Infrared Determination of the Protonation State of a Key Histidine Residue in the Photosynthetic Water Oxidizing Center.
Photosynthetic water oxidation is performed at the Mn4CaO5 cluster in photosystem II (PSII). The protonation structures of amino acid residues and water molecules around the Mn4CaO5 cluster are crucial in water oxidation reactions. In this study, we determined the protonation state of a key His residue in water oxidation, D1-H337, that is directly hydrogen-bonded with the oxygen atom of the Mn4CaO5 cluster, using polarized attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy. Flash-induced polarized ATR-FTIR difference spectra upon the S1 → S2 transition of oriented PSII membranes showed broad negative and positive features at about 2600 and 2900 cm-1, respectively, with large dichroic ratios, accompanied by several minor peaks attributable to the Fermi resonance of a His NH vibration. Quantum mechanics/molecular mechanics (QM/MM) calculations well reproduced the characteristics of these features as the NτH stretching vibrations of D1-H337 in its protonated cation form. The spectral features were reversed in the S3 → S0 transition, indicating that this His remains protonated during the S-state cycle. The redox potential (Em) of the Mn4CaO5 cluster in the S1 → S2 transition, which was estimated from the QM/MM calculations, was found to be comparable to that of water oxidation when D1-H337 is protonated cation. It was thus concluded that the positive charge on the protonated D1-H337 plays an important role in retaining a high Em value of the Mn4CaO5 cluster throughout the reaction cycle to enable water oxidation.


Lateral transport of a lipid probe and labeled proteins on a cell membrane.
Diffusion coefficients (D) of a lipid probe and labeled proteins on L-6 myoblast membranes have been measured giving D(protein) approximately 2 X 10(-10) square centimeter per second and D (lipid probe) approximately 9 X 10(-9) square centimeter per second. Some of the membrane proteins are immobile, but the lipid probe diffuses freely over macroscopic distances. Cytochalasin B slows protein but not lipid probe diffusion.


The limits of earthquake early warning: Timeliness of ground motion estimates.
The basic physics of earthquakes is such that strong ground motion cannot be expected from an earthquake unless the earthquake itself is very close or has grown to be very large. We use simple seismological relationships to calculate the minimum time that must elapse before such ground motion can be expected at a distance from the earthquake, assuming that the earthquake magnitude is not predictable. Earthquake early warning (EEW) systems are in operation or development for many regions around the world, with the goal of providing enough warning of incoming ground shaking to allow people and automated systems to take protective actions to mitigate losses. However, the question of how much warning time is physically possible for specified levels of ground motion has not been addressed. We consider a zero-latency EEW system to determine possible warning times a user could receive in an ideal case. In this case, the only limitation on warning time is the time required for the earthquake to evolve and the time for strong ground motion to arrive at a user's location. We find that users who wish to be alerted at lower ground motion thresholds will receive more robust warnings with longer average warning times than users who receive warnings for higher ground motion thresholds. EEW systems have the greatest potential benefit for users willing to take action at relatively low ground motion thresholds, whereas users who set relatively high thresholds for taking action are less likely to receive timely and actionable information.


[The relative contribution of the muscles of the chest cavity and diaphragm to the work of breathing under inspiratory resistive loading].
The inspiratory resistive load decreases the relative contribution of the diaphragm into formation of the respiratory volume, as has been show in anesthetised cats. The phenomenon can be due to both a sharp increase in the external intercostal muscles activity and to a fatigue of the diaphragmatic muscle in the inspiratory load. The contraphasic changes of these muscles' activity seem to be an adaptive response aiding to a more efficient overcoming of the resistance against breathing.


Axial But Not Sagittal Hinge Axis Affects Posterior Tibial Slope in Medial Open-Wedge High Tibial Osteotomy: A 3-Dimensional Surgical Simulation Study.
The purpose of this 3-dimensional (3D) surgical simulation study was to investigate the effects of axial and sagittal hinge axes (hinge axes in the axial and sagittal planes) on medial and lateral posterior tibial slope (PTS) in medial open-wedge high tibial osteotomy (OWHTO), and evaluate the quantitative relationship between hinge axis and PTS change. Preoperative computed tomography data from patients with varus knee deformity were collected. A standard hinge axis (0°) and 12 different hinge axes (6 axial hinge axes and 6 sagittal hinge axes: ±10°, ±20°, and ±30°) were defined in a 3D surgical simulation of OWHTO using a bone model. The differences between before and after simulation surgery in medial and lateral PTS, medial proximal tibial angle, opening gap, and opening wedge angle were measured. In total, 93 varus knees in 93 patients were included for study. Compared with the standard hinge axis, axial hinge axis significantly affected medial and lateral PTS (P < .001). In contrast, sagittal hinge axis had no significant effect on medial and lateral PTS (P > .05). Every 10° change in axial hinge axis with a mean coronal valgus correction of 10° might result in approximately 1.6° of alteration in PTS. Stepwise regression analysis showed that axial hinge axis is the most significant factors affecting PTS (β coefficient = 0.78, P < .001), followed by opening wedge angle (β coefficient = 0.36, P < .001) and gap ratio (β coefficient = 0.12, P < 0.001). Based on our findings of 3D OWHTO simulation, axial hinge axis significantly influences medial and lateral PTS in OWHTO, but sagittal hinge axis has no effect on change in PTS. Every 10° change of axial hinge axis with a 10° coronal valgus correction caused approximately 1.6° change of PTS. Hinge axis in the axial plane significantly affects PTS, but hinge axis in the sagittal plane has no effect on PTS. To maintain PTS, surgeons should make hinge axis at the true lateral position of the tibia in the axial plane. To intentionally alter PTS, an anterolateral axial hinge axis could be used to decrease PTS or a posterolateral axial hinge axis could be used to increase PTS. Opening wedge angle or gap ratio is also useful for intentional modification of PTS.


Testing for differences in rates of speciation, extinction, and morphological evolution in four tribes of cichlids endemic to Lake Tanganyika, East Africa.
Patterns of morphological disparity yield important insight into the causes of diversification and adaptive radiation in East African cichlids. However, comparisons of cichlid disparity have often failed to consider the effects that differing clade ages or stochasticity may have on disparity before making interpretations. Here, a model of branching morphological evolution allows assessment of the relative contributions of differing turnover and morphological change rates, clade ages, and stochastic variation to the observed patterns of disparity in four endemic tribes of Lake Tanganyika cichlids. Simulations compare the likelihood of generating the observed disparity of the four tribes using 200-parameter combinations and four model conditioning variations, which allows inference of evolutionary rate differences among clades. The model is generally robust to model conditioning, the approach to data analysis, and model assumptions. Disparity differences among the first three cichlid tribes, Ectodini, Lamprologini, and Tropheini, can be explained entirely by stochasticity and age, whereas the fourth tribe, Cyprichromini, has likely experienced lower rates of turnover and morphological change. This rate difference is likely related to the low dietary diversity of the Cyprichromini. These results highlight the importance of considering both clade age and stochastic variation when interpreting morphological diversity and evolutionary processes.


2004 MacLean-Mueller prize enteral or parenteral nutrition for severe pancreatitis: a randomized controlled trial and health technology assessment.
The optimal route of nutrition in severe pancreatitis is controversial. Parenteral nutrition (PN) is preferred, but enteral nutrition (EN) promises to attenuate inflammation and prevent sepsis. We hypothesized that EN was at least equivalent to PN in reducing inflammation, providing effective nutrition and being cost-effective. We conducted a randomized controlled trial comparing PN to EN in pancreatitis in an academic, multi-institutional, tertiary care health system. We screened 728 consecutive patients. Twenty-eight patients with a Ranson's score greater than 2 who did not tolerate clear fluids 4 days after admission were randomized: 18 to PN and 10 to EN. Both groups were provided daily 105 kJ (25 kcal)/kg and 1.5 g/kg of protein, respectively, until they could tolerate a regular diet. C-reactive protein in EN patients was reduced by 50% 5 days faster than PN patients (Wilcoxon test, p = 0.09). Both groups received a similar number of kilojoules and achieved near normal prealbumin and 24-hour urinary nitrogen values. Neither regimen caused a change in cholecystokinin levels. Overall mortality was 4.9% (3 patients in the PN group). In 5 patients (4 PN, 1 EN) there were infected pancreatic collections. Nine EN patients dislodged the nasojejunal tube. EN had an average cost of dollar 1375 per patient compared with dollar 2608 for PN (p = 0.08). After sensitivity analysis, EN cost dollar 957 compared with dollar 2608 for PN (p = 0.03). EN or PN is safe and provides adequate nutrition in severe pancreatitis. EN shows a trend toward faster attenuation of inflammation, with fewer septic complications and is the dominant therapy in terms of cost-effectiveness. This study favours EN for nutritional support in severe pancreatitis.


Inositol Metabolism Regulates Capsule Structure and Virulence in the Human Pathogen Cryptococcus neoformans.
The environmental yeast Cryptococcus neoformans is the most common cause of deadly fungal meningitis in primarily immunocompromised populations. A number of factors contribute to cryptococcal pathogenesis. Among them, inositol utilization has been shown to promote C. neoformans development in nature and invasion of central nervous system during dissemination. The mechanisms of the inositol regulation of fungal virulence remain incompletely understood. In this study, we analyzed inositol-induced capsule growth and the contribution of a unique inositol catabolic pathway in fungal development and virulence. We found that genes involved in the inositol catabolic pathway are highly induced by inositol, and they are also highly expressed in the cerebrospinal fluid of patients with meningoencephalitis. This pathway in C. neoformans contains three genes encoding myo-inositol oxygenases that convert myo-inositol into d-glucuronic acid, a substrate of the pentose phosphate cycle and a component of the polysaccharide capsule. Our mutagenesis analysis demonstrates that inositol catabolism is required for C. neoformans virulence and deletion mutants of myo-inositol oxygenases result in altered capsule growth as well as the polysaccharide structure, including O-acetylation. Our study indicates that the ability to utilize the abundant inositol in the brain may contribute to fungal pathogenesis in this neurotropic fungal pathogen. IMPORTANCE The human pathogen Cryptococcus neoformans is the leading cause of fungal meningitis in primarily immunocompromised populations. Understanding how this environmental organism adapts to the human host to cause deadly infection will guide our development of novel disease control strategies. Our recent studies revealed that inositol utilization by the fungus promotes C. neoformans development in nature and invasion of the central nervous system during infection. The mechanisms of the inositol regulation in fungal virulence remain incompletely understood. In this study, we found that C. neoformans has three genes encoding myo-inositol oxygenase, a key enzyme in the inositol catabolic pathway. Expression of these genes is highly induced by inositol, and they are highly expressed in the cerebrospinal fluid of patients with meningoencephalitis. Our mutagenesis analysis indeed demonstrates that inositol catabolism is required for C. neoformans virulence by altering the growth and structure of polysaccharide capsule, a major virulence factor. Considering the abundance of free inositol and inositol-related metabolites in the brain, our study reveals an important mechanism of host inositol-mediated fungal pathogenesis for this neurotropic fungal pathogen.


