeutic targets for cognitive impairment in AD. This article reviews the potential role of EVs as diagnostic biomarkers and treatments for cognitive dysfunction in AD.


Subunit Compensation and Plasticity of Synaptic GABA(A) Receptors Induced by Ethanol in α4 Subunit Knockout Mice.
There is considerable evidence that ethanol (EtOH) potentiates γ-aminobutyric acid type A receptor (GABA(A)R) action, but only GABA(A)Rs containing δ subunits appear sensitive to low millimolar EtOH. The α4 and δ subunits co-assemble into GABA(A)Rs which are relatively highly expressed at extrasynaptic locations in the dentate gyrus where they mediate tonic inhibition. We previously demonstrated reversible- and time-dependent changes in GABA(A)R function and subunit composition in rats after single-dose EtOH intoxication. We concluded that early tolerance to EtOH occurs by over-activation and subsequent internalization of EtOH-sensitive extrasynaptic α4βδ-GABA(A)Rs. Based on this hypothesis, any highly EtOH-sensitive GABA(A)Rs should be subject to internalization following exposure to suitably high EtOH doses. To test this, we studied the GABA(A)Rs in mice with a global deletion of the α4 subunit (KO). The dentate granule cells of these mice exhibited greatly reduced tonic currents and greatly reduced potentiation by acutely applied EtOH, whereas synaptic currents showed heightened sensitivity to low EtOH concentrations. The hippocampus of naive KO mice showed reduced δ subunit protein levels, but increased α2, and γ2 levels compared to wild-type (WT) controls, suggesting at least partial compensation by these subunits in synaptic, highly EtOH-sensitive GABA(A)Rs of KO mice. In WT mice, cross-linking and Western blot analysis at 1 h after an EtOH challenge (3.5 g/kg, i.p.) revealed increased intracellular fraction of the α1, α4, and δ, but not α2, α5, or γ2 subunits. By contrast, we observed significant internalization of α1, α2, δ, and γ2 subunits after a similar EtOH challenge in KO mice. Synaptic currents from naïve KO mice were more sensitive to potentiation by zolpidem (0.3 μM, requiring α1/α2, inactive at α4/5 GABA(A)Rs) than those from naïve WT mice. At 1 h after EtOH, synaptic currents of WT mice were unchanged, whereas those of KO mice were significantly less sensitive to zolpidem, suggesting decreases in functional α1/2βγ GABA(A)Rs. These data further support our hypothesis that EtOH intoxication induces GABA(A)R plasticity via internalization of highly EtOH-sensitive GABA(A)Rs.


A stochastic optimization model under modeling uncertainty and parameter certainty for groundwater remediation design: part II. Model application.
A new stochastic optimization model under modeling uncertainty (SOMUM) and parameter certainty is applied to a practical site located in western Canada. Various groundwater remediation strategies under different significance levels are obtained from the SOMUM model. The impact of modeling uncertainty (proxy-simulator residuals) on optimal remediation strategies is compared to that of parameter uncertainty (arising from physical properties). The results show that the increased remediation cost for mitigating modeling-uncertainty impact would be higher than those from models where the coefficient of variance of input parameters approximates to 40%. This provides new evidence that the modeling uncertainty in proxy-simulator residuals can hardly be ignored; there is thus a need of investigating and mitigating the impact of such uncertainties on groundwater remediation design. This work would be helpful for lowering the risk of system failure due to potential environmental-standard violation when determining optimal groundwater remediation strategies.


Effect of structurally related flavones/isoflavones on hydrogen peroxide production and oxidative DNA damage in phorbol ester-stimulated HL-60 cells.
We have examined the antioxidant properties of structurally related flavones/isoflavones in 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated HL-60 cells. In the presence of 1.3% dimethyl sulfoxide in the medium for seven days, promyelocytic HL-60 cells were differentiated into neutrophil-like cells possessing phagocytic properties and the capacity to generate H2O2 on TPA stimulation. The effects of five selected flavones/isoflavones on the formation of H2O2 and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were examined in TPA-stimulated HL-60 cells. The results indicated that genistein was the most potent inhibitor of H2O2 production by TPA-stimulated HL-60 cells, followed by apigenin and daidzein, whereas prunectin and biochanin A exhibited no effect. This inhibitory effect correlates well with the scavenging capacity of H2O2 by these flavones/isoflavones in an in vitro system. The formation of 8-OHdG in cellular DNA of HL-60 cells was induced by TPA and further enhanced by the addition of FeCl2 to the medium. Most flavones/isoflavones significantly inhibited TPA + FeCl2-induced 8-OHdG formation in HL-60 cells, with genistein being the most potent quencher. The inhibition of H2O2 production and 8-OHdG formation by these structurally related flavones/isoflavones may contribute to their chemopreventive potentials against human cancers.


Cell signalling in pulmonary vascular cells: do not shoot the messenger!
Pulmonary hypertension is associated with pulmonary vascular remodelling, rendering the vessels unresponsive to vasodilators. An understanding of the mechanisms which cause this remodelling is required, which is likely to be linked to changes in vascular tone whether stimulated by hypoxia or other factors. One way to approach this is to try to understand the intracellular signalling pathways associated with hypoxia in pulmonary artery cells. This understanding could provide opportunities for therapeutic intervention using agents which will interfere with the signalling systems.


Health-related quality of life as an outcome in organizational research.
This article discusses the conceptual and methodological issues that continue to plague health-related quality of life (HRQOL) research. The current conceptualizations of the construct are reviewed to make explicit the issues of diversity and lack of consensus in definitions, validity of the conceptual unity of multiple domains, and lack of attention to the integration of the HRQOL construct into a theoretical meaningful model. Inadequately addressed conceptual issues have resulted in the proliferation of scales to measure HRQOL the measurement issues to a need to focus on precision and sensitivity of measures. The author offers a new conceptualization of HRQOL, which encompasses both health-care provider and patient perspectives.


The effect of unhealthy dietary habits on the incidence of dental caries and overweight/obesity among Egyptian school children (A cross-sectional study).
Obesity and dental caries are public health problems in Egypt. Factors such as unhealthy diet, poor oral hygiene, and physical inactivity can play a major role in both problems. This study was carried out to illuminate the mutual unhealthy dietary risk factors associated with the incidence of both health conditions. Between 1 October 2020 and 1 July 2021, 369 Egyptian children (5-10 years) were examined. Dental status was assessed using decayed, missing/extracted, and filled tooth indices (dmft, deft, and DMFT) for deciduous, mixed, and permanent dentitions, respectively. Moreover, the lifestyle, food habits, and body mass index (BMI) were recorded. A total of 342 (93.7%) of the included subjects suffered from caries, and only 27(7.3%) were caries-free. Based on BMI percentiles, 247 (66.9%) of the youngsters were overweight/obese, while 122 (33.1%) had normal weight. The mean dmft was 6.9 (±4.6), deft 4.2 (±3.3), and DMFT 0.1 (±1.7). In the primary dentition, a significant positive correlation was detected between dmft and BMI, legumes, sweetened milk and juice, soft drinks, and desserts, while a significant negative correlation was detected between dmft/deft, meat/poultry/fish, fresh fruits, and vegetables. A significant positive correlation was detected between deft and BMI, sweetened milk and juice, ice cream, candies, and crackers. In the permanent dentition, a significant positive correlation was detected between age, soft drinks, sweetened juice, desserts, and DMFT, while a significant negative correlation was detected with fresh fruits and vegetables. BMI was significantly negatively correlated with a healthy lifestyle, meat/poultry/fish consumption, and fresh fruits and vegetables while positively correlated with legumes, ice cream, soft drinks, granulated sugars, desserts, fast food, and caffeinated drinks. Overweight/obesity was positively correlated with primary dentition dental caries. Desserts (sweetened snacks) and soft drinks could be the common risk factors associated with high caries and overweight/obesity incidence among Egyptian school children; conversely, consumption of fruits and vegetables could hinder both health conditions. Moreover, sweetened juices were associated with primary and permanent dental caries.


Zeaxanthin and the Induction and Relaxation Kinetics of the Dissipation of Excess Excitation Energy in Leaves in 2% O(2), 0% CO(2).
The relationship between the carotenoid zeaxanthin, formed by violaxanthin de-epoxidation, and nonphotochemical fluorescence quenching (q(NP)) in the light was investigated in leaves of Glycine max during a transient from dark to light in 2% O(2), 0% CO(2) at 100 to 200 micromoles of photons per square meter per second. (a) Up to a q(NP) (which can vary between 0 and 1) of about 0.7, the zeaxanthin content of leaves was linearly correlated with q(NP) as well as with the rate constant for radiationless energy dissipation in the antenna chlorophyll (k(D)). Beyond this point, at very high degrees of fluorescence quenching, only k(D) was directly proportional to the zeaxanthin content. (b) The relationship between zeaxanthin and k(D) was quantitatively similar for the rapidly relaxing quenching induced in 2% O(2), 0% CO(2) at 200 micromoles of photons per square meter per second and for the sustained quenching induced by long-term exposure of Nerium oleander to drought in high light (B Demmig, K Winter, A Krüger, F-C Czygan [1988] Plant Physiol 87: 17-24). These findings suggest that the same dissipation process may be induced by very different treatments and that this particular dissipation process can have widely different relaxation kinetics. (c) A rapid induction of strong nonphotochemical fluorescence quenching within about 1 minute was observed exclusively in leaves which already contained a background level of zeaxanthin.


Urban land use predicts West Nile virus exposure in songbirds.
Urbanization is a widespread phenomenon that is likely to influence the prevalence and impact of wildlife pathogens, with implications for wildlife management and public health policies toward zoonotic pathogens. In this study, wild songbird populations were sampled at 14 sites along an urban rural gradient in the greater metropolitan Atlanta (Georgia, USA) area and tested for antibodies to West Nile virus (WNV). The level of urbanization among sites was quantitatively assessed using a principal component analysis of key land use characteristics. In total, 499 individual birds were tested during the spring and summer over three years (2004-2006). Antibody prevalence of WNV increased from rural to urban sites, and this trend was stronger among adult birds relative to juveniles. Furthermore, antibody prevalence among Northern Cardinals (Cardinalis cardinalis) was significantly higher than in other songbird species along the urban gradient. Findings reported here indicate that ecological factors associated with urbanization can influence infection patterns of this vector-borne viral disease, with likely mechanisms including changes in host species diversity and the tolerance or recovery of infected animals.


