The concept of hospice in theory and practice.
Initially the word 'hospice' was used to convey the friendly and warm feeling between the guest and the host. Later the place where this feeling was experienced represented the meaning of the word. Hospice is a union between the tough and rigid principles of curative clinical science and more flexible 'compassion' of human behaviour. The aim should be more on to relieve distressing symptoms of advanced cancer and other terminal diseases by control of symptoms and good nursing. In India one in 10 deaths is related to cancer and a sizeable section of this huge population die in unrelieved pain and suffering. AIDS cases are rising in the developing countries, which cannot afford expensive treatment. So the provision of good palliative care will remain for many years to come. But with the advent of antibiotics, doctors changed their goal from palliative care to absolute cure. The incurable cases were gradually made to feel unwelcome. The best option between the two is compassion of the old days and the modern scientific advances. Principles of ethics in clinical practice rotate around autonomy, beneficence, non-maleficence and justice. Euthansia poses a big question. Lack of awareness among patients, doctors and paramedical personnel causes unrelieved pain in cancer and other terminal diseases. Gastro-intestinal symptoms, respiratory symptoms, lymphoedema and complications of cancer and other diseases can be looked carefully to give proper benefit to the patients. Complementary and alternative medicine plays a key role in palliative care and improves the quality of life.


Pharmacokinetics and pharmacodynamics of inhaled corticosteroids.
There are significant differences in the pharmacokinetic properties of inhaled corticosteroids currently used in medical practice. All are rapidly cleared from the body but they show varying levels of oral bioavailability and more importantly variation in the rate of absorption after inhalation. Oral bioavailability is lowest for fluticasone propionate, indicating a low potential for unwanted systemic corticosteroid effects. Mathematical modeling has shown pulmonary residence times to be longest for fluticasone propionate and triamcinolone acetonide but shortest for budesonide and flunisolide. These properties appear to relate to pulmonary solubility, which appears to be the rate-limiting step in the absorption process.


Overhauser Geomagnetic Sensor Based on the Dynamic Nuclear Polarization Effect for Magnetic Prospecting.
Based on the dynamic nuclear polarization (DNP) effect, an alternative design of an Overhauser geomagnetic sensor is presented that enhances the proton polarization and increases the amplitude of the free induction decay (FID) signal. The short-pulse method is adopted to rotate the enhanced proton magnetization into the plane of precession to create an FID signal. To reduce the negative effect of the powerful electromagnetic interference, the design of the anti-interference of the pick-up coil is studied. Furthermore, the radio frequency polarization method based on the capacitive-loaded coaxial cavity is proposed to improve the quality factor of the resonant circuit. In addition, a special test instrument is designed that enables the simultaneous testing of the classical proton precession and the Overhauser sensor. Overall, comparison experiments with and without the free radical of the Overhauser sensors show that the DNP effect does effectively improve the amplitude and quality of the FID signal, and the magnetic sensitivity, resolution and range reach to 10 pT/Hz 1 / 2 @1 Hz, 0.0023 nT and 20-100 μ T, respectively.