[Oxidative metabolism and myocardial function in rats with different sensitivities to oxygen deficiency in hypoxia].
In exposure to mild hypoxia, the electron-transport function of the myocardial respiratory chain in the NAD-cytochrome b area is limited in a different manner in animals highly resistant (HR) and those poorly resistant (PR) to hypoxia. In PR animals this process develops very rapidly, leads to diminution of the oxidative capacity of the respiratory chain and of ATP production, and, as a consequence, to suppression of the energy-dependent contractile function of the myocardium. In HR animals this process is less manifest and develops very slowly, which confirms the lesser role of NAD-dependent oxidation of substrates in the metabolism of the myocardium of these animals. The ability of the HR animals to maintain in mild hypoxia a higher ATP level than that in PR animals suggests that ATP synthesis in them occurs through oxidation of endogenous substrates which enter the respiratory chain by bypassing the NAD-dependent area. Compounds of the group of quinones, which facilitate removal of the block of the electron-transport function of the respiratory chain on the level of the first enzyme complex, normalize processes of ATP production and myocardial contractility and may be used as antihypoxic agents.


Accumulation of long-term transcriptionally active integrated retroviral vectors in active promoters and enhancers.
Most retroviruses preferentially integrate into certain genomic locations and, as a result, their genome-wide integration patterns are non-random. We investigate the epigenetic landscape of integrated retroviral vectors and correlate it with the long-term stability of proviral transcription. Retroviral vectors derived from the avian sarcoma/leukosis virus expressing the GFP reporter were used to transduce the human myeloid lymphoblastoma cell line K562. Because of efficient silencing of avian retrovirus in mammalian cells, only ∼3% of established clones displayed stable proviral expression. We analyzed the vector integration sites in non-selected cells and in clones selected for the GFP expression. This selection led to overrepresentation of proviruses integrated in active transcription units, with particular accumulation in promoter-proximal areas. In parallel, we investigated the integration of vectors equipped with an anti-silencing CpG island core sequence. Such modification increased the frequency of stably expressing proviruses by one order. The modified vectors are also overrepresented in active transcription units, but stably expressed in distal parts of transcriptional units further away from promoters with marked accumulation in enhancers. These results suggest that integrated retroviruses subject to gradual epigenetic silencing during long-term cultivation. Among most genomic compartments, however, active promoters and enhancers protect the adjacent retroviruses from transcriptional silencing.


Stimulating effect of diacerein on TGF-beta1 and beta2 expression in articular chondrocytes cultured with and without interleukin-1.
Diacetylrhein or diacerein has shown efficacy in the treatment of both major forms of osteoarthritis (OA), coxarthrosis as well as gonarthrosis, improving clinical symptoms of the disease (pain reduction and algo-functional index). Both in-vitro and animal models studies suggest that diacerein may have also disease-modifying effects. The drug exerts inhibitory effects on interleukin-1-induced expression of cartilage degrading enzymes. However, its mechanism of action is not completely understood. In view of the role that could play the transforming growth factor (TGF)-beta system in the repair potentialities of OA cartilage, we studied the effect of diacerein on the expression of TGF-beta isoforms 1, 2 and 3 and that of their receptor types I and II in cultured bovine chondrocytes. Cultured bovine articular chondrocytes were treated with 10(-5) m diacerein, 10 ng/ml IL-1beta or the combination diacerein+interleukin (IL)-1, and the expression of both TGF-beta isoforms 1, 2 and 3 and that of their receptors TbetaR-I and TbetaR-II was determined by Northern-blot and reverse transcriptase-polymerase chain reaction (RT-PCR). Cell transfections of cDNA constructs containing sequences of the 5'-upstream region of TGF-beta1 promoter were also performed to determine their transcriptional activity in diacerein-treated cultures. The data indicated that diacerein enhances the expression of TGF-beta1 and TGF-beta2. This effect was also found in the presence of IL-1, albeit with smaller intensity. In contrast, the levels of TGF-beta3 and receptors I and II remained unaffected or slighty modified by the compound. Treatment of cells transiently transfected with TGF-beta1 promoter constructs suggested that the stimulating effect on TGF-beta1 expression is mediated by the region -1038 to -1132 base pars. The results suggest that diacerein effects on matrix synthesis and turn-over previously reported in cultured articular chondrocytes might be explained in part by the ability of the drug to enhance TGF-beta1 and TGF-beta2 expression in these cells. This mechanism of action may account for the potential disease-modifying properties of diacerein and might give clues as to how future anti-osteoarthritic drugs should be designed.


COVID-19 Changed the Injury Patterns of Hospitalized Patients.
Injury patterns are closely related to changes in behavior. Pandemics and measures undertaken against them may cause changes in behavior; therefore, changes in injury patterns during the coronavirus disease 2019 (COVID-19) outbreak can be expected when compared to the parallel period in previous years. The aim of this study was to compare injury-related hospitalization patterns during the overall national lockdown period with parallel periods of previous years. A retrospective study was completed of all patients hospitalized from March 15 through April 30, for years 2016-2020. Data were obtained from 21 hospitals included in the national trauma registry during the study years. Clinical, demographic, and circumstantial parameters were compared amongst the years of the study. The overall volume of injured patients significantly decreased during the lockdown period of the COVID-19 outbreak, with the greatest decrease registered for road traffic collisions (RTCs). Patients' sex and ethnic compositions did not change, but a smaller proportion of children were hospitalized during the outbreak. Many more injuries were sustained at home during the outbreak, with proportions of injuries in all other localities significantly decreased. Injuries sustained during the COVID-19 outbreak were more severe, specifically due to an increase in severe injuries in RTCs and falls. The proportion of intensive care unit (ICU) hospitalizations did not change, however more surgeries were performed; patients stayed less days in hospital. The lockdown period of the COVID-19 outbreak led to a significant decrease in number of patients hospitalized due to trauma as compared to parallel periods of previous years. Nevertheless, trauma remains a major health care concern even during periods of high-impact disease outbreaks, in particular due to increased proportion of severe injuries and surgeries.


Influence of preservation methods on the quality of colostrum sourced from New Zealand dairy farms.
To assess the effect of two temperatures (ambient temperature and 4°C), three preservation methods (no preservative, yoghurt and potassium sorbate), and two periods of storage (3 and 7 days) on Brix and total bacterial and coliform counts of colostrum collected from New Zealand dairy farms. One litre of colostrum destined to be fed to newborn calves was collected from 55 New Zealand dairy farms in the spring of 2015. Six aliquots of 150 mL were obtained from each colostrum sample, with two aliquots left untreated, two treated with potassium sorbate and two with yoghurt, and one of each pair of aliquots stored at ambient temperature and the other at 4°C. All samples were tested for Brix, total bacterial counts and coliform counts before treatment (Day 0), and after 3 and 7 days of storage. The effect of preservation method and storage temperature on the change in Brix, bacterial and coliform counts after 3 or 7 days of storage was analysed using multivariable random effects models. For all outcome variables there was a temperature by preservation interaction. For aliquots preserved with potassium sorbate, changes in Brix and bacterial counts did not differ between aliquots stored at ambient temperature or 4°C, but for aliquots preserved with yoghurt or no preservative the decrease in Brix and increase in bacterial counts was greater for aliquots stored at ambient temperature than 4°C (p<0.001). For aliquots preserved with potassium sorbate, coliform counts decreased at both temperatures, but for aliquots preserved with yoghurt or no preservative coliform counts increased for aliquots stored at 4°C, but generally decreased at ambient temperatures (p<0.001). There was also an interaction between duration of storage and temperature for bacterial counts (p<0.001). The difference in the increase in bacterial counts between aliquots stored at 4°C and ambient temperature after 3 days was greater than between aliquots stored at 4°C and ambient temperature after 7 days. Use of potassium sorbate to preserve colostrum for 3 or 7 days resulted in little or no reduction in Brix and a lower increase in total bacterial counts than colostrum stored without preservative or with yoghurt added. Colostrum quality was not affected by storage temperature for samples preserved with potassium sorbate, but storage at 4°C resulted in better quality colostrum than storage at ambient temperatures for colostrum with no preservative or yoghurt added.


Pain and its treatment in outpatients with metastatic cancer.
Pain is often inadequately treated in patients with cancer. A total of 1308 outpatients with metastatic cancer from 54 treatment locations affiliated with the Eastern Cooperative Oncology Group rated the severity of their pain during the preceding week, as well as the degree of pain-related functional impairment and the degree of relief provided by analgesic drugs. Their physicians attributed the pain to various factors, described its treatment, and estimated the impact of pain on the patients' ability to function. We assessed the adequacy of prescribed analgesic drugs using guidelines developed by the World Health Organization, studied the factors that influenced whether analgesia was adequate, and determined the effects of inadequate analgesia on the patients' perception of pain relief and functional status. Sixty-seven percent of the patients (871 of 1308) reported that they had had pain or had taken analgesic drugs daily during the week preceding the study, and 36 percent (475 of 1308) had pain severe enough to impair their ability to function. Forty-two percent of those with pain (250 of the 597 patients for whom we had complete information) were not given adequate analgesic therapy. Patients seen at centers that treated predominantly minorities were three times more likely than those treated elsewhere to have inadequate pain management. A discrepancy between patient and physician in judging the severity of the patient's pain was predictive of inadequate pain management (odds ratio, 2.3). Other factors that predicted inadequate pain management included pain that physicians did not attribute to cancer (odds ratio, 1.9), better performance status (odds ratio, 1.8), age of 70 years or older (odds ratio, 2.4), and female sex (odds ratio, 1.5). Patients with less adequate analgesia reported less pain relief and greater pain-related impairment of function. Despite published guidelines for pain management, many patients with cancer have considerable pain and receive inadequate analgesia.