Introducing novel approaches for examining the variability of individuals' physical activity.
Tudor-Locke and colleagues previously assessed steps/day for 1 year. The aim of this study was to use this data set to introduce a novel approach for the investigation of whether individual's physical activity exhibits periodicity fluctuating round a mean and, if so, the degree of fluctuation and whether the mean changes over time. Twenty-three participants wore a pedometer for 365 days, recorded steps/day and whether the day was a workday. Fourier transform of each participant's daily steps data showed the physical activity had a periodicity of 7 days in half of the participants, matching the periodicity of the workday pattern. Activity level remained stable in half of the participants, decreased in ten participants and increased in two. In conclusion, the 7-day periodicity of activity in half of the participants and correspondence with the workday pattern suggest a social or environmental influence. The novel analytical approach introduced herein allows the determination of the periodicity of activity, the degree of variability in activity that is tolerated during day-to-day life and whether the activity level is stable. Results from the use of these methodologies in larger data sets may enable a more focused approach to the design of interventions that aim to increase activity.


Hot spots-making directed evolution easier.
Directed evolution has emerged as a powerful strategy to engineer various properties of proteins. Traditional methods to construct libraries such as error-prone PCR and DNA shuffling commonly produce large, relatively inefficient libraries. In the absence of a high-throughput screening method, searching such libraries is time-consuming, laborious and costly. On the other hand, targeted mutagenesis guided by structure or sequence information has become a popular way to produce so-called smart libraries. With an increased ratio of advantageous to deleterious mutations, smart libraries increase the efficiency of directed evolution, provided that target site prediction is reliable. Mutation target site or hot spot prediction is critical to the quality of libraries and the performance of directed evolution. Appropriate selection of hot spots enables the generation of proteins with desired properties efficiently and rationally. Here, we give an overview of seven kinds of hot spots that are divided into two categories: sequence-based hot spots including CbD (conserved but different) sites and coevolving residues, and then 3D structure-based hot spots including active-site residues, access tunnel sites, flexible sites, distal sites coupled to active center, and interface sites. This review also covers the latest advances in computational tools for identifying these hot spots and many successful cases using them for enzyme engineering.


Efficacy and safety of concurrent chemoradiation with weekly cisplatin ± low-dose celecoxib in locally advanced undifferentiated nasopharyngeal carcinoma: a phase II-III clinical trial.
This is the first study that aimed to determine the efficacy and safety of concurrent chemoradiation with weekly cisplatin ± celecoxib 100 mg twice daily in locally advanced undifferentiated nasopharyngeal carcinoma. Eligible patients had newly diagnosed locally advanced (T3-T4, and/or N2-N3, M0) undifferentiated nasopharyngeal carcinoma, no prior therapy, Karnofsky performance status ≥ 70, and normal organ function. The patients were assigned to receive 7 weeks concurrent chemoradiation (70 Gy) with weekly cisplatin 30 mg/m 2 with either celecoxib 100 mg twice daily, (study group, n = 26) or placebo (control group, n = 27) followed by adjuvant combined chemotherapy with cisplatin 70 mg/m 2 on day 1 plus 5-fluorouracil 750 mg/m 2 /d with 8-h infusion on days 1-3, 3-weekly for 3 cycles. Overall clinical response rate was 100% in both groups. Complete and partial clinical response rates were 64% and 36% in the study group and 44% and 56% in the control group, respectively (P > 0.25). The addition of celecoxib to concurrent chemoradiation was associated with improved 2-year locoregional control rate from 84% to 100% (P = 0.039). The addition of celecoxib 100 mg twice daily to concurrent chemoradiation improved 2-year locoregional control rate.


Knockdown of WHIRLY1 Affects Drought Stress-Induced Leaf Senescence and Histone Modifications of the Senescence-Associated Gene HvS40.
The plastid-nucleus located protein WHIRLY1 has been described as an upstream regulator of leaf senescence, binding to the promoter of senescence-associated genes like HvS40. To investigate the impact of WHIRLY1 on drought stress-induced, premature senescence, transgenic barley plants with an RNAi-mediated knockdown of the HvWHIRLY1 gene were grown under normal and drought stress conditions. The course of leaf senescence in these lines was monitored by physiological parameters and studies on the expression of senescence- and drought stress-related genes. Drought treatment accelerated leaf senescence in WT plants, whereas WHIRLY 1 knockdown lines (RNAi-W1) showed a stay-green phenotype. Expression of both senescence-associated and drought stress-responsive genes, was delayed in the transgenic plants. Notably, expression of transcription factors of the WRKY and NAC families, which are known to function in senescence- and stress-related signaling pathways, was affected in plants with impaired accumulation of WHIRLY1, indicating that WHIRLY1 acts as an upstream regulator of drought stress-induced senescence. To reveal the epigenetic indexing of HvS40 at the onset of drought-induced senescence in WT and RNAi-W1 lines, stress-responsive loading with histone modifications of promoter and coding sequences of HvS40 was analyzed by chromatin immunoprecipitation and quantified by qRT-PCR. In the wildtype, the euchromatic mark H3K9ac of the HvS40 gene was low under control conditions and was established in response to drought treatment, indicating the action of epigenetic mechanisms in response to drought stress. However, drought stress caused no significant increase in H3K9ac in plants impaired in accumulation of WHIRLY1. The results show that WHIRLY1 knockdown sets in motion a delay in senescence that involves all aspects of gene expression, including changes in chromatin structure.


Behaviour of endocrine disrupting chemicals during the treatment of municipal sewage sludge.
Agricultural application of municipal sewage sludge has been emotionally discussed in the last decades, because the latter contains endocrine disrupting chemicals (EDCs) and other organic micropollutants with unknown fate and risk potential. Bisphenol A (BPA) was chosen as a model substance to investigate the influence of sludge conditioning on the end-concentration of EDCs in sludge. Adsorption studies with radioactive-labelled BPA showed that more than 75% BPA in anaerobically digested sludge is bound to solids (log Kd = 2.09-2.30; log Koc = 2.72-3.11). Sludge conditioning with polymer or iron (III) chloride alone had no influence on the adsorption of BPA. After conditioning with iron (III) chloride and calcium hydroxide desorption of BPA took place. Apparently, it occurred due to the deprotonation of BPA (pKa= 10.3) as the pH-value reached 12.4 during the process. The same behaviour is expected for other phenolic EDCs with similar pKa (nonylphenol, 17beta-estradiol, estron, estriol, 17alpha-ethinylestradiol). This study shows high affinity of BPA to the anaerobically digested sludge and importance of conditioning in the elimination of EDCs during the sludge treatment. Addition of polymer is favourable in the case of sludge incineration. Conditioning with iron (III) chloride and calcium hydroxide shows advantages for the use of sludge as fertiliser.


Structure, expression and chromosome assignment of the human catenin (cadherin-associated protein) alpha 1 gene (CTNNA1).
We have isolated the human alpha-catenin gene (CTNNA1), which encodes a cadherin-associated protein, and have determined its primary structure and chromosomal localization. The transcript of CTNNA1 is 3.4 kb long and consists of 16 coding exons encoding 906 amino acids and at least one 5' noncoding exon. The 102-kDa predicted protein is the same size as the murine homolog, and the amino acid sequences of the two proteins are 99.2% homologous. Analysis by reverse transcription-PCR revealed that this gene is expressed ubiquitously in normal tissues. It was mapped to chromosome band 5q31 by fluorescent in situ hybridization.


Polyamine Uptake, Kinetics, and Competition among Polyamines and between Polyamines and Inorganic Cations.
Polyamine uptake, the kinetics of this uptake, and the competition among polyamines and between polyamines and inorganic cations were studied in petals of Saintpaulia ionantha Wendl. Uptake experiments using (14)C-labeled polyamines were carried out on single petals, at room temperaure (20 degrees C) and in the light. The results show that putrescine, spermidine, and spermine uptake was dependent on the external pH and occurred up to high external polyamine concentrations with K(m) values of 8.6, 1.2, and 2.1 millimolar, respectively, with spermidine being the most absorbed at low concentration (17 micromolar). Putrescine and spermidine did not seem to compete for the same site of absorption. Furthermore, putrescine and spermidine uptake was not inhibited by Ca(2+), Mg(2+), and K(+) at the same concentrations (17 micromolar), whereas 1.7 millimolar Ca(2+) inhibited and K(+) enhanced spermidine uptake. The intracellular localization of the absorbed putrescine was determined using two different methods. Very little label was found in the apoplast, while most of it was localized in the 98,500g supernatant. According to our data the vacuole, which represents a substantial part of Saintpaulia parenchyma cells, could be a site of putrescine accumulation. 2,4-Dinitrophenol and diethylstilbestrol did not inhibit uptake; however, at 0 degrees C there was a 35% inhibition of spermidine uptake, compared with the controls kept at 20 degrees C as well as a 68% inhibition with 20 millimolar NaSCN.


Experiences with screening for atrial fibrillation: a qualitative study in general practice.
Guidelines recommend screening for atrial fibrillation (AF). Currently, screening is not considered standard care among GPs. To explore the experiences of primary care workers with different methods of screening for AF and with implementation in daily practice. A qualitative study using semi-structured interviews with GPs, nurses, and healthcare assistants (HCAs) who were experienced with implementing different methods of screening. Two independent researchers audio-recorded and analysed interviews using a thematic approach. They asked participants about their experiences with the different methods used for screening AF and which obstacles they faced when implementing screening in daily practice. In total 15 GPs, nurse practitioners, and HCAs from seven different practices were interviewed. The GP's office is suited for screening for AF, which ideally should be integrated with standard care. Participants considered pulse palpation, automated sphygmomanometer with AF detection, and single-lead electrocardiography (ECG) as practical tests. Participants trusted pulse palpation over the algorithm of the devices. The follow-up of a positive test with a time-consuming 12-lead ECG hindered integration of screening. The single-lead ECG device reduced the need for immediate follow-up because it can record a rhythm strip. The extra workload of screening and lack of financial coverage form obstacles for implementation. Pulse palpation, automated blood pressure measure monitors with AF detection, and single-lead ECGs might facilitate screening in a general practice setting. When implementing screening, focus should be on how to avoid disruption of consultation hours by unplanned 12-lead ECGs.