Computational and Pharmacological Evaluation of Ferrocene-Based Acyl Ureas and Homoleptic Cadmium Carboxylate Derivatives for Anti-diabetic Potential.
We investigated possible anti-diabetic effect of ferrocene-based acyl ureas: 4-ferrocenyl aniline (PFA), 1-(4-chlorobenzoyl)-3-(4-ferrocenylphenyl) urea (DPC1), 1-(3-chlorobenzoyl)-3-(4-ferrocenylphenyl) urea (DMC1), 1-(2-chlorobenzoyl)-3-(4-ferrocenylphenyl) urea (DOC1) and homoleptic cadmium carboxylates: bis (diphenylacetato) cadmium (II) (DPAA), bis (4-chlorophenylacetato) cadmium (II) (CPAA), using in silico and in vivo techniques. PFA, DPC1, DMC1, DOC1, DPAA and CPAA exhibited high binding affinities (ACE ≥ -350 Kcal/mol) against targets: aldose reductase, peroxisome proliferator-activated receptor γ, 11β-hydroxysteroid dehydrogenase-1, C-alpha glucosidase and glucokinase, while showed moderate affinities (ACE ≥ -250 Kcal/mol) against N-alpha glucosidase, dipeptidyl peptidase-IV, phosphorylated-Akt, glycogen synthase kinase-3β, fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase, whereas revealed lower affinities (ACE < -250 Kcal/mol) vs. alpha amylase, protein tyrosine phosphatases 1B, glycogen phosphorylase and phosphatidylinositol 3 kinase. In alloxan (300 mg/Kg)-induced diabetic mice, DPAA and DPC1 (1-10 mg/Kg) at day 1, 5, 10, 15, and 20th decreased blood glucose levels, compared to diabetic control group and improved the treated animals body weight. DPAA (10 mg/Kg) and DPC1 (5 mg/Kg) in time-dependent manner (30-120 min.) enhanced tolerance of oral glucose overload in mice. DPAA and DPCI dose-dependently at 1, 5, and 10 mg/Kg decreased glycosylated hemoglobin levels in diabetic animals, as caused by metformin. These results indicate that aforementioned derivatives of ferrocene and cadmium possess anti-diabetic potential.


Characterization of putative cis-regulatory elements that control the transcriptional activity of the human Oct4 promoter.
Octamer-binding transcription factor-4 (Oct4), a member of the POU domain transcription factors, is crucial for both early embryonic development and the maintenance of stem cell pluripotency. The human Oct4 (hOct4) 5' upstream sequence contains four conserved regions (CR1, 2, 3, 4) that are homologous in the murine. In this study, we constructed a series of deletion mutants of the hOct4 5' upstream region and identified cis-regulatory elements that may be important determinants for the transcriptional activity of the hOct4 promoter. Our studies showed that CR2, 3, and 4 each acted as positive cis-regulatory elements in hOct4 promoter activity. We also newly identified a putative negative cis-acting element located between CR1 and CR2. In addition, the sequence -380/-1 at CR1 that contains a GC box was sufficient to provide the minimal promoter activity. Site-directed mutagenesis and electrophoretic mobility shift assays revealed the GC box located in the -380/-1 region may play a critical role in controlling the transcriptional activity of hOct4 by the direct binding of Sp1 or Sp3 transcription factors to the GC box. An overexpression study showed that Sp1 and Sp3 positively and negatively regulate hOct4 promoter activity. Thus, the hOct4 promoter upstream region contains multiple regulatory elements, one of which, the GC box, may be an important cis-regulatory element that regulates the transcription of the hOct4 promoter by the binding of Sp family transcription factors.


Molecular analysis of the diversity of sulfate-reducing and sulfur-oxidizing prokaryotes in the environment, using aprA as functional marker gene.
The dissimilatory adenosine-5'-phosphosulfate reductase is a key enzyme of the microbial sulfate reduction and sulfur oxidation processes. Because the alpha- and beta-subunit-encoding genes, aprBA, are highly conserved among sulfate-reducing and sulfur-oxidizing prokaryotes, they are most suitable for molecular profiling of the microbial community structure of the sulfur cycle in environment. In this study, a new aprA gene-targeting assay using a combination of PCR and denaturing gradient gel electrophoresis is presented. The screening of sulfate-reducing and sulfur-oxidizing reference strains as well as the analyses of environmental DNA from diverse habitats (e.g., microbial mats, invertebrate tissue, marine and estuarine sediments, and filtered hydrothermal water) by the new primer pair revealed an improved microbial diversity coverage and less-pronounced template-to-PCR product bias in direct comparison to those of the previously published primer set (B. Deplancke, K. R. Hristova, H. A. Oakley, V. J. McCracken, R. Aminov, R. I. Mackie, and H. R. Gaskins, Appl. Environ. Microbiol. 66:2166-2174, 2000). The concomitant molecular detection of sulfate-reducing and sulfur-oxidizing prokaryotes was confirmed. The new assay was applied in comparison with the 16S rRNA gene-based analysis to investigate the microbial diversity of the sulfur cycle in sediment, seawater, and manganese crust samples from four study sites in the area of the Lesser Antilles volcanic arc, Caribbean Sea (Caribflux project). The aprA gene-based approach revealed putative sulfur-oxidizing Alphaproteobacteria of chemolithoheterotrophic lifestyle to have been abundant in the nonhydrothermal sediment and water column. In contrast, the sulfur-based microbial community that inhabited the surface of the volcanic manganese crust was more complex, consisting predominantly of putative chemolithoautotrophic sulfur oxidizers of the Betaproteobacteria and Gammaproteobacteria.