Health surveillance among a team of Australian health workers assisting tsunami victims in Aceh, Indonesia.
To determine the extent and nature of health-related behaviours and outcomes among members of the first foreign medical team to arrive in Aceh, following the Boxing Day tsunami in 2004. A cross sectional survey of team members 4 weeks after return from Aceh. Compliance with antimalarial chemoprophylaxis and insect repellent was high while in Aceh, but only one-third completed the course of chemoprophylaxis. The provision of prepackaged food and water was likely to have prevented enteric disease. Members reported mosquito bites, fatigue, sunburn, headache and anxiety about earthquakes. Provision of prepackaged food and water, preventive measures and information to members may be important in avoiding illness in such teams.


[Changes in the heart in various acute respiratory infections in children].
Hearts of 45 children dying with respiratory infections were studied by light and luminescent microscopy. Specific and nonspecific changes in tissues were found. Nonspecific changes consisted in disorders of microcirculation, degenerative, and necrotic processes in cardiomyocytes, and disorganization of the connective tissue of the endocardium and interstitial tissue of the myocardium, whereas specific changes included the presence of viral and mycoplasmal antigens in endotheliocytes and cardiomyocytes as well as metamorphosis of the latter detected mainly in adenovirus infection and mycoplasmosis. Analogous nonspecific and specific changes were also discovered in cytomegalovirus and Coxsackie virus infections which in some children were accompanied by acute respiratory infections.


End-of-Life Skills and Professionalism for Critical Care Residents in Training: The ESPRIT Survey.
End-of-life (EOL) care is a key aspect of critical care medicine (CCM) training. The goal of this study was to survey CCM residents and program directors (PDs) across Canada to describe current EOL care education. Using a literature review, we created a self-administered survey encompassing 10 CCM national objectives of training to address: (1) curricular content and evaluation methods, (2) residents' preparedness to meet these objectives, and (3) opportunities for educational improvement. We performed pilot testing and clinical sensibility testing, then distributed it to all residents and PDs across the 13 Canadian CCM programs. Our response rate was 84.3% overall (77 [81.1%] for residents and 13 [100%] for PDs). Residents rated direct observation, informal advice, and self-reflection as both the top 3 most utilized and perceived most effective teaching modalities. Residents most commonly reported comfort with skills related to pain and symptom management (n = 67, 94.3%; score > 3 on 5-point Likert scale), and least commonly reported comfort with donation after cardiac death skills (n = 26-38; 44.8%-65.5%). Base specialty and time in CCM training were independently associated with comfort ratings for some, but not all, EOL skills. With respect to family meetings, residents infrequently received feedback; however, most PDs believed feedback on 6 to 10 meetings is required for competence. When PD perceptions of teaching effectiveness were compared with resident comfort ratings, differences were most apparent for skills related to pain and symptom management, cultural awareness, and ethical principles. By the end of their first subspecialty training year, PDs expect residents to be competent at most, but not all, EOL skills. In summary, trainees and programs rely on clinical activities to develop competency in EOL care, resulting in some educational gaps. Transitioning to competency-based medical education presents an opportunity to address some of these gaps, while other gaps will require more specific curricular intervention.


Identifying comorbidity patterns of health conditions via cluster analysis of pairwise concordance statistics.
Identification of comorbidity patterns of health conditions is critical for evidence-based practice to improve the prevention, treatment and health care of relevant diseases. Existing approaches focus mainly on either using descriptive measures of comorbidity in terms of the prevalence of coexisting conditions, or addressing the prevalence of comorbidity based on a particular disease (e.g. psychosis) or a specific population (e.g. hospital patients). As coincidental comorbidity by chance increases with the prevalence rates of the conditions, which in turn depend heavily on the population under study, research findings on comorbidity patterns using those approaches may provide unreliable results. In this paper, we propose an asymmetric version of Somers' D statistic to provide a quantitative measure of comorbidity that accounts for co-occurrence of conditions by chance, and develop a unified clustering algorithm to identify comorbidity patterns with adjustment for multiple testing and control for the false discovery rate. We assess the applicability of the proposed comorbidity measure and investigate the performance of the proposed procedure for the adjustment of multiple testing by conducting a comparative study and a sensitivity analysis, respectively. The proposed method is illustrated using a national survey data set of mental health and wellbeing and a national health survey data set in Australia.


Perceptions of Customer Incivility, Job Satisfaction, Supervisor Support, and Participative Climate: A Multi-Level Approach.
Perceived customer incivility can be a significant day-to-day demand that affects frontline service employees' job satisfaction. The current research focuses on job resources on multiple levels that serve as buffers in the face of this demand. We tested a multi-level model in which supervisor support (at the employee level) and participative climate (at the work-unit level) moderate the negative relationship between perceived customer incivility and job satisfaction. We used multi-level analysis with self-reported cross-sectional data collected from 934 employees nested in 107 work units of a large clothing shop chain in Belgium. The results showed that both supervisor support and participative climate moderate the negative relationship between perceived customer incivility and job satisfaction. The theoretical contribution of this study resides in an extension of the JD-R theory to simultaneously conceptualize resources on multiple levels. In the meantime, we focus on practical, hands-on resources that organizations can implement to protect service employees from the adverse effects of perceived customer incivility.


Saperconazole therapy of murine disseminated candidiasis: efficacy and interactions with amphotericin B.
The efficacy of a new triazole antifungal agent, saperconazole, in a murine model of disseminated candidiasis was studied. Mice were intravenously infected with Candida albicans blastoconidia and treated for 14 days with oral saperconazole, intraperitoneal amphotericin B, or a combination of these. Amphotericin B alone was the most efficacious in prolonging survival and in decreasing renal colony counts, usually with complete sterilization of the kidneys by the end of the treatment course. Saperconazole improved survival rates and effected a decrease in renal colony counts, but kidneys were not microbiologically sterilized. Combination therapy with saperconazole and amphotericin B did not result in a decrease in the efficacy of amphotericin B by either end point (survival or renal colony counts). High-pressure liquid chromatographic analysis of saperconazole concentrations in serum indicated low levels of absorption of the drug. We conclude that saperconazole is effective in the treatment of murine invasive candidiasis and that the theoretical concern about adverse interactions between the two drugs does not apply to the dosages studied in these experiments.


Transcriptomics in pain research: insights from new and old technologies.
Despite significant advances in our understanding of the molecular basis of pain, the precise contributions of individual genes to our perception of this primal sensation remains incomplete. However, transcriptomic studies - providing a snapshot of the mRNA expression of a given cell or tissue - have considerably increased insight into the gene expression fingerprint of specific sensory neuronal subtypes, as well as gene expression changes that occur in diverse pathologies associated with pain. Moreover, transcriptomic studies have accelerated the identification of venom-derived peptides that may provide novel leads for the development of analgesics. This review discusses some of the key techniques, insights and limitations of transcriptomic studies that have contributed to pain research and highlights how the application of transcriptomics can be used to accelerate analgesic venom peptide drug discovery.


Disease state, age, sex, and post-mortem time-dependent expression of proteins in AD vs. control frontal cortex brain samples.
Human post-mortem brain samples are excellent source material for the analysis of age-related disorders such as Alzheimer's disease (AD). Moreover, data obtained from cell culture- or mouse model-related experiments often need to be validated by using human tissue. In a variety of studies over the last few years, a huge list of genes or proteins with differential expression or abundance between AD-related and control tissue has been reported. However, highly important issues such as changes in post-mortem time, sex, age etc. of the patients have been rarely included in the analysis. In our study we examined human frontal brain samples of 10 AD patients vs. 10 unaffected controls using state-of-the-art two dimensional DIGE proteomics in order to analyze protein expression of up to 10,000 proteins in parallel. Data were analyzed using well established DIGE-software tool as well as an analysis of covariance model including the factor effects of group and sex and the covariable effects of age and post-mortem time. Within this study we report protein expression changes in AD vs. control human frontal brain samples without any influence of other parameters as well as expression changes depending on the parameters mentioned above. In fact, some proteins previously suggested a state of being dysregulated in AD vs. controls revealed age or sex-dependent regulation. Our analysis suggests the necessity of integrating additionally available covariables in comparative proteome studies of two different sets of human tissue.


Heat shock protein is tightly associated with the recombinant human glucocorticoid receptor:glucocorticoid response element complex.
The association of heat shock proteins (hsp) with steroid hormone receptors may have functional significance for steroid receptor action. The association of hsp90 with steroid receptors is thought to maintain the receptors in the nonactivated state until their interaction with the respective ligand. The association of hsp70 with progesterone receptor has been well documented. However, there is evidence both for and against the association of hsp70 with the glucocorticoid receptor (GR). We have examined the interaction between hsp70 and human (h) GR over-expressed in the Baculovirus system. Immunoprecipitation and sucrose gradient centrifugation studies demonstrated the association of hsp70 with both the nonactivated and in vitro activated hGR. We were unable to dissociate hGR and hsp70 by incubation of crude cytosol with 3 mM ATP and 0.5 M NaCl. In vivo activation of hGR did not result in dissociation of hsp70 from hGR. Hsp70 coeluted with hGR from a glucocorticoid response element (GRE)-Sepharose column, suggesting that hsp70 is part of the GRE-hGR complex. Both an anti-hGR antibody and an anti-hsp70 antibody were capable of further retarding the migration of a [32P]GRE-hGR complex in polyacrylamide gels. The in vitro activated hGR has been shown to be highly active in an in vitro transcription system. We speculate that hsp70 may influence the DNA-binding and/or transcriptional activities of hGR.


Alternate oscillations of Martian hydrogen and oxygen upper atmospheres during a major dust storm.
Dust storms on Mars play a role in transporting water from its lower to upper atmosphere, seasonally enhancing hydrogen escape. However, it remains unclear how water is diurnally transported during a dust storm and how its elements, hydrogen and oxygen, are subsequently influenced in the upper atmosphere. Here, we use multi-spacecraft and space telescope observations obtained during a major dust storm in Mars Year 33 to show that hydrogen abundance in the upper atmosphere gradually increases because of water supply above an altitude of 60 km, while oxygen abundance temporarily decreases via water ice absorption, catalytic loss, or downward transportation. Additionally, atmospheric waves modulate dust and water transportations, causing alternate oscillations of hydrogen and oxygen abundances in the upper atmosphere. If dust- and wave-driven couplings of the Martian lower and upper atmospheres are common in dust storms, with increasing escape of hydrogen, oxygen will less efficiently escape from the upper atmosphere, leading to a more oxidized atmosphere. These findings provide insights regarding Mars' water loss history and its redox state, which are crucial for understanding the Martian habitable environment.