Slow unfolding of monomeric proteins from hyperthermophiles with reversible unfolding.
Based on the differences in their optimal growth temperatures microorganisms can be classified into psychrophiles, mesophiles, thermophiles, and hyperthermophiles. Proteins from hyperthermophiles generally exhibit greater stability than those from other organisms. In this review, we collect data about the stability and folding of monomeric proteins from hyperthermophilies with reversible unfolding, from the equilibrium and kinetic aspects. The results indicate that slow unfolding is a general strategy by which proteins from hyperthermophiles adapt to higher temperatures. Hydrophobic interaction is one of the factors in the molecular mechanism of the slow unfolding of proteins from hyperthermophiles.


Cyclic strain stimulates monocyte chemotactic protein-1 mRNA expression in smooth muscle cells.
Hemodynamic forces are important determinants for the formation of atherosclerotic plaques. The recruitment of circulating monocytes into the arterial wall is an important step during atherogenesis. Monocyte chemotactic protein-1 (MCP-1) has been shown to be a key factor for monocyte transmigration. This study examined the effects of cyclic strain on MCP-1 mRNA expression levels of cultured rat aortic smooth muscle cells. The MCP-1 mRNA levels of aortic smooth muscle cells first increased as the duration of cyclic strain increased, reaching the maximum at 6-12 h, maintained at high levels throughout the 48-h strain period. To explore signaling pathways mediating cyclic strain-stimulated MCP-1 mRNA expression, we examined the involvement of tyrosine kinase and protein kinase C (PKC). Tyrosine kinase inhibitors, genistein and tyrphostin 51, at 50 microM blocked cyclic strain-stimulated MCP-1 mRNA expression. Preincubation with a PKC activator, phorbol 12-myristate 13-acetate (PMA), 2 microM, for 24 h to downregulate PKC did not decrease cyclic strain-induced MCP-1 mRNA expression. A 6-h incubation with 0. 1 microM PMA to activate PKC, which stimulated MCP-1 expression when applied alone, abolished the stimulatory effects of cyclic strain. A specific PKC inhibitor, calphostin C (0.1 microM), diminished cyclic strain-stimulated MCP-1 mRNA expression. Angiotensin II at 10 or 1,000 nM induced a moderate upregulation of MCP-1 mRNA, and no synergistic effects were observed between angiotensin II and cyclic strain. These results indicate that cyclic strain stimulates MCP-1 mRNA expression in smooth muscle cells through signaling pathway(s) mediated by tyrosine kinase activation.


Safety and efficacy of fiducial marker implantation for robotic stereotactic body radiation therapy with fiducial tracking.
The purpose of this study was to assess the feasibility, efficacy and toxicity of fiducial marker implantation and tracking in CyberKnife® stereotactic radiation therapy (SBRT) applied to extracranial locations. This is a retrospective, single-centre, observational study to collect the data of all patients treated by stereotactic radiation therapy with fiducial marker tracking at extracranial locations, conducted between June 2014 and November 2017. Information regarding the implantation procedure, the types of toxicity related to marker implantation and the number of markers implanted/tracked during treatment were collected. Complication rates were evaluated using the CTCAE v4 [Common Terminology Criteria for Adverse Events] scale. The technical success rate was based on the ability to optimally track the tumor throughout all treatment fractions. Out of 2505 patients treated by stereotactic radiation therapy, 25% received treatment with fiducial marker tracking. The total number of implantation procedures was 616 and 1543 fiducial markers were implanted. The implantation-related complication rate was 3%, with 16 Grade 1 events and 4 Grade 2 events. The number of treated patients and the number of implanted markers has gradually increased since the technique was first implemented. The median treatment time was 27 min (range 10-76). 1295 fiducials were effectively tracked throughout all treatment fractions, corresponding to a technical success rate of 84%. The difference between the number of fiducials implanted and those tracked during treatment decreased significantly as the site's experience increased. Fiducial marker implantation and tracking is feasible, well-tolerated, and technically effective technique in SBRT for extracranial tumors.


The socialization of newly hired medical staff into a large health system.
The acquisition of private medical practices by large health care systems often results in the transition of the physician from self-employment to salaried employee. In order to be successful, new physicians must be socialized into the new environment, requiring both concrete information and cultural orientation. This Mayo Clinic study of recently hired physicians yielded information about both content and delivery mechanisms that will help in planning an integrated system of orientation experiences.


Temporal and spatial patterns on serra, Scomberomorus brasiliensis (Teleostei, Scombridae), catches from the fisheries on the Maranhão coast, Brazil.
The displacement pattern of the serra, Scomberomorus brasiliensis, in North-eastern Brazil was analyzed from landing data recorded form the fleet fishing serra. Serra fishery has two seasons: from Septemer to February (demersal species plus serra), and from March to August (almost only large amounts of serra). S. brasilienisis relative abundance increases similarly along the coast from March. but decreases first on the West coast from June. Records indicate that serra is near the coast at least until September/October in Eastern grounds. From October to March (strongest spawning season) there is no record of shoals on the coast. We concluded that the Maranhão coast is just a part of the migration circuit of S. brasilienisis that may exceed 300 nautical miles.


Effects of vancomycin, daptomycin, fosfomycin, tigecycline, and ceftriaxone on Staphylococcus epidermidis biofilms.
Infection of medical implanted material is associated with considerable morbidity and costs. In the following work, we investigated the effects of vancomycin, daptomycin, fosfomycin, tigecycline, and ceftriaxone on biofilms formed by Staphylococcus epidermidis isolates causative for implant infection and catheter-associated bacteremia. Biofilms were studied using the static microtiter plate model and incubated with the antibiotics increasing the concentration from 1x to 128 x the minimal inhibitory concentration (MIC) of the respective isolate tested. To quantify the reduction of the biomass, the optical density ratio (ODr) of stained biofilms and the number of growing bacteria were determined. Incubation of the staphylococcal biofilms with the antibiotics decreased the biofilm ODr (at baseline = 1) for ceftriaxone (0.83 +/- 0.48) but minimally only for fosfomycin (0.96 +/- 0.64), daptomycin (1.05 +/- 0.59), tigecycline (1.18 +/- 0.66), and vancomycin (0.98 +/- 0.44) at exceedingly high concentrations of 128 x MIC. The significant reduction of the bacterial growth was not achieved for all antibiotics, not even at the highest concentrations tested. Using higher doses of the antibiotics may be of some value in the treatment of biofilm-associated infections, although effects are seen only at clinically unachievable doses. However, to eradicate the staphylococcal biofilm, additional measures like debridement and/or removal of the implant are needed.


The prevalence of retained testes in Dunedin.
A cohort of approximately 500 boys was screened for retained testes at ages five and seven years and when the boys were aged three, five, seven and nine years, their parents were questioned about hospitalisation for surgery. Orchidopexy for retained testes had been performed on 15 of the 536 boys (2.8%) while one other had orchidopexy for high retractile testes (0.2%). Eighty-one percent of this surgery was performed between the seventh and ninth years of age.


Prolonged SARS-CoV-2 RNA shedding in a young man recovering from traumatic pneumothorax.
We describe a case of prolonged SARS-CoV-2 RNA shedding in an HIV-negative 21-year-old man recovering from abdominal and thoracic trauma. Nasopharyngeal (NP) swabs collected at 12 time points over a 95-day span all tested positive for SARS-CoV-2 by reverse transcription polymerase chain reaction (RT-PCR). Genotyping revealed canonical beta-variant E484K and N501Y mutations at earlier time points. Human rhinovirus, coronavirus NL63 and respiratory syncytial virus B were detected at different time points by RT-PCR. Full blood analysis at time point 9 (day 82) showed leukopenia with lymphocytosis. The patient's NP swab tested negative for SARS-CoV-2 by RT-PCR 101 days after the first positive test. The prolonged duration of SARS-CoV-2 RNA shedding in the context of trauma presented here is unique and has important implications for COVID-19 diagnosis, management and policy guidelines.


[Rural communes and small towns in the urban hierarchy].
"A determining factor in the demographic and employment dynamics of rural communes and certain small towns [in France] is how far they are from the nearest large town. Demographic dynamics and employment trends are somewhat adverse for those living far from urban influences. The main reasons for this would appear to be the slump in agriculture. This said, demographic and employment trends are much improved nearer the large towns, especially since the towns exerting the influence have more inhabitants." (SUMMARY IN ENG AND GER AND SPA)


PPE51 mediates uptake of trehalose across the mycomembrane of Mycobacterium tuberculosis.
The disaccharide trehalose is essential for viability of Mycobacterium tuberculosis, which synthesizes trehalose de novo but can also utilize exogenous trehalose. The mycobacterial cell wall encompasses two permeability barriers, the cytoplasmic membrane and the outer mycolic acid-containing mycomembrane. The ABC transporter LpqY-SugA-SugB-SugC has previously been demonstrated to mediate the specific uptake of trehalose across the cytoplasmic membrane. However, it is still unclear how the transport of trehalose molecules across the mycomembrane is mediated. In this study, we harnessed the antimycobacterial activity of the analogue 6-azido trehalose to select for spontaneous resistant M. tuberculosis mutants in a merodiploid strain harbouring two LpqY-SugA-SugB-SugC copies. Mutations mediating resistance to 6-azido trehalose mapped to the proline-proline-glutamate (PPE) family member PPE51 (Rv3136), which has recently been shown to be an integral mycomembrane protein involved in uptake of low-molecular weight compounds. A site-specific ppe51 gene deletion mutant of M. tuberculosis was unable to grow on trehalose as the sole carbon source. Furthermore, bioorthogonal labelling of the M. tuberculosis Δppe51 mutant incubated with 6-azido trehalose corroborated the impaired internalization. Taken together, the results indicate that the transport of trehalose and trehalose analogues across the mycomembrane of M. tuberculosis is exclusively mediated by PPE51.