Analysis of beta-carotene absorbance for studying structural properties of human plasma low-density lipoproteins.
A novel spectrophotometric assay for monitoring structural rearrangements of native low-density lipoproteins (LDL) is proposed. The approach is based on the analysis of the visible light absorbance maximum of lipoproteins at approximately 461 nm assigned to beta-carotene situated in the hydrophobic parts of LDL. It offers a direct method to study the surface-interior coupling of the lipoprotein particle under physiological conditions. The detected signal is intrinsic to LDL and responsible for the most of the beta-carotene signal from the whole plasma. The negligible interference of beta-carotene absorbance due to the high-density lipoproteins is experimentally verified. Since beta-carotene absorbance belongs to the visible spectral region, no spectral overlapping/artifacts in plasma are expected. The signal sensitivity has been studied through conformational changes of LDL induced by ionic strength, by temperature, and by ligand binding. The results of caffeine binding to LDL indicate that there could be only one dominant type of binding site for caffeine on LDL particles. It can be concluded that visible spectrum characteristics of beta-carotene molecules offer advantages in LDL ligand binding studies which can possibly be extended to monitor the interactions of LDL directly in plasma.


[Diagnostic value of laboratory examination of ascites fluid (author's transl)].
Measurement of lactate dehydrogenase (LDH), glucose and protein was performed in ascites fluid of 44 patients in addition to bacteriological and cytological examinations. In patients with cirrhosis of the liver protein content of ascites was low, LDH normal, and the ascites/serum ratio of glucose concentration was higher than 1. These values were statistically significant different from the values in patients with tumorous or inflammatory disease of the peritoneum - protein and LDH in the ascites fluid being high and the ascites/serum ratio of glucose concentration being below 1. Cirrhosis however and tumors of the liver could not be differentiated by this method. Ascites from patients with cardiac failure had high protein content. In patients with liver cirrhosis high concentrations of protein in ascitic fluid may mean possibly a better survival time.


Charting Recent Progress and Challenges in Metastatic Castration-resistant Prostate Cancer: Is There an Optimal Treatment Sequence?
Recent developments in the treatment of metastatic castration-resistant prostate cancer (mCRPC) have led to uncertainty about the optimal sequence of agents. To review and assess treatment options and sequence in patients with mCRPC. To identify data on the optimal use of approved treatments, we searched PubMed for studies on the use of recently approved agents for men with mCRPC published before March 2015. Phase 3 and other key studies were included in the review of efficacy and safety. In this review, we offer our critical interpretation of potential treatment sequences for drug use in the light of our clinical experience. Since 2004, the treatment landscape for mCRPC has changed dramatically following the approval of docetaxel, abiraterone acetate, enzalutamide, cabazitaxel, denosumab, and radium-223 chloride. To date, only small-scale studies have been undertaken that provide evidence on the sequencing of these treatments. Ideally, randomised, prospective studies would evaluate different sequence options thoroughly so that physicians could make evidence-based decisions, but the number of new agents makes this impractical. When deciding which treatment to prescribe, physicians will need to use the available evidence combined with their own clinical judgement. The potential for cross-resistance between taxanes and hormonal therapies and the possibility that patients might not be suitable for aggressive therapies in later lines should be taken into account. Prevention of complications associated with bone metastases should also be a key consideration because of the major impact these events have on quality of life and healthcare costs. The recent approval of numerous new agents has resulted in considerable improvements in outcomes for patients with mCRPC. Further studies determining the optimal treatment algorithm, in addition to open discussion of best practice among physicians, are required to ensure patients obtain the maximum possible benefit from their treatment. In recent years a large number of new treatment options have been approved for use in men with prostate cancer. In the absence of clinical trials assessing the use of one option versus another in specific patient groups, it is important to review the currently published evidence to try to understand patients receive the best treatment options in the correct order.