Cloning and analysis of ermG, a new macrolide-lincosamide-streptogramin B resistance element from Bacillus sphaericus.
To analyze the regulation of a newly discovered macrolide-lincosamide-streptogramin B resistance element (ermG) found in a soil isolate of Bacillus sphaericus, we cloned this determinant and obtained its DNA sequence. Minicell analysis revealed that ermG specifies a 29,000-dalton protein, the synthesis of which is induced by erythromycin. S1 nuclease mapping was used to identify the transcriptional start site. These experiments demonstrated the presence on the ermG mRNA of a 197 to 198-base leader. Within the leader are two small open reading frames (ORFs) capable of encoding 11- and 19-amino-acid peptides. Each ORF is preceded by a suitably spaced Shine-Dalgarno sequence. The ermG protein is encoded by a large ORF that encodes a 244-amino-acid protein, in agreement with the minicell results. This protein and the 19-amino-acid peptide are highly homologous to the equivalent products of ermC and ermA. We conclude, on the basis of this homology, that ermG encodes an rRNA transmethylase. The leader of ermG can be folded into a structure that sequesters the Shine-Dalgarno sequence and start codon for the large ORF (SD3). On the basis of these data and on the observed greater responsiveness of the ermG system than of the ermC system to low concentrations of erythromycin, we propose a model for the regulation of this gene in which the stalling of a ribosome under the influence of an inducer, while reading either peptide, suffices to uncover SD3 and allow translation of the rRNA transmethylase. The evolution of ermG is discussed.


Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment.
To identify factors associated with outcome after surgical management of intrahepatic cholangiocarcinoma (ICC) and examine the impact of lymph node (LN) assessment on survival. From an international multi-institutional database, 449 patients who underwent surgery for ICC between 1973 and 2010 were identified. Clinical and pathologic data were evaluated using uni- and multivariate analyses. Median tumor size was 6.5 cm. Most patients had a solitary tumor (73%) and no vascular invasion (69%). Median survival was 27 months, and 5-year survival was 31%. Factors associated with adverse prognosis included positive margin status (hazard ratio [HR], 2.20; P < .001), multiple lesions (HR, 1.80; P = .001), and vascular invasion (HR, 1.59; P = .015). Tumor size was not a prognostic factor (HR, 1.03; P = .23). Patients were stratified using the American Joint Committee on Cancer/International Union Against Cancer T1, T2a, and T2b categories (seventh edition) in a discrete step-wise fashion (P < .001). Lymphadenectomy was performed in 248 patients (55%); 74 of these (30%) had LN metastasis. LN metastasis was associated with worse outcome (median survival: N0, 30 months v N1, 24 months; P = .03). Although patients with no LN metastasis were able to be stratified by tumor number and vascular invasion (N0; P < .001), among patients with N1 disease, multiple tumors and vascular invasion, either alone or together, failed to discriminate patients into discrete prognostic groups (P = .34). Although tumor size provides no prognostic information, tumor number, vascular invasion, and LN metastasis were associated with survival. N1 status adversely affected overall survival and also influenced the relative effect of tumor number and vascular invasion on prognosis. Lymphadenectomy should be strongly considered for ICC, because up to 30% of patients will have LN metastasis.


[Perioperatory artificial nutrition].
Malnutrition increases post surgical morbimortality, hospital stance and economical costs. Possibilities of nutritional intervention in surgical patients are important. Early enteral nutrition is better than total parenteral nutrition in patients under surgery. Periroperaoty nutritional support must be administrated to patients with severe or middle undernutrition and will be under surgery, during 7-14 days before surgical intervention, if this intervention could be delayed. Total parenteral nutrition will be not used regularly in patients under mayor digestive surgical procedures. Inmunonutrition has been demonstrated useful in surgical patients. Evidence demonstrates that inmunotritional formulas decrease incidence of infections, hospital stance and time of ventilation in patients in UCI wards. New research areas have been explored in this topic area, carbohydrate utility in presurgical patients and probiotic in enteral formulas.


Immunopharmacological studies on Picrorhiza kurroa Royle-ex-Benth. Part IV: Cellular mechanisms of anti-inflammatory action.
In this work abroagation of anti-inflammatory effect of Picrorhiza kurroa extract (PK) by beta-adrenergic blockade was confirmed, which suggests alteration in cell-surface biology by PK treatment. Blockade of protein synthesis by cycloheximide pretreatment reduced PK effect, suggesting protein mediation. Metabolic inhibitor dinitrophenol inhibited inflammatory cedema equally in control and PK treated animals, and masking of PK effect was concluded. Discriminations of anti-inflammatory mechanism(s) of PK and the latter two cytotoxic agents was inferred from these observations and from existing knowledge. Selective PK influence on membrane linked activation events in inflammatory effector cells could be the basis of anti-inflammatory and perhaps other biological activities reported with the herb.


Dimensions of adolescent motherhood in India.
The practice of early marriage of girls is still widely followed in India. The expectation in the Indian sociocultural milieu that after marriage a woman will become pregnant as soon as possible encourages early onset of maternity and higher adolescent fertility. The age-specific fertility rate for married Indian women 15-19 years ranged between 83 and 89 in the last decade.


Treatment of Rheumatoid Arthritis Using Combination of Methotrexate and Tripterygium Glycosides Tablets-A Quantitative Plasma Pharmacochemical and Pseudotargeted Metabolomic Approach.
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by chronic destructive synovitis and is associated with progressive disability, systemic difficulties, premature death, and socioeconomic costs. Early intervention with disease-modifying antirheumatic drugs (DMARDs) like methotrexate (MTX) and its combination regimen would provide obvious benefits to patients, healthcare systems and society. MTX and tripterygium glycosides tablets (TGTS) are most frequently prescribed medicines for RA, and the combination of them occurs frequently in anti-RA prescriptions. While the underlying combination mechanisms and the affected variation of drug blood level remain unclear. According to the American College of Rheumatology criteria for improvement, clinical evaluation following three treatment groups (i.e., MTX and TGTS mono- and combined groups) were carried out at baseline and at the end of 12 weeks in a randomized controlled clinical trial. To monitor the affected variation of drug blood level and perturbation of metabolites caused by MTX plus TGTS combined to treat active RA, the collected plasma samples were analyzed using RRLC-QqQ-MS and UHPLC-QE Orbitrap HRMS instruments. As a result, 39 metabolites including 7 MTX-related metabolites, 13 TGTS-related migratory ingredients and 19 characteristic endogenous metabolites, were quantitatively determined in plasma samples of RA patients after oral administration. The potential mechanism of MTX and TGTS combination were preliminarily elucidated on the aspect of clinical biochemical test indicators integrated with quantitative plasma pharmacochemistry and the pseudotargeted metabolomics.


Follicle-stimulating hormone (FSH) during the secondary surge in gilts as influenced by administration of porcine follicular fluid (pFF).
The effect of volume and frequency of administration of porcine follicular fluid (pFF) on FSH concentration was determined in mature gilts during the period of the secondary FSH surge (d 0 to 5; d 0 = onset of estrus) and following withdrawal of pFF (d 5.5 to 9). Crossbred gilts (n = 14) were randomized in a 3 x 2 factorial treatment design involving three doses of pFF (0, 5, or 10 ml) and once- vs twice-daily pFF administration. Porcine FF was aspirated from medium and large follicles and treated with 5 mg of activated charcoal per milliliter of pFF to remove steroids. Once-daily administration of pFF, regardless of dose, failed to suppress mean concentrations of FSH during the secondary FSH surge. Treatment of gilts twice daily with 10 ml of pFF suppressed (P less than .05) area under the FSH curve during the secondary FSH surge compared with gilts given saline. Gilts treated twice daily with 5 ml pFF showed comparable suppression of plasma FSH from d 0 to 3 but began to overcome FSH inhibition after d 3. As a result, FSH release only tended to be lower than controls for the entire treatment period (P less than .1). Mean FSH concentrations were increased (P less than .05) during the post-treatment period (d 5.5 to 9) by treatment with intermediate (5 ml pFF, two times daily and 10 ml pFF, one time daily) and high (10 ml pFF, two times daily) doses of pFF. Neither ovulation rate nor interestrous interval was affected by pFF administration.(ABSTRACT TRUNCATED AT 250 WORDS)


Chloride channels in the eel intestine
Patches of freshly isolated epithelial cells from eel Anguilla anguilla intestine bathed by the same solution on both sides in the cell-attached configuration had conductances of 57.0+/-1.8 pS (for positive voltages) and 13.3+/-0.7 pS (for negative voltages) (means +/- s.e.m., N=25). Electrical activity was spontaneous in the cell-attached configuration, but was frequently lost after excision. In inside-out patches, channel activity was restored by strong hyperpolarization (-150 mV for 5 s) or depolarization (+150 mV for 5 s). Channel activity was inhibited by the Cl- transport blocker DIDS (1 mmol l-1). The membrane potential measured using the nystatin slow whole-cell technique in primary cultured eel intestine epithelial cells was -35.4+/-1.0 mV (N=14), similar to the expected equilibrium potential for Cl- (-38.2 mV). Removal of Cl- from the bath or application of DIDS caused 16 mV and 6-7 mV depolarizing shifts in reversal potential, respectively. In one experiment, DIDS also induced a reduction in cell conductance from 0. 011+/-0.014 to 0.002+/-0.005 nS. The addition of 0.5 mmol l-1 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (a membrane-permeable analogue of cyclic AMP) to the bath caused an increase in conductance without affecting the reversal potential.