Formulation and evaluation of novel coated floating tablets of bergenin and cetirizine dihydrochloride for gastric delivery.
A novel coated gastric floating drug-delivery system (GFDDS) of bergenin (BN) and cetirizine dihydrochloride (CET) was developed. First, the pharmacodynamic studies were performed and the results revealed that the new compounds of bergenin/cetirizine dihydrochloride had comparative efficacy as commercial products (bergenin/chlorphenamine maleate) but with fewer side effects on central nervous system (CNS). Subsequently, bergenin was formulated as an extended-release core tablet while cetirizine dihydrochloride was incorporated into the gastric coating film for immediate release. The formulation of GFDDS was optimized by CET content uniformity test, in vitro buoyancy and drug release. Herein, the effects of sodium bicarbonate (effervescent), hydroxypropyl methylcellulose (HPMC, matrix polymer) and coating weight gain were investigated respectively. The optimized GFDDS exhibited good floating properties (buoyancy lag time < 2 min; floating duration > 10 h) and satisfactory drug-release profiles (immediate release of CET in 10 min and sustained release of BN for 12 h). In vivo gamma scintigraphy proved that the optimized GFDDS could retain in the stomach with a prolonged gastric retention time (GRT) of 5 h, and the coating layer showed no side effect for gastric retention. The novel coated gastric floating drug-delivery system offers a new approach to enhance BN's absorption at its absorption site and the efficacy of both CET and BN.


A new cavity based absorption instrument for detection of water isotopologues in the upper troposphere and lower stratosphere.
We describe here the Harvard integrated cavity output spectroscopy (ICOS) isotope instrument, a mid-IR infrared spectrometer using ICOS to make in situ measurements of the primary isotopologues of water vapor (H(2)O, HDO, and H(2) (18)O) in the upper troposphere and lower stratosphere (UTLS). The long path length provided by ICOS provides the sensitivity and accuracy necessary to measure these or other trace atmospheric species at concentrations in the ppbv range. The Harvard ICOS isotope instrument has been integrated onto NASA's WB-57 high-altitude research aircraft and to date has flown successfully in four field campaigns from winter 2004-2005 to the present. Off-axis alignment and a fully passive cavity ensure maximum robustness against the vibrationally hostile aircraft environment. The very simple instrument design permitted by off-axis ICOS is also helpful in minimizing contamination necessary for accurate measurements in the dry UTLS region. The instrument is calibrated in the laboratory via two separate water addition systems and crosscalibrated against other instruments. Calibrations have established an accuracy of 5% for all species. The instrument has demonstrated measurement precision of 0.14 ppmv, 0.10 ppbv, and 0.16 ppbv in 4 s averages for H(2)O, HDO, and H(2) (18)O, respectively. At a water vapor mixing ratio of 5 ppmv the isotopologue ratio precision is 50[per thousand] and 30[per thousand] for deltaD and delta(18)O, respectively.


Extensive involvement of the gastrointestinal tract by a de novo presentation of the monoblastic type of myeloid sarcoma: a case report of a rare entity that is often misdiagnosed.
We present the first known case of the monoblastic type of myeloid sarcoma (also known as extramedullary myeloid tumor, chloroma, and granulocytic sarcoma) with diffuse involvement of the gastrointestinal tract. The patient originally presented with diarrhea and crampy abdominal discomfort. Endoscopically, the disease showed a diffuse inflammatory process mimicking a number of benign conditions, such as inflammatory bowel disease and autoimmune enteropathy. Sequential biopsies of the upper and lower gastrointestinal tract showed a diffuse infiltrate of increasingly atypical cells. The disease progressed to systemic involvement, including widespread lymphadenopathy, splenomegaly, and pulmonary deposits; the patient died 13 months after the development of initial symptoms. The immunohistochemical and histologic profiles of this case are diagnostic of the monoblastic type of myeloid sarcoma.


The role of environment and microorganisms in diseases of corals: overview of DAO Special 5.
Coral reefs are in decline worldwide. In the last several decades, bleaching and disease in a warming ocean have emerged as dominant drivers of ecological change on coral reefs. This special issue of DAO presents papers based on presentations from the 11th International Coral Reef Symposium (2008, Fort Lauderdale, Florida, USA). The articles herein document disease outbreaks involving novel hosts, pathogens and/or locations, experimental studies investigating processes and mechanisms underlying pathogen dynamics, and the application of increasingly sophisticated laboratory and modeling approaches to understanding disease epizootiology.


Nasal leech--a rare cause of severe anemia.
Spontaneous epistaxis, nasal trauma and foreign bodies are common causes of nasal bleed in children. Epistaxis and haematemesis due to leeches have been reported in literature. Here we present a rare case of severe anemia caused by a single leech infestation of nasal cavity that required blood transfusion.


Spectral evidence of interaction of spice constituents with hepatic microsomal cytochrome P-450.
Spectral evidence has been obtained of the interaction of constituents of two commonly used spices, capsicum and cinnamon, with hepatic microsomal cytochrome P-450. It is proposed that influences of spice constituents on hepatic mixed-function oxidase activities may merit consideration during the investigation of some health-related problems characteristic of, or peculiar to, a given region or cultural group. An example considered relates to the evaluation of certain 'traditional medicines'.


Manganese, iron, and total particulate exposures to welders.
Welders are exposed to a variety of metal fumes, including manganese, that may elevate the risk for neurological disease. This study examines several large data sets to characterize manganese, iron, and total particulate mass exposures resulting from welding operations. The data sets contained covariates for a variety of exposure modifiers, including the presence of ventilation, the degree of confinement, and the location of the personal sampler (i.e., behind or in front of the welding helmet). The analysis suggests that exposures to manganese are frequently at or above the current ACGIH(R) threshold limit value of 0.2 mg/m(3). In addition, there is evidence that local exhaust ventilation can control the exposures to manganese and total fume but that mechanical ventilation may not. The data suggest that higher exposures are associated with a greater degree of enclosure, particularly when local exhaust ventilation is absent. Samples taken behind the helmet were, in general, lower than those measured outside of it. There were strong correlations among manganese, iron, and total particulate mass exposures, suggesting simple equations to estimate one fume component from any of the others.


Self-selection of dietary protein and energy by turkey breeder hens.
1. An experiment was conducted to determine the effects of self-selection of dietary protein and energy by turkey hens on reproductive performance in a warm environment. 2. Dietary self-selection had no significant effect on egg production, egg weight, or body weight of turkey hens. 3. Fertility and hatchability of eggs produced by self-selecting hens were significantly reduced compared to eggs from control hens fed on a complete diet. 4. Protein intake was significantly reduced among self-selecting hens when compared to control hens fed on a complete diet (P less than or equal to 0.001). 5. Food and energy intake decreased as the ambient temperature increased. Nevertheless, protein intake of self-selecting hens increased over the course of egg production despite decreasing food intake. Therefore, self-selecting hens preferred a diet with a greater protein content (g protein/kg diet) in the last 10 weeks of egg production than during the first 10 weeks of egg production.


Partial deletions of long arm of chromosome 6: biologic and clinical implications in adult acute lymphoblastic leukemia.
Within 285 adult acute lymphoblastic leukemias (ALL) included in the multicenter GIMEMA 0496 trial and prospectively studied by conventional cytogenetics, 18 cases (6%) with long arm deletion of chromosome 6 (6q) were identified. These cases were divided into: (i) del(6q) only (n = 6); (ii) del(6q) plus other numerical and/or structural abnormalities (n = 8); (iii) del(6q) and other 'specific' translocations (n = 4). The biologic and clinical features of the patients carrying this anomaly, as well as their outcome, were compared with those of 267 patients without del(6q). A T cell phenotype was more frequently associated with del(6q) cases in general (P = 0.001) and particularly with cases presenting del(6q) as the isolated abnormality (P = 0.0027). No significant difference with respect to multidrug resistance (MDR)/P glycoprotein expression was observed between the two groups of patients (21% vs 28% of MDR-positive cases, respectively). A BCR-ABL fusion transcript was less frequently detected in cases with del(6q) (11%) compared with those without the anomaly (29%). p15 and p16 deletions were identified by Southern blot analysis in 21% of cases with del(6q) and in 26% of cases without del(6q). In this latter group, a T cell phenotype was less frequently associated with p15 and/or p16 deletion than in the group carrying del(6q) (36% vs 100% of cases, P = 0.011). Overall, patients with ALL and del(6q) had a high complete remission (CR) rate (83%); however, they had a lower 18 month event-free survival (31% vs 41%) and a higher relapse rate (70% vs 37%, P = 0.02) compared with patients without del(6q). To date, this is the largest series of adult ALL cases reported with del(6q) homogeneously treated, which have also been prospectively studied for MDR expression and for the detection of known fusion genes. This anomaly, as an isolated change, identifies a subset of cases with hyperleukocytosis (median WBC count 52 x 10(9)/l) and a strict correlation with a T cell phenotype. Overall, del(6q) seems to be associated with an unfavorable clinical outcome, although this finding will need to be confirmed by extended FISH analysis.


Number of teeth and residual alveolar ridge height in subjects with a history of self-reported osteoporotic fractures.
The purpose of this case-control study was to determine if elderly subjects with a history of osteoporotic fractures have fewer teeth and greater residual ridge resorption than subjects without such fractures. Patients older than 60 with a panoramic radiograph were invited to a phone interview. Information was obtained regarding fracture history, smoking, and hormone replacement therapy (HRT). The number of teeth was obtained from the panoramic radiograph. The residual ridge height of the edentulous mandible was measured at the site of the mental foramen. Multiple regression models were used to assess the association between fracture status and number of teeth or residual ridge height (controlling for age, gender, HRT, smoking, height and weight). Cases (n=93) were individuals reporting osteoporotic fractures (fractures occurring after minor impact). Controls (n=394) were individuals reporting traumatic fractures (n=105) or no fractures (n=289). Fracture status in this population affect neither the number of teeth nor the residual ridge height. In the regression model, the variables that had a statistically-significant effect on the number of teeth were age (p<0.0001) and smoking (p<0.0001). There was a dose-effect of smoking on the number of teeth. In the regression model, the variables that had a significantly-significant on residual ridge height (n=95 edentulous subjects) were age and gender. Our conclusion was that in elderly dental-school patients the number of teeth and residual ridge height were not influenced by fracture status. Age and smoking had the most influence; there was no effect from HRT. The clinical implication is that a history of osteoporotic fractures is not an important cause for tooth loss and residual ridge resorption in an elderly dental-school population.