Trypanosoma equiperdum Low Molecular Weight Proteins As Candidates for Specific Serological Diagnosis of Dourine.
The diagnosis of dourine can be difficult because the clinical signs of this disease in horses are similar to those of surra, caused by Trypanosoma evansi. Moreover, T. equiperdum and T. evansi are closely related and, so far, they cannot be distinguished using serological tests. In a previous work, the T. equiperdum protein pattern recognized by antibodies from dourine-infected horses and the humoral immune response kinetics were investigated by immunoblotting assay; a total of 20 sera from naturally and experimentally infected horses and from healthy animals were tested. Immunoblotting analysis showed that antibodies from infected horses specifically bind T. equiperdum low molecular weight proteins (from 16 to 35 kDa), which are not recognized by antibodies from uninfected horses. In this work, we tested other 615 sera (7 from naturally infected horses and 608 sera from healthy horses and donkeys): results confirmed the data obtained previously. In addition, six SDS-PAGE bands with molecular weight ranging from 10 to 37 kDa were analyzed by mass spectrometry, in order to identify immunogenic proteins that could be used as biomarkers for the diagnosis of dourine. A total of 167 proteins were identified. Among them, 37 were found unique for T. equiperdum. Twenty-four of them could represent possible candidate diagnostic antigens for the development of serological tests specific for T. equiperdum.


Reaction Mechanism of a New Glycosyltrehalose-producing Enzyme Isolated from the Hyperthermophilic Archaeum, Sulfolobus solfataricus KM1.
An amylolytic activity, which converts soluble starch to α,α-trehalose (trehalose), was found in the cell homogenate of the hyperthermophilic, acidophilic archaeum Sulfolobus solfataricus KM1. Two enzymes, a glycosyltransferase and an amylase, which are essential for this activity, were purified to homogeneity. A glycosyltransferase catalyzed the conversion of maltooligosaccharides to glycosyltrehaloses. Based on a detailed analysis of the reaction products, kinetic parameters, and an experiment using (3)H-labeled substrates, it was verified that glycosyltransferase transferred an oligomer segment of maltooligosaccharide to the Cl-OH position of glucose, located at the reducing end of the maltooligosaccharide, to produce a glycosyltrehalose having an α-1,1 linkage. The reaction appears to be intramolecular. Nine strains of the Sulfolobaceae family were found to have glycosyltransferases.


Effects of upper-airway stimulation on sleep architecture in patients with obstructive sleep apnea.
Selective upper-airway stimulation (UAS) is a novel therapy for patients with obstructive sleep apnea (OSA). The aim of this study was to compare changes in sleep architecture during the diagnostic polysomnography and the post-implantation polysomnography in UAS in patients with OSA. Twenty-six patients who received a UAS device (Inspire Medical Systems) were included. Treatment outcome was evaluated 2 and 3 months after surgery. Data collection included demographics, body mass index (BMI), apnea hypopnea index (AHI), oxygen saturation and desaturation index (ODI), Epworth sleepiness score (ESS), arousal parameter, and sleep patterns. The mean age was 60.2 years, 25 patients were male, 1 patient was female. Mean BMI was 29.0 kg/m2. The mean pre-implantation AHI of 33.9/h could be reduced to 9.1/h at 2 months post-implantation (p < 0.001). The amount of time spent in N1-sleep could be reduced from 23.2% at baseline to 16.0% at month 3 post-implantation. The amount of time spent in N2- and N3-sleep did not change during the observation period. A significant increase of the amount of REM sleep at month 2 (15.7%) compared to baseline (9.5%; p = 0.010) could be observed. A reduction of the number of arousals and the arousal index could be observed. In conclusion, significant changes in sleep architecture of patients with OSA and sufficient treatment with UAS could be observed. A reduction of the amount of time spent in N1-sleep could be caused by treatment with UAS and the rebound of REM sleep, observed for the first time in a study on UAS, is also a potential marker of the efficacy of UAS on sleep architecture. NCT02293746.