In vitro toxicity of kava alkaloid, pipermethystine, in HepG2 cells compared to kavalactones.
Kava herbal supplements have been recently associated with acute hepatotoxicity, leading to the ban of kava products in approximately a dozen countries around the world. It is suspected that some alkaloids from aerial kava may have contributed to the problem. Traditionally, Pacific Islanders use primarily the underground parts of the shrub to prepare the kava beverage. However, some kava herbal supplements may contain ingredients from aerial stem peelings. The aim of this study was to test the in vitro effects of a major kava alkaloid, pipermethystine (PM), found mostly in leaves and stem peelings, and kavalactones such as 7,8-dihydromethysticin (DHM) and desmethoxyyangonin (DMY), which are abundant in the roots. Exposure of human hepatoma cells, HepG2, to 100 microM PM caused 90% loss in cell viability within 24 h, while 50 microM caused 65% cell death. Similar concentrations of kavalactones did not affect cell viability for up to 8 days of treatment. Mechanistic studies indicate that, in contrast to kavalactones, PM significantly decreased cellular ATP levels, mitochondrial membrane potential, and induced apoptosis as measured by the release of caspase-3 after 24 h of treatment. These observations suggest that PM, rather than kavalactones, is capable of causing cell death, probably in part by disrupting mitochondrial function. Thus, PM may contribute to rare but severe hepatotoxic reactions to kava.


Amelioration of experimental autoimmune uveitis by leflunomide in Lewis rats.
To investigate the efficacy of leflunomide in experimental autoimmune uveitis (EAU) in rats. Lewis rats were immunized with interphotoreceptor retinoid-binding peptide (IRBP) in order to generate EAU. Rats received three dose of leflunomide through intragastric administration (prevention or treatment protocols) after immunization at three separate doses (3 mg/kg/d; 6 mg/kg/d; 12 mg/kg/d). Cyclosporin A was administered as a positive) control. Rats were euthanized during peak disease activity (day 14 or 15). Treatment effectiveness was evaluated in vivo using clinical EAU scoring (d14) and histopathological evaluation of enucleated eyes after experimental termination. The expression levels of inflammatory cytokines in the serum were quantified by ELISA. Eyeball of rats were harvested and mRNA expression of interleukin 17 (IL17) and IFN-γ were quantified through RT-PCR. Intracellular expression of interleukin (IL)-17 in the activated CD4(+) T cells was assessed by flow cytometry. The effects of leflunomide inhibition on immune responses in rats were investigated in isolated lymphocytes. Histopathological and clinical data revealed severe intraocular inflammation in the immunized rat. Inflammation reached its peak on day 14 in this EAU model. Treatment with leflunomide significantly prevented and treated EAU-induced ocular inflammation and decreased clinical and pathological scores compared to vehicle-treated eyes. Gene expression of IL17 and IFN-γ was markedly reduced in leflunomide-treated eyes. Leflunomide significantly decreased the serum levels of IL17 and IFN-γ. The study of IL17+ T cells in peripheral blood and spleen by flow cytometry showed a decreased number of Th17 cell in rats of leflunomide prevented group. Lymphocytes from animals treated with leflunomide had decreased antigen-specific proliferation in vitro compared with lymphocytes from untreated animals. Oral administration of leflunomide effectively suppressed IRBP-induced uveitis in rats. These results suggest that leflunomide may be potentially clinical application in uveitis.


Underuse of coronary revascularization procedures: application of a clinical method.
Our main objective was to apply a new method to determine whether coronary revascularization procedures are underused, especially among African-Americans and uninsured patients. Although overuse of revascularization procedures has been studied, underuse as defined clinically has not been examined before. The study was conducted at four public and two academically affiliated private hospitals in Los Angeles; 671 patients who underwent coronary angiography between June 1, 1990 and September 30, 1991 and met explicit clinical criteria for coronary revascularization were included. The main outcome measure was the proportion of patients undergoing an indicated procedure within 12 months (ascertained by medical record review and confirmed with a telephone survey). Adjusted relative odds of undergoing an indicated procedure for African-Americans and patients in public hospitals compared with whites and patients in private hospitals were calculated. Overall, 75% of patients underwent a revascularization procedure. Of 424 patients requiring bypass surgery, 107 angioplasty and 140 either bypass surgery or angioplasty, 59%, 66% and 75% underwent the procedure, respectively. African-Americans were less likely than whites to undergo operation (adjusted odds ratio [OR] 0.49, p < 0.05) and angioplasty (adjusted OR 0.20, p < 0.05). Patients in public hospitals were less likely than those in private hospitals to undergo angioplasty (adjusted OR 0.10, p < 0.005). Underuse of coronary revascularization procedures is measurable and occurs to a significant degree even among insured patients attending private hospitals. Underuse is especially pronounced among African-Americans and patients attending public hospitals. Future cost-containment efforts must incorporate safeguards against underuse of necessary care.


The MUC1 SEA module is a self-cleaving domain.
MUC1, a glycoprotein overexpressed by a variety of human adenocarcinomas, is a type I transmembrane protein (MUC1/TM) that soon after its synthesis undergoes proteolytic cleavage in its extracellular domain. This cleavage generates two subunits, alpha and beta, that specifically recognize each other and bind together in a strong noncovalent interaction. Proteolysis occurs within the SEA module, a 120-amino acid domain that is highly conserved in a number of heavily glycosylated mucin-like proteins. Post-translational cleavage of the SEA module occurs at a site similar to that in MUC1 in the glycoproteins IgHepta and MUC3. However, as in the case of other proteins containing the cleaved SEA module, the mechanism of MUC1 proteolysis has not been elucidated. Alternative splicing generates two transmembrane MUC1 isoforms, designated MUC1/Y and MUC1/X. We demonstrated here that MUC1/X, whose extracellular domain is comprised solely of the SEA module in addition to 30 MUC1 N-terminal amino acids, undergoes proteolytic cleavage at the same site as the MUC1/TM protein. In contrast, the MUC1/Y isoform, composed of an N-terminally truncated SEA module, is not cleaved. Cysteine or threonine mutations of the MUC1/X serine residue (Ser-63) immediately C-terminal to the cleavage site generated cleaved proteins, whereas mutation of the Ser-63 residue of MUC1/X to any other of 17 amino acids did not result in cleavage. In vitro incubation of highly purified precursor MUC1/X protein resulted in self-cleavage. Furthermore, addition of hydroxylamine, a strong nucleophile, markedly enhanced cleavage. Both these features are signature characteristics of self-cleaving proteins, and we concluded that MUC1 undergoes autoproteolysis mediated by an N --> O-acyl rearrangement at the cleavage site followed by hydrolytic resolution of the unstable ester and concomitant cleavage. It is likely that all cleaved SEA module-containing proteins follow a similar route.


Induction of apoptosis in mouse [correction of rat] olfactory neuroepithelium by synaptic target ablation.
The olfactory system provides a useful in vivo model for studying the influence of synaptic targets on the survival of relay neurones. The bipolar sensory neurones located in the olfactory mucosa project synaptically onto the ipsilateral olfactory bulb, and their survival depends on the integrity of this connection. We demonstrate here that the retrograde neuronal degeneration induced by olfactory bulb removal involves apoptosis. As revealed by typical nucleosome-sized fragmentations of the genomic DNA, the apoptosis rate reaches a maximum 32 h after bulbectomy. A transient c-fos mRNA accumulation was detected, peaking 16 h after bulbectomy, suggesting that c-fos is involved in the early steps of programmed cell death.


Public anxiety and information seeking following the H1N1 outbreak: blogs, newspaper articles, and Wikipedia visits.
Web-based methodologies may provide a new and unique insight into public response to an infectious disease outbreak. This naturalistic study investigates the effectiveness of new web-based methodologies in assessing anxiety and information seeking in response to the 2009 H1N1 outbreak by examining language use in weblogs ("blogs"), newspaper articles, and web-based information seeking. Language use in blogs and newspaper articles was assessed using Linguistic Inquiry and Word Count, and information seeking was examined using the number of daily visits to H1N1-relevant Wikipedia articles. The results show that blogs mentioning "swine flu" used significantly higher levels of anxiety, health, and death words and lower levels of positive emotion words than control blogs. Change in language use on blogs was strongly related to change in language use in newspaper coverage for the same day. Both the measure of anxiety in blogs mentioning "swine flu" and the number of Wikipedia visits followed similar trajectories, peaking shortly after the announcement of H1N1 and then declining rapidly. Anxiety measured in blogs preceded information seeking on Wikipedia. These results show that the public reaction to H1N1 was rapid and short-lived. This research suggests that analysis of web behavior can provide a source of naturalistic data on the level and changing pattern of public anxiety and information seeking following the outbreak of a public health emergency.


Acute oxygen sensing by the carotid body: a rattlebag of molecular mechanisms.
The molecular underpinnings of the oxygen sensitivity of the carotid body Type I cells are becoming better defined as research begins to identify potential interactions between previously separate theories. Nevertheless, the field of oxygen chemoreception still presents the general observer with a bewildering array of potential signalling pathways by which a fall in oxygen levels might initiate Type I cell activation. The purpose of this brief review is to address five of the current oxygen sensing hypotheses: the lactate-Olfr 78 hypothesis of oxygen chemotransduction; the role mitochondrial ATP and metabolism may have in chemotransduction; the AMP-activated protein kinase hypothesis and its current role in oxygen sensing by the carotid body; reactive oxygen species as key transducers in the oxygen sensing cascade; and the mechanisms by which H2 S, reactive oxygen species and haem oxygenase may integrate to provide a rapid oxygen sensing transduction system. Over the previous 15 years several lines of research into acute hypoxic chemotransduction mechanisms have focused on the integration of mitochondrial and membrane signalling. This review places an emphasis on the subplasmalemmal-mitochondrial microenvironment in Type I cells and how theories of acute oxygen sensing are increasingly dependent on functional interaction within this microenvironment.