Visualisation of plasmid replication intermediates containing reversed forks.
Blockage of replication forks can have deleterious consequences for the cell as it may prompt premature termination of DNA replication. Moreover, the blocked replication intermediate (RI) could be particularly sensitive to recombination processes. We analysed the different populations of RIs generated in vivo in the bacterial plasmid pPI21 after pausing of replication forks at the inversely oriented ColE1 origin. To achieve this goal, a new method was developed based on two-dimensional agarose gel electrophoresis. This method allows the isolation of specific RIs, even when they were rather scarce, from the total DNA. Here we describe the occurrence of RI restriction fragments containing reversed forks. These Holliday-like structures have been postulated but never observed before.


Acute toxicity and repellent activity of the Origanum scabrum Boiss. & Heldr. (Lamiaceae) essential oil against four mosquito vectors of public health importance and its biosafety on non-target aquatic organisms.
The recent outbreaks of dengue, chikungunya, and Zika virus highlighted the pivotal importance of mosquito vector control in tropical and subtropical areas worldwide. However, mosquito control is facing hot challenges, mainly due to the rapid development of pesticide resistance in Culicidae and the limited success of biocontrol programs on Aedes mosquitoes. In this framework, screening botanicals for their mosquitocidal potential may offer effective and eco-friendly tools in the fight against mosquitoes. In the present study, the essential oil (EO) obtained from the medicinal plant Origanum scabrum was analyzed by GC-MS and evaluated for its mosquitocidal and repellent activities towards Anopheles stephensi, Aedes aegypti, Culex quinquefasciatus, and Culex tritaeniorhynchus. GC-MS analysis showed a total of 28 compounds, representing 97.1 % of the EO. The major constituents were carvacrol (48.2 %) and thymol (16.6 %). The EO was toxic effect to the A. stephensi, A. aegypti, C. quinquefasciatus, and C. tritaeniorhynchus larvae, with LC50 of 61.65, 67.13, 72.45, and 78.87 μg/ml, respectively. Complete ovicidal activity was observed at 160, 200, 240, and 280 μg/ml, respectively. Against adult mosquitoes, LD50 were 122.38, 134.39, 144.53, and 158.87 μg/ml, respectively. In repellency assays, the EOs tested at 1.0, 2.5, and 5.0 mg/cm2 concentration of O. scabrum gave 100 % protection from mosquito bites up to 210, 180, 150, and 120 min, respectively. From an eco-toxicological point of view, the EO was tested on three non-target mosquito predators, Gambusia affinis, Diplonychus indicus, and Anisops bouvieri, with LC50 ranging from 4162 to 12,425 μg/ml. Overall, the EO from O. scabrum may be considered as a low-cost and eco-friendly source of phytochemicals to develop novel repellents against Culicidae.


The nucleoid-associated proteins H-NS and FIS modulate the DNA supercoiling response of the pel genes, the major virulence factors in the plant pathogen bacterium Dickeya dadantii.
Dickeya dadantii is a pathogen infecting a wide range of plant species. Soft rot, the visible symptom, is mainly due to the production of pectate lyases (Pels) that can destroy the plant cell walls. Previously we found that the pel gene expression is modulated by H-NS and FIS, two nucleoid-associated proteins (NAPs) modulating the DNA topology. Here, we show that relaxation of the DNA in growing D. dadantii cells decreases the expression of pel genes. Deletion of fis aggravates, whereas that of hns alleviates the negative impact of DNA relaxation on pel expression. We further show that H-NS and FIS directly bind the pelE promoter and that the response of D. dadantii pel genes to stresses that induce DNA relaxation is modulated, although to different extents, by H-NS and FIS. We infer that FIS acts as a repressor buffering the negative impact of DNA relaxation on pel gene transcription, whereas H-NS fine-tunes the response of virulence genes precluding their expression under suboptimal conditions of supercoiling. This novel dependence of H-NS effect on DNA topology expands our understanding of the role of NAPs in regulating the global bacterial gene expression and bacterial pathogenicity.


[Protein phosphatases and protein kinases in higher plants].
The recent gain in knowledge concerning enzymes involved in signal transduction pathways is a direct consequence of the considerable advances made in molecular biology. Protein kinases and protein phosphatases, the two major enzymes implicated in post-translational modifications, have been studied in particular. The number of characterized plant genes and/or cDNAs encoding these enzymes is increasing everyday. Since 1991, 26 genes and cDNAs coding for plant protein phosphatases have been isolated and characterized. The huge number of protein kinases (estimated at several thousands) makes it impossible to give an exhaustive list of the genes already identified, but a classification of these enzymes, based on phylogenetic criteria, allows us to appreciate the range of functions this protein family may play in plants.


Long-distance proton transfer with a break in the bacteriorhodopsin active site.
Bacteriorhodopsin is a proton-pumping membrane protein found in the plasma membrane of the archaeon Halobacterium salinarium. Light-induced isomerization of the retinal chromophore from all-trans to 13-cis leads to a sequence of five conformation-coupled proton transfer steps and the net transport of one proton from the cytoplasmic to the extracellular side of the membrane. The mechanism of the long-distance proton transfer from the primary acceptor Asp85 to the extracellular proton release group during the O --> bR is poorly understood. Experiments suggest that this long-distance transfer could involve a transient state [O] in which the proton resides on the intermediate carrier Asp212. To assess whether the transient protonation of Asp212 participates in the deprotonation of Asp85, we performed hybrid Quantum Mechanics/Molecular Mechanics proton transfer calculations using different protein structures and with different retinal geometries and active site water molecules. The structural models were assessed by computing UV-vis excitation energies and C=O vibrational frequencies. The results indicate that a transient [O] conformer with protonated Asp212 could indeed be sampled during the long-distance proton transfer to the proton release group. Our calculations suggest that, in the starting proton transfer state O, the retinal is strongly twisted and at least three water molecules are present in the active site.


Effect of a scoring system and protocol for sedation on duration of patients' need for ventilator support in a surgical intensive care unit.
Need for improved sedation strategy for adults receiving ventilator support. Observational study of effect of introduction of guidelines to improve the doctors' and nurses' performance. The project was a prospective improvement and was part of a national quality improvement collaborative. A general mixed surgical intensive care unit in a university hospital; all doctors and nurses in the unit; all adult patients (>18 years) treated by intermittent positive pressure ventilation for more than 24 hours. Reduction in patients' mean time on a ventilator and length of stay in intensive care over a period of 11 months; anonymous reporting of critical incidents; staff perceptions of ease and of consequences of changes. Multiple measures (protocol development, educational presentations, written guidelines, posters, flyers, emails, personal discussions, and continuous feedback) were tested, rapidly assessed, and adopted if beneficial. Mean ventilator time decreased by 2.1 days (95% confidence interval 0.7 to 3.6 days) from 7.4 days before intervention to 5.3 days after. Mean stay decreased by 1.0 day (-0.9 to 2.9 days) from 9.3 days to 8.3 days. No accidental extubations or other incidents were identified. Relatively simple changes in sedation practice had significant effects on length of ventilator support. The change process was well received by the staff and increased their interest in identifying other areas for improvement.


Asymmetric Notch activation specifies photoreceptors R3 and R4 and planar polarity in the Drosophila eye.
Planar polarity is seen in epidermally derived structures throughout the animal kingdom. In the Drosophila eye, planar polarity is reflected in the mirror-symmetric arrangement of ommatidia (eye units) across the dorsoventral midline or equator; ommatidia on the dorsal and ventral sides of the equator exhibit opposite chirality. Photoreceptors R3 and R4 are essential in the establishment of the polarity of ommatidia. The R3 cell is thought to receive the polarizing signal, through the receptor Frizzled (Fz), before or at higher levels then the R4 cell, generating a difference between neighbouring R3 and R4 cells. Both loss-of-function and overexpression of Fz in the R3/R4 pair result in polarity defects and loss of mirror-image symmetry. Here we identify Notch and Delta (Dl) as dominant enhancers of the phenotypes produced by overexpression of fz and dishevelled (dsh), which encodes a signalling component downstream of Fz, and we show that D1-mediated activation of Notch is required for establishment of ommatidial polarity. Whereas fz signalling is required to specify R3, Notch signalling induces the R4 fate. Our data indicate that Dl is a transcriptional target of Fz/Dsh signalling in R3, and activates Notch in the neighbouring R4 precursor. This two-tiered mechanism explains how small differences in the level and/or timing of Fz activation reliably generate a binary cell-fate decision, leading to specification of R3 and R4 and ommatidial chirality.


Phase I trial of PALA.
PALA was given iv on a weekly schedule to 32 patients with advanced malignant tumors. A course of treatment consisted of three weekly doses. Patients were treated at eight dose levels, ranging from 900 to 6750 mg/m2. Gastrointestinal toxicity (diarrhea) and skin rash were dose-limiting. No consistent myelosuppression occurred, and no renal or hepatic toxicity was observed. Two patients who did not have metastatic intracranial disease experienced episodes of encephalopathy and seizures. No major therapeutic responses were observed during this phase I trial; however minor responses (greater than or equal to 25% tumor decrease) occurred in three patients (one with adenocarcinoma of the lung and two with epidermoid carcinoma of the bladder). Doses of 4500 mg/m2/week for patients with a performance status greater than or equal to 70 and 3750 mg/m2/week for patients with a lower performance status are recommended for phase II studies.