Effect of albumin on human liver microsomal and recombinant CYP1A2 activities: impact on in vitro-in vivo extrapolation of drug clearance.
Long-chain unsaturated fatty acids inhibit several cytochrome P450 and UDP-glucuronosyltransferase (UGT) enzymes involved in drug metabolism, including CYP2C8, CYP2C9, UGT1A9, UGT2B4, and UGT2B7. Bovine serum albumin (BSA) enhances these cytochrome P450 and UGT activities by sequestering fatty acids that are released from membranes, especially with human liver microsomes (HLM) as the enzyme source. Here, we report the effects of BSA on CYP1A2-catalyzed phenacetin (PHEN) O-deethylation and lidocaine (LID) N-deethylation using HLM and Escherichia coli-expressed recombinant human CYP1A2 (rCYP1A2) as the enzyme sources. BSA (2% w/v) reduced (p < 0.05) the K(m) values of the high-affinity components of human liver microsomal PHEN and LID deethylation by approximately 70%, without affecting V(max). The K(m) (or S(50)) values for PHEN and LID deethylation by rCYP1A2 were reduced to a similar extent. A fatty acid mixture, comprising 3 μM concentrations each of oleic acid and linoleic acid plus 1.5 μM arachidonic acid, doubled the K(m) value for PHEN O-deethylation by rCYP1A2. Inhibition was reversed by the addition of BSA. K(i) values for the individual fatty acids ranged from 4.7 to 16.7 μM. Single-point in vitro-in vivo extrapolation (IV-IVE) based on the human liver microsomal kinetic parameters obtained in the presence, but not absence, of BSA predicted in vivo hepatic clearances of PHEN O-deethylation and LID N-deethylation that were comparable to values reported in humans, although in vivo intrinsic clearances were underpredicted. Prediction of the in vivo clearances of the CYP1A2 substrates observed here represents an improvement on other experimental systems used for IV-IVE.


Blue Light Enhances Bacterial Clearance and Reduces Organ Injury During Sepsis.
The physiology of nearly all mammalian organisms are entrained by light and exhibit circadian rhythm. The data derived from animal studies show that light influences immunity, and these neurophysiologic pathways are maximally entrained by the blue spectrum. Here, we hypothesize that bright blue light reduces acute kidney injury by comparison with either bright red or standard, white fluorescent light in mice subjected to sepsis. To further translational relevance, we performed a pilot clinical trial of blue light therapy in human subjects with appendicitis. Laboratory animal research, pilot human feasibility trial. University basic science laboratory and tertiary care hospital. Male C57BL/6J mice, adult (> 17 yr) patients with acute appendicitis. Mice underwent cecal ligation and puncture and were randomly assigned to a 24-hour photoperiod of bright blue, bright red, or ambient white fluorescent light. Subjects with appendicitis were randomized to receive postoperatively standard care or standard care plus high-illuminance blue light. Exposure to bright blue light enhanced bacterial clearance from the peritoneum, reduced bacteremia and systemic inflammation, and attenuated the degree of acute kidney injury. The mechanism involved an elevation in cholinergic tone that augmented tissue expression of the nuclear orphan receptor REV-ERBα and occurred independent of alterations in melatonin or corticosterone concentrations. Clinically, exposure to blue light after appendectomy was feasible and reduced serum interleukin-6 and interleukin-10 concentrations. Modifying the spectrum of light may offer therapeutic utility in sepsis.


Surface extensions of 3T3 cells towards distant infrared light sources.
Using a specially designed phase-contrast light microscope with an infrared spot illuminator we found that approximately 25% of 3T3 cells were able to extend pseudopodia towards single microscopic infrared light sources nearby. If the cells were offered a pair of such light sources next to each other, 47% of the cells extended towards them. In the latter case 30% of the responding cells extended separate pseudopodia towards each individual light source of a pair. The strongest responses were observed if the infrared light sources emitted light of wavelengths in the range of 800-900 nm intermittently at rates of 30-60 pulses per min. The temperature increases of the irradiated spots can be shown to be negligible. The results suggest that the cells are able to sense specific infrared wavelengths and to determine the direction of individual sources.


Free vascularized fibular grafting preserves athletic activity level in patients with osteonecrosis.
Athletic patients with osteonecrosis of the femoral head have few desirable therapeutic options that preserve athletic ability. Because these patients are usually young and healthy, any procedure that avoids total hip arthroplasty would be most desirable. This study prospectively evaluated 15 patients (19 hips) who presented with an average age of 28.5 (range, 12 to 46) years and stages 2 (6/19), 3 (2/19), 4 (9/19), and 5 (2/19) of osteonecrosis of the femoral head. All patients were treated with free vascularized fibular autografting (FVFG) to the femoral head. Postoperative evaluations of pain symptoms and functional activity showed improvements in all patients. The average follow-up time was 8 years. Harris hip scores significantly increased from an average preoperative score of 75.3 to an average postoperative score of 94.8. Seventy-five percent of patients were able to return to their sport after recovery and all patients reported being satisfied with the procedure and would repeat their decision to have surgery. Three patients' hips were converted to arthroplasty at 3, 11, and 17 years post-FVFG. The results demonstrate that FVFG is a successful therapeutic treatment in athletes with osteonecrosis of the femoral head. It reduces pain, increases activity, and allows most patients to return to their sport, an achievement often not possible with other treatment options.


Delaying defibrillation to give basic cardiopulmonary resuscitation to patients with out-of-hospital ventricular fibrillation: a randomized trial.
Defibrillation as soon as possible is standard treatment for patients with ventricular fibrillation. A nonrandomized study indicates that after a few minutes of ventricular fibrillation, delaying defibrillation to give cardiopulmonary resuscitation (CPR) first might improve the outcome. To determine the effects of CPR before defibrillation on outcome in patients with ventricular fibrillation and with response times either up to or longer than 5 minutes. Randomized trial of 200 patients with out-of-hospital ventricular fibrillation in Oslo, Norway, between June 1998 and May 2001. Patients received either standard care with immediate defibrillation (n = 96) or CPR first with 3 minutes of basic CPR by ambulance personnel prior to defibrillation (n = 104). If initial defibrillation was unsuccessful, the standard group received 1 minute of CPR before additional defibrillation attempts compared with 3 minutes in the CPR first group. Primary end point was survival to hospital discharge. Secondary end points were hospital admission with return of spontaneous circulation (ROSC), 1-year survival, and neurological outcome. A prespecified analysis examined subgroups with response times either up to or longer than 5 minutes. In the standard group, 14 (15%) of 96 patients survived to hospital discharge vs 23 (22%) of 104 in the CPR first group (P =.17). There were no differences in ROSC rates between the standard group (56% [58/104]) and the CPR first group (46% [44/96]; P =.16); or in 1-year survival (20% [21/104] and 15% [14/96], respectively; P =.30). In subgroup analysis for patients with ambulance response times of either up to 5 minutes or shorter, there were no differences in any outcome variables between the CPR first group (n = 40) and the standard group (n = 41). For patients with response intervals of longer than 5 minutes, more patients achieved ROSC in the CPR first group (58% [37/64]) compared with the standard group (38% [21/55]; odds ratio [OR], 2.22; 95% confidence interval [CI], 1.06-4.63; P =.04); survival to hospital discharge (22% [14/64] vs 4% [2/55]; OR, 7.42; 95% CI, 1.61-34.3; P =.006); and 1-year survival (20% [13/64] vs 4% [2/55]; OR, 6.76; 95% CI, 1.42-31.4; P =.01). Thirty-three (89%) of 37 patients who survived to hospital discharge had no or minor reductions in neurological status with no difference between the groups. Compared with standard care for ventricular fibrillation, CPR first prior to defibrillation offered no advantage in improving outcomes for this entire study population or for patients with ambulance response times shorter than 5 minutes. However, the patients with ventricular fibrillation and ambulance response intervals longer than 5 minutes had better outcomes with CPR first before defibrillation was attempted. These results require confirmation in additional randomized trials.


2-DE proteomics analysis of drought treated seedlings of Quercus ilex supports a root active strategy for metabolic adaptation in response to water shortage.
Holm oak is a dominant tree in the western Mediterranean region. Despite being well adapted to dry hot climate, drought is the main cause of mortality post-transplanting in reforestation programs. An active response to drought is critical for tree establishment and survival. Applying a gel-based proteomic approach, dynamic changes in root proteins of drought treated Quercus ilex subsp. Ballota [Desf.] Samp. seedlings were followed. Water stress was applied on 20 day-old holm oak plantlets by water limitation for a period of 10 and 20 days, each followed by 10 days of recovery. Stress was monitored by changes in water status, plant growth, and electrolyte leakage. Contrary to leaves, holm oak roots responded readily to water shortage at physiological level by growth inhibition, changes in water status and membrane stability. Root proteins were extracted using trichloroacetate/acetone/phenol protocol and separated by two-dimensional electrophoresis. Coomassie colloidal stained gel images were analyzed and spot intensity data subjected to multivariate statistical analysis. Selected consistent spots in three biological replicas, presenting significant changes under stress, were subjected to MALDI-TOF mass spectrometry (peptide mass fingerprinting and MS/MS). For protein identification, combined search was performed with MASCOT search engine over NCBInr Viridiplantae and Uniprot databases. Data are available via ProteomeXchange with identifier PXD002484. Identified proteins were classified into functional groups: metabolism, protein biosynthesis and proteolysis, defense against biotic stress, cellular protection against abiotic stress, intracellular transport. Several enzymes of the carbohydrate metabolism decreased in abundance in roots under drought stress while some related to ATP synthesis and secondary metabolism increased. Results point at active metabolic adjustment and mobilization of the defense system in roots to actively counteract drought stress.


ChIP-Atlas 2021 update: a data-mining suite for exploring epigenomic landscapes by fully integrating ChIP-seq, ATAC-seq and Bisulfite-seq data.
ChIP-Atlas (https://chip-atlas.org) is a web service providing both GUI- and API-based data-mining tools to reveal the architecture of the transcription regulatory landscape. ChIP-Atlas is powered by comprehensively integrating all data sets from high-throughput ChIP-seq and DNase-seq, a method for profiling chromatin regions accessible to DNase. In this update, we further collected all the ATAC-seq and whole-genome bisulfite-seq data for six model organisms (human, mouse, rat, fruit fly, nematode, and budding yeast) with the latest genome assemblies. These together with ChIP-seq data can be visualized with the Peak Browser tool and a genome browser to explore the epigenomic landscape of a query genomic locus, such as its chromatin accessibility, DNA methylation status, and protein-genome interactions. This epigenomic landscape can also be characterized for multiple genes and genomic loci by querying with the Enrichment Analysis tool, which, for example, revealed that inflammatory bowel disease-associated SNPs are the most significantly hypo-methylated in neutrophils. Therefore, ChIP-Atlas provides a panoramic view of the whole epigenomic landscape. All datasets are free to download via either a simple button on the web page or an API.


Attachment Characteristics Among Women Victimized in No, One, and Multiple IPV Relationships: A Case-Control Study.
This cross-sectional study compared attachment characteristics among women victimized by intimate partner violence (IPV) in no, one, and multiple relationships (N = 154). Results indicated that compared with the nonvictimized, victimized women had increased likelihood of higher attachment avoidance. Compared with women victimized in one relationship, women victimized in multiple relationships had higher likelihood of higher attachment anxiety scores. Adjusting for childhood adversities, childhood sexual abuse was an independent risk factor for IPV. Childhood emotional abuse mediated the association between attachment anxiety and IPV victimization in multiple relationships in particular. Attachment theory appeared useful for better understanding women's vulnerability for multiple violent relationships.


Improved light extraction in the bioluminescent lantern of a Photuris firefly (Lampyridae).
A common problem of light sources emitting from an homogeneous high-refractive index medium into air is the loss of photons by total internal reflection. Bioluminescent organisms, as well as artificial devices, have to face this problem. It is expected that life, with its mechanisms for evolution, would have selected appropriate optical structures to get around this problem, at least partially. The morphology of the lantern of a specific firefly in the genus Photuris has been examined. The optical properties of the different parts of this lantern have been modelled, in order to determine their positive or adverse effect with regard to the global light extraction. We conclude that the most efficient pieces of the lantern structure are the misfit of the external scales (which produce abrupt roughness in air) and the lowering of the refractive index at the level of the cluster of photocytes, where the bioluminescent production takes place.


Chemotherapy for advanced thymoma. Preliminary results of an intergroup study.
To determine the efficacy of combination therapy with cisplatin, doxorubicin, and cyclophosphamide alone or with radiotherapy for patients with extensive and those with limited unresectable thymoma. Nonrandomized, prospective phase I-II trial. A Cooperative Oncology Group trial involving tertiary medical centers. Twenty of twenty-two patients with measurable, extensive or limited, unresectable thymoma were evaluable for response. Patients were given cisplatin, 50 mg/m2 body surface area, doxorubicin, 50 mg/m2, and cyclophosphamide, 500 mg/m2, on day 1, with cycles repeated every 21 days until progression or until the maximally tolerated total doxorubicin dosage (for example, 450 mg/m2) was reached. Intravenous hydration with normal saline was administered during treatment courses. For responding patients with limited disease, 4500 cGy was administered to primary tumors after the second cycle of chemotherapy and before the initiation of the third cycle. Three complete and eleven partial remissions were seen in 20 evaluable patients, for a total response rate of 70% (95% CI, 46% to 88%). The median duration of remission was 13 months with three patients remaining continuously disease free for over 2 years. The median survival time of all eligible patients was 59 months (CI, 22 months to infinity). Four patients developed infections, including listerial and aseptic meningitides, mucocutaneous candidiasis, and cryptococcal pneumonia, that were indicative of a defect in cell-mediated immunity. Combination therapy with cisplatin, doxorubicin, and cyclophosphamide frequently produces objective remissions in patients with advanced thymoma. Further experience with this treatment regimen is warranted to clarify potential prognostic factors in patients with unresectable thymoma.


DSM-III, draft DSM-III-R, and the diagnosis and prevalence of bulimia in Australia.
A self-report questionnaire for bulimic symptoms was administered to three different groups of community residents and to patients in a hospital's weight disorders unit and its dietetics department. The prevalence of DSM-III bulimia was 12.7% among female community residents, while the prevalence of draft DSM-III-R bulimia was 1.7%. The questionnaire, scored to reflect DSM-III, categorized as bulimic large numbers of patients who were not given that diagnosis by clinicians. The draft DSM-III-R criteria seemed more closely aligned to clinical experience.


Linking an agency strategic review to increase knowledge management: San Francisco County Human Service Agency.
Led by the agency director, the agency engaged in a Strategic Review, based on a comprehensive assessment of agency performance that identified strategies to improve organizational effectiveness through increased data-informed practice and knowledge management. The Strategic Review gathered information on staff perceptions, perceptions of external stakeholders, changing citywide and neighborhood demographics, policy mandates, and budget and workload issues. The need for the review was based upon multiple, substantial changes not addressed in the 2000 Strategic Plan, including the 2004 merger of the Department of Human Services and the Department of Aging and Adult Services, changes among the executive management team, transitions among key political entities, new policy mandates and changing budget allocations. This case study describes the Strategic Review process and content, summarizing key challenges and lessons related to addressing workload demands, fostering positive staff attitudes, balancing internal and external information needs, and integrating data use and planning processes across the agency.


Toward a model of school inspections in a polycentric system.
Many education systems are developing towards more lateral structures where schools collaborate in networks to improve and provide (inclusive) education. These structures call for bottom-up models of network evaluation and accountability instead of the current hierarchical arrangements where single schools are evaluated by a central agency. This paper builds on available research about network effectiveness to present evolving models of network evaluation. Network effectiveness can be defined as the achievement of positive network level outcomes that cannot be attained by individual organizational participants acting alone. Models of network evaluation need to take into account the relations between network members, the structure of the network, its processes and its internal mechanism to enforce norms in order to understand the achievement and outcomes of the network and how these may evolve over time. A range of suitable evaluation models are presented in this paper, as well as a tentative school inspection framework which is inspired by these models. The final section will present examples from Inspectorates of Education in Northern Ireland and Scotland who have developed newer inspection models to evaluate the effectiveness of a range of different networks.


Logotherapy for clinical practice.
Logotherapy is based on the meaning-focused existential philosophy of Viktor E. Frankl (1905-1997). Numerous mental health professionals have been inspired by his most popular book, Man's Search for Meaning; however, many are unfamiliar with the depth of Frankl's work. The purpose of this article is to discuss the tenets of logotherapy, including fundamental concepts, applicability and techniques, roles of the therapist, and assessment tools and new research findings. Logotherapy can readily be integrated with techniques that mental health professionals frequently use, and thus it has much to offer mental health professionals regardless of their theoretical orientation. (PsycINFO Database Record (c) 2010 APA, all rights reserved).


Sense of coherence mediates the relationship between digital health literacy and anxiety about the future in aging population during the COVID-19 pandemic: a path analysis.
Objectives: During the COVID-19 pandemic, older adults experience various challenges, including information uncertainties, financial pressure, and visit restrictions, which may lead to anxiety about the future. As a protective factor, sense of coherence (SOC) may play a role to reduce some psychological discomfort. This study aimed to analyze the relationships of SOC with anxiety, digital health literacy (DHL), information, and financial satisfaction among older adults during the outbreak.Methods: This is part of a large-scale DHL study with a cross-sectional survey across 41 countries. This study extracted data from three Asian countries (China, the Philippines, and Singapore) and included people aged ≥60. Structural equation modeling with path analysis was utilized to examine the relationships of SOC with anxiety about the future and other variables.Results: A total of 266 older adults were included, with 43.2% expressed anxiety about the future. DHL (β=-0.13, p < 0.05) and SOC (β=-0.26, p = 0.01) were negatively associated with anxiety, while financial and information satisfaction were not. However, financial satisfaction (β = 0.34, p < 0.01) and DHL (β = 0.32, p = 0.01) were positively associated with SOC. Higher SOC further mediated the negative relationships of DHL (β= -0.11, p = 0.004) and financial satisfaction (β= -0.12, p = 0.004) on anxiety of older adults.Conclusions: SOC had direct negative effect on anxiety and mediated the relationships between anxiety and DHL/financial satisfaction. Strategies should be developed to enhance SOC and DHL among older adults, as these capacities may help to manage anxiety during the pandemic.


A large open-label study of venlafaxine in depressed outpatients by community-based physicians.
Studies to date suggest that venlafaxine is effective, well tolerated, and safe in a broad spectrum of patients. We examined the clinical utility and tolerability of venlafaxine in patients treated by community-based psychiatrists and family physicians in a naturalistic clinical setting. Nineteen physicians each recruited 10 to 20 physicians to enroll 5 patients each maximum, diagnosed with DSM-IV major depression or dysthymia. The patients were at least moderately ill (Clinical Global Impressions) with a score of at least 32 on the Zung Self-Rating Depression Scale. After baseline clinical and laboratory assessments, each patient received 37.5 mg of venlafaxine b.i.d., with adjustments possible at the 5 visits during the next 8 weeks. Of the 880 patients at baseline, 682 completed the 8-week study. The daily doses of venlafaxine ranged between 18.75 mg and 375 mg, with 80% receiving between 75 and 150 mg/day by 8 weeks. The intent-to-treat analysis revealed that at 8 weeks, 62% (522 of 843) of patients were either much or very much improved. Nausea was the most frequent side effect, followed by somnolence, headache, and dry mouth. Venlafaxine has good clinical utility and tolerability in a community-based sample of a broad spectrum of depressed outpatients.


Malondialdehyde-protein adducts in the spleens of aniline-treated rats: immunochemical detection and localization.
Previously it was reported that aniline exposure in rats induces increased lipid peroxidation and formation of malondialdehyde (MDA)-protein adducts in the spleen. In order to further elucidate the role of MDA-protein adducts in the splenic toxicity of aniline, studies were conducted to detect and localize these adducts in the spleen. Rabbit polyclonal antisera to MDA-keyhole limpet hemocyanin were employed for immunohistochemical localization and Western blot analyses of MDA-protein adducts in the spleens of aniline-treated (65 mg/kg/d aniline in the drinking water for 30 d) and control rats. For immunohistochemical localization of MDA-protein adducts in the spleen, a new approach using alkaline phosphatase-fast red (red color) to demonstrate bound primary antibodies was adopted, providing a sharper and increased contrast compared to horseradish peroxidase-diaminobenzidine (brown color) methodology. This new approach allowed us to differentiate the changes in aniline-treated spleens, which had extensive brownish deposits of iron proteins. Spleens from aniline-treated rats showed intense staining for these adducts in the red pulp areas (where iron was also localized), especially within the sinusoidal macrophages. Spleens from control rats showed only mild staining for adducts and only traces of iron. Western blot analyses of splenic microsomal proteins from aniline-treated and control rats showed the presence of 13 different MDA-modified proteins. However, 26-, 32-, and 14-kD proteins were more prominent in the aniline-treated rats. The colocalization of MDA-protein adducts with iron in the red pulp of the spleen suggests that iron-catalyzed lipid peroxidation leading to formation of MDA-protein adducts could be a potential mechanism for splenic toxicity of aniline.