Effect of partial and complete blockade of vanilloid (TRPV1-6) and ankyrin (TRPA1) transient receptor potential ion channels on urinary bladder motor activity in an experimental hyperosmolar overactive bladder rat model.
The study investigated the mechanisms through which the hyperosmolarity might induce detrusor overactivity (DO). We compared the bladder activity in response to partial and complete blockade of TRPV1-6 and TRPA1 receptors. Experiments were performed on 42 rats. DO was induced by using hyperosmolar saline. All animals were randomly divided into six groups. The measurements represent the average of five bladder micturition cycles. Hyperosmolar saline induced DO. The complete blockade of TRPV1-6 and TRPA1 prevented DO. The partial blockade of TRPV1 didn't prevented DO. In the voiding phase periodical bladder contractions complexes occurred leading to slow urine flow due to bladder distension. Ruthenium red and capsaicin resulted in complete disorganisation of detrusor muscle contractility impairing urine voiding and leading to constantly lasting urine retention in healthy rats. hyperosmolar-induced DO is mediated by TRPV and TRPA1 channels; the hyperosmolar stimuli of urinary bladder might be transmitted mostly via ruthenium red sensitivity pathway.


AANA journal course: update for nurse anesthetists--serotonin agonists and antagonists: anesthetic implications.
A number of important new pharmacologic agents in widespread clinical use share the ability of manipulate serotonin as their mechanism of action. Drugs as diverse as the antidepressants fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), and venlafaxine (Effexor); the antimigraine agent sumatriptan (Imitrex); the antiobesity agent dexfenfluramine (Redux); and the antiemetics ondansetron (Zofran) and granisetron (Kytril) are routinely encountered in the perioperative patient. A thorough understanding of the pharmacology, physiologic effects, significant drug interactions and anesthetic implications of serotonin agonists or antagonists is vital for proper anesthetic management of patients receiving these drugs.


Does face inversion change spatial frequency tuning?
The authors examined spatial frequency (SF) tuning of upright and inverted face identification using an SF variant of the Bubbles technique (F. Gosselin & P. G. Schyns, 2001). In Experiment 1, they validated the SF Bubbles technique in a plaid detection task. In Experiments 2a-c, the SFs used for identifying upright and inverted inner facial features were investigated. Although a clear inversion effect was present (mean accuracy was 24% higher and response times 455 ms shorter for upright faces), SF tunings were remarkably similar in both orientation conditions (mean r = .98; an SF band of 1.9 octaves centered at 9.8 cycles per face width for faces of about 6 degrees ). In Experiments 3a and b, the authors demonstrated that their technique is sensitive to both subtle bottom-up and top-down induced changes in SF tuning, suggesting that the null results of Experiments 2a-c are real. The most parsimonious explanation of the findings is provided by the quantitative account of the face inversion effect: The same information is used for identifying upright and inverted inner facial features, but processing has greater sensitivity with the former.


A systematic compilation and classification of the literature on lameness in cattle.
This paper presents the first systematic review of the literature on lameness in cattle. It identifies, tabulates and classifies relevant published work and was conducted using electronic reference databases (BIDS ISI, BIOSIS, MEDLINE and the CAB Abstracts CD-ROM). A total of 1373 unique references were obtained from 1981 to 2000, of which 914 were written in the English language. A written search protocol was designed to ensure transparency and repeatability. Pilot studies were undertaken to create search terms that minimised bias and ensured relevance. Electronic files of the search terms allow the database to be updated in future. A further 93 references were included from the most recent international conference on lameness giving a total of 1007 English language references. The systematic review process is described, including a method of classifying papers according to their study design and statistical analysis, and it is hoped that other veterinary researchers will conduct similar reviews in their fields. The compiled and classified references are available as a searchable database through the web-sitehttp://cattle-lameness.dhs.org/. The review may be used in several ways; to identify practical interventions to reduce lameness in dairy cows and to use the resultant web-site as the basis of a decision support system for farmers, veterinarians and advisors.


The implementation of a national trauma registry in Greece. Methodology and preliminary results.
Trauma is a leading cause of death worldwide and a major health problem of the modern society. Trauma systems are considered the gold standard of managing patients with trauma. An integral part of any trauma system is a trauma registry. In Europe, and particularly in Greece, trauma registries and systems are in an embryonic stage. In this study, we present an attempt to record trauma in Greece. The Hellenic Society of Trauma and Emergency Surgery invited all the official representatives of the society throughout the country to participate in the study. In succeeding meetings of the representatives, the reporting form was developed and the inclusion criteria were defined meticulously. Inclusion criteria were defined as patients with trauma requiring admission, transfer to a higher level center, or arrived dead or died in the emergency department of the reporting hospital. All reports were accumulated by the Hellenic Trauma society, imported in an electronic database, and analyzed. Thirty-two hospitals receiving patients with trauma participated in the country, representing 40% of the country's healthcare facilities and serving 40% of the country's population. In 12 months time, (October 2005 to September 2006), 8,862 patients were included in the study. Of them, 66.9% were men and 31.3% were women. The compilation rate of the reporting forms was surprisingly high, considering that the final reporting form included 150 data points and that there were no independent personnel in charge of filling the forms. Trauma registries are feasible even in health care systems where funding of medical research is sparse.


The effect of reflux and bile acid aspiration on the lung allograft and its surfactant and innate immunity molecules SP-A and SP-D.
Gastro-esophageal reflux and related pulmonary bile acid aspiration were prospectively investigated as possible contributors to postlung transplant bronchiolitis obliterans syndrome (BOS). We also studied the impact of aspiration on pulmonary surfactant collectin proteins SP-A and SP-D and on surfactant phospholipids--all important components of innate immunity in the lung. Proximal and distal esophageal 24-h pH testing and broncho-alveolar lavage fluid (BALF) bile acid assays were performed prospectively at 3-month posttransplant in 50 patients. BALF was also assayed for SP-A, SP-D and phospholipids expressed as ratio to total lipids: phosphatidylcholine; dipalmitoylphosphatidylcholine; phosphatidylglycerol (PG); phosphatidylinositol; sphingomyelin (SM) and lysophosphatidylcholine. Actuarial freedom from BOS was assessed. Freedom from BOS was reduced in patients with abnormal (proximal and/or distal) esophageal pH findings or BALF bile acids (Log-rank Mantel-Cox p < 0.05). Abnormal pH findings were observed in 72% (8 of 11) of patients with bile acids detected within the BALF. BALF with high levels of bile acids also had significantly lower SP-A, SP-D, dipalmitoylphosphatidylcholine; PG and higher SM levels (Mann-Whitney, p < 0.05). Duodeno-gastro-esophageal reflux and consequent aspiration is a risk factor for the development of BOS postlung transplant. Bile acid aspiration is associated with impaired lung allograft innate immunity manifest by reduced surfactant collectins and altered phospholipids.


Plasmodium falciparum Kelch13 and its artemisinin-resistant mutants assemble as hexamers in solution: a SAXS data-driven modelling study.
The artemisinin-resistant mutations in Plasmodium falciparum (PfKelch13) identified worldwide are mostly confined to the Broad-complex, tramtrack and bric-à-brac/poxvirus and zinc-finger (BTB/POZ) and Kelch-repeat propeller (KRP) domains. To date, only two crystal structures of the BTB/POZ-KRP domains as tight dimers are available, which limits structure-based predictions and interpretation of its role(s) in inducing clinical artemisinin resistance. Our solution Small-Angle X-ray Scattering (SAXS) data analysis and shape restoration brought forth that: (a) PfKelch13 forms a stable hexamer in P6 symmetry, (b) interactions of the N-termini drive the hexameric assembly, and (c) the six KRP domains project independently in space, forming a cauldron-like architecture. We further deduce that the artemisinin-sensitive mutant A578S is packed like the wild-type protein, however, hexameric assemblies of the predominant artemisinin-resistant mutants R539T and C580Y displayed detectable differences in the spatial positioning of their BTB/POZ-KRP domains. Lastly, mapping of mutations known to enable artemisinin resistance suggested evolutionary pressure in the selection for mutations in the BTB/POZ-KRP domains. These mutations appear non-detrimental to the hexameric assembly of proteins, and yet somehow alter the flux of downstream events essential for the susceptibility to artemisinin.


Impact of sewage sludge conditioning and dewatering on the fate of nonylphenol in sludge-amended soils.
The fate of (14)C-labelled p353-nonylphenol (NP) in soils amended with differently treated sludges originating from the same precursor sludge was assessed. The effects of commonly applied conditioning and dewatering techniques were investigated. Nonylphenol was degraded considerably faster in soils amended with liquid sludge, while a significant portion of it remained intact and extractable by organic solvents when sludge had been centrifuged before soil amendment. Mineralization was reduced or even inhibited when freeze-thaw or lime conditioning was applied, respectively. Flocculation by an acrylamide-based cationic polymer led to the formation of a nitro-addition product of nonylphenol in soil, as well to decreased mineralization rates after prolonged incubation times. Possible mechanisms underlying the observations are suggested and discussed.


The prevalence and audience reach of food and beverage advertising on Chilean television according to marketing tactics and nutritional quality of products.
In the light of Chile's comprehensive new restriction on unhealthy food marketing, we analyse food advertising on Chilean television prior to the first and final phases of implementation of the restriction. Content analysis of marketing strategies of 6976 advertisements, based on products' nutritional quality. Statistical analysis of total and child audience reached using television ratings data. Advertising from television aired between 06.00 and 00.00 hours during two random composite weeks across April-May 2016 from the four broadcast and four cable channels with the largest youth audiences. Food ads represented 16 % of all advertising; 34 % of food ads featured a product high in energy, saturated fats, sugars and/or salt (HEFSS), as defined by the initial regulation. HEFSS ads were seen by more children and contained more child-directed marketing strategies than ads without HEFSS foods. If HEFSS advertising was restricted only in programmes where 20 % are children aged 4-12 years, 31 % of children's and 8 % of the general audience's HEFSS advertising exposure would be reduced. The newest 06.00-22.00 hours restriction captures 80 % of all audience exposure. HEFSS advertising was seen by a large proportion of children before Chile's regulation. Chile's first implementation based on audience composition should reduce a third of this exposure and its second restriction across the television day should eliminate most of the exposure. The current study is a crucial first step in evaluating how Chile's regulation efforts will impact children's diets and obesity prevalence.