Effects of Phonomotor Treatment on discourse production.
Aphasia is an acquired language disorder that makes it difficult for people to produce and comprehend language, with every person with aphasia (PWA) demonstrating difficulty accessing and selecting words (anomia). While aphasia treatments typically focus on a single aspect of language, such as word retrieval, the ultimate goal of aphasia therapy is to improve communication, which is best seen at the level of discourse. This retrospective study investigated the effects of one effective anomia therapy, Phonomotor Treatment, on discourse production. Twenty-six PWA participated in 60 hours of Phonomotor Treatment, which focuses on building a person's ability to recognise, produce, and manipulate phonemes in progressively longer non-word and real-word contexts. Language samples were collected prior to, immediately after, and three months after the treatment program. Percent Correct Information Units (CIUs) and CIUs per minute were calculated. Overall, PWA showed significantly improved CIUs per minute, relative to baseline, immediately after treatment and three months later, as well as significantly improved percent CIUs, relative to baseline, three months following treatment. Phonomotor Treatment, which focuses on phonological processing, can lead to widespread improvement throughout the language system, including to the functionally critical level of discourse production.


A near-infrared fluorescent probe for ratiometric sensing of SO2 in cells and zebrafish.
Developing suitable molecular tools for monitoring SO2 and its derivatives in living organisms is attractive due to their importance for human health. Herein, the first near-infrared fluorescent probe Mito-HN with aggregation-induced emission enhancement (AIEE) characteristics for ratiometric sensing of SO2 derivatives in vitro, in cells, and in zebrafish was designed and synthesized. By connecting the electron-donating naphthopyran and electron-withdrawing hemicyanine via the alkenyl group, this probe displays a near-infrared fluorescence emission and notable solid-state luminescence with AIEE features. Based on the specific 1,4-addition reaction of HSO3-/SO32- with the C[double bond, length as m-dash]C double bond of Mito-HN, this probe can specifically sense HSO3- in real time with an excellent near-infrared ratiometric fluorescence effect, a low detection limit of 0.17 μM, and a fast response time of less than 30 s. Cell imaging and zebrafish imaging results demonstrate that Mito-HN can ratiometrically not only sense endogenous SO2 derivatives in mitochondria but also monitor SO2 in living organisms. We anticipate that Mito-HN could be applied for the diagnosis of SO2-related diseases in the future.


The self-evaluation of Slovenian prospective chemistry teachers' progress during their practical pedagogical training in primary schools.
The present research deals with the self-evaluation of prospective chemistry teachers' progress during their practical pedagogical training (PPT) in primary schools. The sample consisted of 42 students from the 3rd and 4th years of the undergraduate programmes "Chemistry and Biology" or "Chemistry and Physics" at the Faculty of Education, University of Ljubljana. For the purpose of the investigation, the students completed questionnaires after each day of their practical pedagogical training, and at the end the entire training wrote reflective essays about their most significant experiences. Analysis of the results reveals that the students believe that practical pedagogical training makes a crucial contribution to their practical pedagogical education in the light of their future profession. The students also reported on their progress concerning the various skills that were developed.


Innovations and challenges in reducing maternal mortality in Tamil Nadu, India.
Although India has made slow progress in reducing maternal mortality, progress in Tamil Nadu has been rapid. This case study documents how Tamil Nadu has taken initiatives to improve maternal health services leading to reduction in maternal morality from 380 in 1993 to 90 in 2007. Various initiatives include establishment of maternal death registration and audit, establishment and certification of comprehensive emergency obstetric and newborn-care centres, 24-hour x 7-day delivery services through posting of three staff nurses at the primary health centre level, and attracting medical officers to rural areas through incentives in terms of reserved seats in postgraduate studies and others. This is supported by the better management capacity at the state and district levels through dedicated public-health officers. Despite substantial progress, there is some scope for further improvement of quality of infrastructure and services. The paper draws out lessons for other states and countries in the region.


The M2 muscarinic receptor mediates in vitro bladder contractions from patients with neurogenic bladder dysfunction.
Bladder muscle specimens from seven patients with neurogenic bladder dysfunction were analyzed to determine whether the muscarinic receptor subtype mediating contraction shifts from M(3) to the M(2) subtype as found in the denervated, hypertrophied rat bladder. Seven bladder specimens were analyzed from six female and one male patients. Six of the patients had traumatic cervical spinal cord injuries (C(4)-C(7)), and the other patient had an L(1) congenital myelomeningocele. This was compared with results from bladder specimens obtained from eight organ transplant donors. The affinities of three subtype-selective muscarinic receptor antagonists for inhibition of carbachol-induced contractions were determined. The affinity of the M(3) selective antagonists darifenacin or p-fluoro-hexahydrosiladifenadol (p-F-HHSiD) was determined in six of the seven spinal injury patient specimens. The affinity was consistent with M(2)-mediated contractions in four of these six specimens, intermediate between M(2) and M(3) in one specimen, and within the M(3) range in one specimen. The other specimen, tested only with the M(2) selective antagonist methoctramine, showed an M(3) affinity. In the organ donors, the affinity of p-F-HHSiD was within the M(2) range for six of seven specimens, whereas the affinity of darifenacin was within the M(3) range for five of six and intermediate between M(2) and M(3) for the other specimen tested. The affinity of methoctramine in both organ donor specimens tested was within the M(3) range. Whereas normal detrusor contractions are mediated by the M(3) receptor subtype, in patients with neurogenic bladder dysfunction as well as certain organ transplant donors, contractions can be mediated by the M(2) muscarinic receptor subtype.


Characterisation of denatured states of sensory rhodopsin II by solution-state NMR.
Sensory rhodopsin II (pSRII), a retinal-binding photophobic receptor from Natronomonas pharaonis, is a novel model system for membrane protein folding studies. Recently, the SDS-denatured states and the kinetics for reversible unfolding of pSRII have been investigated, opening the door to the first detailed characterisation of denatured states of a membrane protein by solution-state nuclear magnetic resonance (NMR) using uniformly 15N-labelled pSRII. SDS denaturation and acid denaturation of pSRII both lead to fraying of helix ends but otherwise small structural changes in the transmembrane domain, consistent with little changes in secondary structure and disruption of the retinal-binding pocket and tertiary structure. Widespread changes in the backbone amide dynamics are detected in the form of line broadening, indicative of μs-to-ms timescale conformational exchange in the transmembrane region. Detailed analysis of chemical shift and intensity changes lead to high-resolution molecular insights on structural and dynamics changes in SDS- and acid-denatured pSRII, thus highlighting differences in the unfolding pathways under the two different denaturing conditions. These results will form the foundation for furthering our understanding on the folding and unfolding pathways of retinal-binding proteins and membrane proteins in general, and also for investigating the importance of ligand-binding in the folding pathways of other ligand-binding membrane proteins, such as GPCRs.


[Mixed methods research in public health: issues and illustration].
For many years, researchers in a range of fields have combined quantitative and qualitative methods. However, the combined use of quantitative and qualitative methods has only recently been conceptualized and defined as mixed methods research. Some authors have described the emerging field as a third methodological tradition (in addition to the qualitative and quantitative traditions). Mixed methods research combines different perspectives and facilitates the study of complex interventions or programs, particularly in public health, an area where interdisciplinarity is critical. However, the existing literature is primarily in English. By contrast, the literature in French remains limited. The purpose of this paper is to present the emergence of mixed methods research for francophone public health specialists. A literature review was conducted to identify the main characteristics of mixed methods research. The results provide an overall picture of the mixed methods approach through its history, definitions, and applications, and highlight the tools developed to clarify the approach (typologies) and to implement it (integration of results and quality standards). The tools highlighted in the literature review are illustrated by a study conducted in France. Mixed methods research opens new possibilities for examining complex research questions and provides relevant and promising opportunities for addressing current public health issues in France.


Surface treatment effect of carbon fiber fabric counter electrode in dye sensitized solar cell.
Dye sensitized solar cells (DSSC) with surface modified carbon fiber fabric (CF) counter electrodes were prepared and tested. Four different type of CF were used; carbon fiber (CF); carbon fiber etched with NaOH (ECF); carbon fiber with thermally deposited platinum (CFPt); and carbon fiber etched with NaOH followed by thermal deposition of platinum (ECFPt). For comparison, DSSC with thermally Pt deposited fluorine doped tin oxide (FTO/Pt) glass counter electrode was also prepared and tested. Scanning electron microscope (SEM) proved that surface morphology of the carbon fiber was roughened by the etching process and platinum deposition process. The I-V curves of each DSSC were measured under simulated light (1 Sun, AM 1.5) to get open circuit voltage (Voc), short circuit current density (Jsc), fill factor (FF) and efficiency (eta). Electrochemical impedance spectroscopy of each cell was measured also. It was found that higher efficiency is obtained in order of using ECFPt > CFPt > FTO/Pt > ECF > CF counter electrode.


Biochemical characterization of a temperature-sensitive adenovirus DNA polymerase.
Involvement of adenovirus DNA polymerase (AdPol) in viral DNA replication was initially demonstrated using two temperature-sensitive (ts) adenoviruses, Ad5ts36 and Ad5ts149. Ad5ts36 is particularly interesting because a single mutation mapping to Leu391-->Phe in the AdPol gene confers ts phenotype not only for DNA replication in human cells but also for transformation in rat cells. In order to elucidate the mechanism(s) involved in the ts phenotype, we introduced the ts36 mutation in AdPol of adenovirus type 2 and overexpressed the protein using recombinant vaccinia virus expression system in order to study its biochemical properties. The results show that the ts36 AdPol is defective in the in vitro DNA replication initiation and DNA polymerase elongation assays if the protein is expressed at the nonpermissive temperature (37 degrees) independent of whether the assays are performed at 32 or 37 degrees. In contrast, the ts36 AdPol expressed at 32 degrees had activities similar to that of the wild-type protein when assayed at either temperature. Furthermore, unlike the wild-type protein, ts36 AdPol expressed at 37 degrees failed to recognize the viral DNA replication origin, but bound to a single-stranded DNA cellulose column with greater affinity, suggesting that the defect in the ts36 AdPol for DNA replication can be attributed to its altered DNA-binding properties.