SiLEncing SLE: the power and promise of small noncoding RNAs.
In this study, we outline the evidence suggesting that defects in the RNA silencing machinery can lead to the prototypic systemic autoimmune disease, systemic lupus erythematosus, and describe the potential for RNA interference to provide novel therapeutic agents. Over the last year, a class of small noncoding RNAs--microRNAs--have been shown to play key roles in immune regulation including T-cell selection in the thymus, B cell affinity maturation and selection in germinal centres, and development of regulatory T cells, suggesting that the microRNA machinery may be crucial in the maintenance of immunological tolerance. Two RNA silencing mechanisms have been shown to be involved in lupus pathogenesis: failed Roquin-mediated repression of inducible costimulatory receptors messenger RNA through miR-101 in roquin(san/san) mice and decreased expression of pro-apoptotic molecule and phosphatase and tensin homologue on chromosome 10 in mice transgenic for the miR-17-92 cluster, leading to lymphoproliferation and other lupus manisfestations. MicroRNA array experiments performed on peripheral blood mononuclear cells have revealed different expression profiles in systemic lupus erythematosus patients. RNA interference has also been used ex vivo to silence dysregulated T-cell molecules in cells from systemic lupus erythematosus patients. Dysregulation of the RNA silencing machinery has been implicated in systemic lupus erythematosus pathogenesis. Although microRNA profiling may prove to be a useful diagnostic and prognostic tool for a notoriously heterogeneous disease, manipulation of RNA interference emerges as a powerful and potentially specific means to correct dysregulated gene expression in systemic lupus erythematosus patients.


iTRAQ-based quantitative proteomic analysis reveals NtGNL1-dependent regulatory network underlying endosome trafficking for pollen tube polar growth.
Endosome trafficking has been reported to play an essential role in pollen tube polar growth and NtGNL1 (Nicotiana tabacum GNOM-LIKE 1) regulates the polar growth through endosome trafficking. However, the regulation network and detailed molecular mechanisms underlying endosome trafficking remain unclear. Here, comparative proteomic analysis was carried out to survey the overall effect of NtGNL1 on pollen tube polar growth and NtGNL1-dependent endosome trafficking. With multiple comparative systems (RNAi, Wild type, and BFA or wortmannin treatments), 481 distinct proteins were identified including 43 common DEPs (differentially expressed proteins), of which 16 significant DEPs were common among RNAi, BFA, and wortmannin treated pollen tubes, indicating their close relation to the endosome trafficking. GO annotation indicates that the vesicle trafficking of gnl1HE pollen tubes differs from that of the BFA and wortmannin treated pollen tubes in the COPII-coated vesicle budding process. KEGG pathway analysis suggests that the Pentose phosphate pathway is critical for the NtGNL1-dependent endosome trafficking. Yeast two-hybrid further confirmed that the NtGNL1-Sec7 domain interacted strongly with VPS32.2, TCTP, PIS2, and PDIL2-1, suggesting that the core functional region of NtGNL1 is the Sec7 domain. Therefore, NtGNL1 likely functions via its Sec7 binding with these proteins to affect endosome trafficking. Our results provide a clear outline of proteins involving in NtGNL1-dependent endosome trafficking and valuable clues for understanding the regulatory mechanism of NtGNL1 guided pollen tube polar growth.


Endothelin and free radicals modulate microvascular responses in streptozotocin-induced diabetic rats.
The quantitative contribution of endothelin and free radicals in modulating peripheral endothelial and smooth muscle-dependent vascular responses in 4 weeks streptozotocin-induced diabetic rats was investigated. Skin blood flow was monitored in base of blisters raised on the hind footpad. Smooth muscle-dependent vasodilation was tested using sodium nitroprusside (SNP). Endothelial-mediated inflammatory responses were induced via either electrical stimulation (ES) of the sciatic nerve or substance P (SP) perfusion over the blister base. Role of endothelin and free radicals was examined using ET-A or ET-B receptor antagonists (BQ-123 or BQ-788) and superoxide anions or hydroxyl radicals scavengers (superoxide dismutase (SOD) or N-acetyl cysteine (NAC)). Diabetic rats showed a significant reduction (75%) in SNP responses that coincided with a 70 and 60% reduction in responses to ES and SP. Their basal plasma extravasation (PE) was significantly higher while PE response to SP was significantly reduced. BQ-788, was more potent than BQ-123, improving responses to ES and SP in diabetic rats by 85%. Likewise, NAC was more potent than SOD normalizing the ES response and improving SP response by 85%. Combined treatment with BQ-123 and SOD normalized all vasodilatation responses in diabetic rats. BQ-123 and BQ-788 were equally potent normalizing the PE responses to SP whereas SOD and NAC had no effect. We conclude that endothelin and free radicals play a role in altering microvascular function in diabetes and that their effect could be reversed early in the disease.


Effect of lipid compositions on gene transfer into 293 cells using Sendai F/HN-virosomes.
Fusogenic liposomes that incorporate Sendai virus envelope proteins, so-called Sendai virosomes, have been developed for in vitro and in vivo genetic modification of animal cells. In this study, several different virosomes of varying lipid compositions were formulated and their in vitro gene-transfer efficiencies compared. The virosomes were prepared by quantitative reconstitution of the Sendai envelope, fusion (F) and hemagglutinin-neuraminidase (HN) proteins into liposomal vesicles. Virosomes that contained luciferase reporter genes were tested in 293 transformed human kidney cells. F/HN-virosomes that were prepared with an artificial Sendai viral envelope (ASVE-virosomes) or phosphatidylserine (PS-virosomes) exhibited an 8- or 6-fold higher gene-transfer efficiency than cationic liposomes that were made with 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP). F/HNvirosomes that were prepared with phosphatidic acid (PA-virosomes) instead of PS were less efficient in gene transfer than either ASVE- or PS-virosomes. In addition, the gene-transfer capability of ASVE- and PS-virosomes was maximal at a Ca2+ concentration of 510 mM. These results suggest that the incorporated lipid components significantly affect the in vitro gene transfer that is mediated by Sendai F/HN-virosomes.


Spectral sensitivity of vertically migrating marine copepods.
Light is a critical factor in the proximate basis of diel vertical migration (DVM) in zooplankton. A photobehavioral approach was used to examine the spectral sensitivity of four coastal species of calanoid copepod, representing a diversity of DVM patterns, to test whether species that migrate (nocturnal or reverse DVM) have response spectra that differ from non-migratory surface dwellers. The following species were given light stimuli at wavelengths from 350 to 740 nm, and their photoresponses were measured: Centropages typicus (nocturnal migrator), Calanopia americana (nocturnal migrator), Anomalocera ornata (reverse migrator), and Labidocera aestiva (non-migrator). Centropages typicus and A. ornata had peak responses at 500 and 520 nm, respectively, while Calanopia americana had maximum responses at 480 and 520 nm. Thus, the species that undergo DVM have peak photobehavioral responses at wavelengths corresponding to those available during twilight in coastal water, although the range of wavelengths to which they respond is variable. Non-migratory surface-dwelling L. aestiva had numerous response peaks over a broad spectral range, which may serve to maximize photon capture for vision in their broad-spectrum shallow-water habitat.


Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival protein of human myeloma cells.
Multiple myeloma (MM) is a plasma cell malignancy that occurs mainly in bone marrow. As MM cells proliferate slowly, it would seem essential to find means of preventing their growth and accumulation inside bone marrow. The present study used an antisense strategy to elucidate the respective roles of Bcl-2, Bcl-x(L), and Mcl-1 proteins in myeloma cell survival. Each antisense oligonucleotide (ASO; Bcl-2, Bcl-x(L), or Mcl-1 ASO) introduced into human myeloma cell lines by electroporation induced a marked reduction in the level of the corresponding protein. Mcl-1 ASO triggers an important decrease of viability in all myeloma cell lines tested and in 2 primary myeloma cells, whereas neither Bcl-2 nor Bcl-x(L) ASO affected the viability of myeloma cells. The decrease of cell viability induced by Mcl-1 ASO treatment was associated with an induction of apoptosis that occurred through the disruption of mitochondrial membrane potential Delta Psi m and the activation of executioner caspase-3. Furthermore, we have shown that interleukin 6 cannot prevent the Mcl-1 ASO-induced apoptosis. Finally, although Bcl-2 ASO treatment alone has no effect, it can sensitize myeloma cell lines to dexamethasone (Dex), whereas Bcl-x(L) ASO in combination with Dex still had no effect. As MM remains an incurable disease despite intensive chemotherapy, these results suggest that Mcl-1 antisense strategy rather than Bcl-2 antisense strategy could be of considerable importance in the treatment of MM.


Electrically evoking and electrochemically resolving quantal release on a microchip.
A microchip was applied to electrically depolarize rat pheochromocytoma (PC12) cells and to simultaneously detect exocytotic catecholamine release amperometrically. Results demonstrate exocytosis elicited by flowing cells through an electric field generated by a potentiostat circuit in a microchannel, as well as exocytosis triggered by application of an extracellular voltage pulse across. Electrical finite element model (FEM) analysis illustrated that larger cells experienced greater depolarizing excitation from the extracellular electric fields due to the smaller shunt path and higher resistance to current flow in the channel around the cell. Consistent with these simulations, data recorded from cell clusters and large cells exhibited increased release rates relative to data from the smaller cells. Overall, the system was capable of resolving single vesicle quantal release, in the zeptomole range, as well as the kinetics associated with the vesicle fusion process. Analysis of spike population statistics suggested detection of catecholamines from multiple release sites around the cells. The potential for such a device to be used in flow cytometry to evoke and detect exocytosis was demonstrated.


Clinical and histopathologic spectrum of necrotizing vasculitis. Report of findings in 101 cases.
Clinical and histopathologic features of 101 cases of necrotizing vasculitis were selected on the basis of the following histopathologic criteria: fibrinoid necrosis of blood vessel walls, endothelial cell hyperplasia, and an infiltrate within and around the blood vessel walls predominantly of polymorphonuclear leukocytes. There were three clinical patterns of vasculitis: (1) associated with other coexistent disease, (2) associated with known precipitating events, and (3) idiopathic. Two histologic features were particularly notable in view of the clinical findings. First, vasculitis extending deep into the reticular dermis or subcutaneous tissue seemed to be associated more often with systemic disease such as malignancy or connective tissue disease. Second, in biopsy specimens from patients with hypocomplementemia, the inflammatory infiltrate was composed almost exclusively of neutrophils, as compared with the mixed infiltrate seen in normocomplementemic vasculitis.


Efficient and stereocontrolled synthesis of 1,2,4-trioxolanes useful for ferrous iron-dependent drug delivery.
Ferrous iron-promoted reduction of a hindered peroxide bond underlies the antimalarial action of the 1,2,4-trioxane artemisinin and the 1,2,4-trioxolane arterolane. In appropriately designed systems, a 1,2,4-trioxolane ring can serve as a trigger to realize ferrous iron-dependent and parasite-selective drug delivery, both in vitro and in vivo. A stereocontrolled, expeditious (three steps), and efficient (67-71% overall yield) synthesis of 1,2,4-trioxolanes possessing the requisite 3″ substitution pattern that enables ferrous iron-dependent drug delivery is reported. The key synthetic step involves a diastereoselective Griesbaum co-ozonolysis reaction to afford primarily products with a trans relationship between the 3″ substituent and the peroxide bridge, as confirmed by X-ray structural analysis of a 3″-substituted 4-nitrobenzoate analogue.


Total body 100-mGy X-irradiation does not induce Alzheimer's disease-like pathogenesis or memory impairment in mice.
The cause and progression of Alzheimer's disease (AD) are poorly understood. Possible cognitive and behavioral consequences induced by low-dose radiation are important because humans are exposed to ionizing radiation from various sources. Early transcriptional response in murine brain to low-dose X-rays (100 mGy) has been reported, suggesting alterations of molecular networks and pathways associated with cognitive functions, advanced aging and AD. To investigate acute and late transcriptional, pathological and cognitive consequences of low-dose radiation, we applied an acute dose of 100-mGy total body irradiation (TBI) with X-rays to C57BL/6J Jms mice. We collected hippocampi and analyzed expression of 84 AD-related genes. Mouse learning ability and memory were assessed with the Morris water maze test. We performed in vivo PET scans with (11)C-PIB, a radiolabeled ligand for amyloid imaging, to detect fibrillary amyloid beta peptide (Aβ) accumulation, and examined characteristic AD pathologies with immunohistochemical staining of amyloid precursor protein (APP), Aβ, tau and phosphorylated tau (p-tau). mRNA studies showed significant downregulation of only two of 84 AD-related genes, Apbb1 and Lrp1, at 4 h after irradiation, and of only one gene, Il1α, at 1 year after irradiation. Spatial learning ability and memory were not significantly affected at 1 or 2 years after irradiation. No induction of amyloid fibrillogenesis or changes in APP, Aβ, tau, or p-tau expression was detected at 4 months or 2 years after irradiation. TBI induced early or late transcriptional alteration in only a few AD-related genes but did not significantly affect spatial learning, memory or AD-like pathological change in mice.


Rye Bs disclose ancestral sequences in cereal genomes with a potential role in gametophyte chromatid segregation.
Two sequence families, E3900 and D1100, are amplified on the subtelomeric domain of the long arm of rye B chromosomes, the region that controls its drive mechanism. In this work, polymerase chain reaction (PCR) with a number of primers spanning E3900 shows that the organization and nucleotide sequence of E3900-related portions are present and highly conserved on rye A chromosomes as well as in other cereals. Quantitative Real-Time PCR estimates two E3900 sequences to be represented in 100-150 copies on Bs and at least as single copies on As. A novel E3900-related sequence, with a deletion that results in a frameshift and subsequently an open reading frame with putative DNA binding motifs, is identified. Expression analysis of E3900 indicates identical transcription levels in leaves from plants with and without Bs, showing that the expression of these sequences must be silenced on Bs and tightly regulated on As in leaves. In contrast, E3900 transcription is upregulated during meiosis exclusively in plants with Bs, maintaining a high level of transcription in the gametophyte. Interestingly, Bs not only influence their own chromatid segregation but also that of the regular chromosome complement of both rye and wheat. There is a drastic increase in frequency of disrupted metaphase and anaphase cells in the first mitosis of pollen grains carrying Bs, which appears to be due to anomalous adherences between sister chromatids. Taken together, this work provides insight into how E3900 sequences are potentially associated with important evolutionary mechanisms involved in basic cellular processes.


Third-generation cephalosporins in the treatment of acute pneumococcal otitis media. An animal study.
There is concern that third-generation cephalosporins may not be effective in the treatment of acute otitis media due to Streptococcus pneumoniae. Using the chinchilla animal model, we compared two third-generation cephalosporins, cefixime (Suprax) and ceftibuten (investigational), with ampicillin and saline controls in an investigator-blinded, randomized trial. Whereas the saline controls performed worse than all other groups, no significant differences were detected among the three antibiotics regarding the time required to sterilize the middle ear cleft, or the prevalence of positive cultures after 10 days of therapy. The statistical power of the comparisons of cefixime and ceftibuten with ampicillin were 98% and 67%, respectively. The results of this in vivo animal study fail to support the contention that the two third-generation cephalosporins investigated are not effective in the treatment of pneumococcal acute otitis media. Caution is advised when extrapolating these results to the general clinical setting.


The Nup98 Homolog APIP12 Targeted by the Effector AvrPiz-t is Involved in Rice Basal Resistance Against Magnaporthe oryzae.
The effector AvrPiz-t of Magnaporthe oryzae has virulence function in rice. However, the mechanism underlying its virulence in host is not fully understood. In this study, we analyzed the function of AvrPiz-t interacting protein 12 (APIP12) in rice immunity. APIP12 significantly bound to AvrPiz-t and APIP6 in its middle portion and N-terminus, respectively, in yeast two-hybrid assay. Glutathione S-transferase (GST) pull-down assay further verified the interactions of APIP12 with AvrPiz-t and APIP6. APIP12 encodes a homologue of nucleoporin protein Nup98 without the conserved domain of Phe-Gly repeats and has no orthologue in other plants. Both knockout and knockdown of APIP12 caused enhanced susceptibility of rice plants to virulent isolates of M. oryzae. The expression of some pathogenesis-related (PR) genes was reduced in both knockout and knockdown mutants, suggesting that APIP12 is required for the accumulation of transcripts of PR genes upon the infection. It is worth noting that neither knockout/knockdown nor overexpression of APIP12 attenuates Piz-t resistance. Taken together, our results demonstrate that APIP12 is a virulence target of AvrPiz-t and is involved in the basal resistance against M. oryzae in rice.


Geochemical characterization of oceanic basalts using Artificial Neural Network.
The geochemical discriminate diagrams help to distinguish the volcanics recovered from different tectonic settings but these diagrams tend to group the ocean floor basalts (OFB) under one class i.e., as mid-oceanic ridge basalts (MORB). Hence, a method is specifically needed to identify the OFB as normal (N-MORB), enriched (E-MORB) and ocean island basalts (OIB). We have applied Artificial Neural Network (ANN) technique as a supervised Learning Vector Quantisation (LVQ) to identify the inherent geochemical signatures present in the Central Indian Ocean Basin (CIOB) basalts. A range of N-MORB, E-MORB and OIB dataset was used for training and testing of the network. Although the identification of the characters as N-MORB, E-MORB and OIB is completely dependent upon the training data set for the LVQ, but to a significant extent this method is found to be successful in identifying the characters within the CIOB basalts. The study helped to geochemically delineate the CIOB basalts as N-MORB with perceptible imprints of E-MORB and OIB characteristics in the form of moderately enriched rare earth and incompatible elements. Apart from the fact that the magmatic processes are difficult to be deciphered, the architecture performs satisfactorily.


Knowledge and practices on malaria treatment measures among pregnant women in Abeokuta, Nigeria.
The knowledge and practices on malaria treatment measures were assessed among 1400 pregnant women in semi-urban and rural communities (Akomoje, Iberekodo, Osiele and Sabopapamaru) of Abeokuta, Nigeria in 2006. Data was collected using structured questionnaires and focus group discussions. The largest proportion (41%) of the respondents was in the age group 21-25years. About three quarters (74%) of the women were multigravids. Sixty-five percent of the women had between three to four episodes of malaria per year. According to the respondents, symptoms associated with malaria in pregnancy included abdominal pains and foetal weakness due to reduced kicks (53%), body pains and headaches (27%) and anaemia (20%). Sixty-eight percent of the pregnant women utilized herbs for treating symptoms associated with malaria due to its effectiveness and suitability and not due to financial constraint or lack of access to health facility. Though most women utilized herbs, 32% relied more on the use of antimalarials. Sulfadoxine-pyrimethamine was the preferred antimalarial during pregnancy at the 2nd and 3rd trimesters. Only 15% of the women were using insecticide treated mosquito nets for personal protection. The majority (77%) of respondents used nylon net to screen their windows off mosquitoes. Since malaria poses adverse effect on the mother and developing foetus, health education becomes very essential to the traditional birth attendants and the women who patronize them. Pregnant women who attend traditional birth homes should be encouraged to also attend orthodox antenatal clinics, in order to receive proper and adequate treatment against malaria for themselves and the foetus.


Cerebrospinal fluid entrapment cysts with subarachnoid dissemination of medulloblastoma: CT findings.
We report an unusual case of meningeal dissemination of medulloblastoma in which multiple cerebrospinal fluid entrapment cysts developed within the cerebral fissures and cisterns. The condition was first diagnosed by CT. Cysts reduced in size following radiotherapy.


Gut Microbiota Parameters Potentially Useful in Clinical Perspective.
Interest in gut microbiota analyses is at an all-time high. Gut microbiota is thought to relate to an increasing range of diseases of interest to physicians and nutritionists. Overweight, obesity, response to diet, metabolic syndrome, low grade inflammation, diabetes and colon neoplasms could maybe be observed in microbiota if affordable markers were available. Possible biomarkers like the Firmicutes/Bacteroidetes ratio, the Gram-positive/Gram-negative ratio, the Prevotella/Bacteroides ratio, and the Fusobacterium nucleatum/Faecalibacterium prausnitzii ratio are here reviewed in a narrative way in the attempt to highlight their possible future role in routine practice and clinically relevant diagnostics.