Aquatic dance flies (Diptera, Empididae, Clinocerinae and Hemerodromiinae) of Greece: species richness, distribution and description of five new species.
All records of aquatic dance flies (37 species in subfamily Clinocerinae and 10 species in subfamily Hemerodromiinae) from the territory of Greece are summarized, including previously unpublished data and data on five newly described species (Chelifera horvati Ivković & Sinclair, sp. n., Wiedemannia iphigeniae Ivković & Sinclair, sp. n., W. ljerkae Ivković & Sinclair, sp. n., W. nebulosa Ivković & Sinclair, sp. n. and W. pseudoberthelemyi Ivković & Sinclair, sp. n.). The new species are described and illustrated, the male terminalia of Clinocera megalatlantica (Vaillant) are illustrated and the distributions of all species within Greece are listed. The aquatic Empididae fauna of Greece consists of 47 species, with the following described species reported for the first time: Chelifera angusta Collin, Hemerodromia melangyna Collin, Clinocera megalatlantica, Kowarzia plectrum (Mik), Phaeobalia dimidiata (Loew), W. (Chamaedipsia) beckeri (Mik), W. (Philolutra) angelieri Vaillant and W. (P.) chvali Joost. A key to species of aquatic Empididae of Greece is provided for the first time. Information related to the European Ecoregions in which species were found is given. Compared to the other studied countries in the Balkans, the Greek species assemblage is most similar to that of the Former Yugoslav Republic of Macedonia.


Mutation Space of Spatially Conserved Amino Acid Sites in Proteins.
The mutation space of spatially conserved (MSSC) amino acid residues is a protein structural quantity developed and described in this work. The MSSC quantifies how many mutations and which different mutations, i.e., the mutation space, occur in each amino acid site in a protein. The MSSC calculates the mutation space of amino acids in a target protein from the spatially conserved residues in a group of multiple protein structures. Spatially conserved amino acid residues are identified based on their relative positions in the protein structure. The MSSC examines each residue in a target protein, compares it to the residues present in the same relative position in other protein structures, and uses physicochemical criteria of mutations found in each conserved spatial site to quantify the mutation space of each amino acid in the target protein. The MSSC is analogous to scoring each site in a multiple sequence alignment but in three-dimensional space considering the spatial location of residues instead of solely the order in which they appear in a protein sequence. MSSC analysis was performed on example cases, and it reproduces the well-known observation that, regardless of secondary structure, solvent-exposed residues are more likely to be mutated than internal ones. The MSSC code is available on GitHub: "https://github.com/Cantu-Research-Group/Mutation_Space".


Untargeted voltammetric approaches for characterization of oxidation patterns in white wines.
Chemical and electrochemical changes associated with controlled oxidation were measured in thirteen commercial white wines, in order to evaluate the potential of linear sweep voltammetry to provide relevant information on the oxidative behavior of individual wines. For a given amount of oxygen consumed, substantial diversity of oxidative behaviors was observed. A good correlation (R2 = 0.69) was observed between the rate of O2 consumption of individual wines and the total charged passed during linear sweep voltammetry, but not with their Folin-Ciocalteu values. Onset potential of anodic oxidation was also related to oxygen consumption capacity of wine, indicating an important contribution of easily oxidizable substrates. Subtraction of voltammograms of oxidized wines from their corresponding non-oxidized controls generated new voltammograms representative of the global changes induced by oxidation. These new voltammograms contained several features related to oxygen consumption rates of each wine, and could be considered as a 'wine oxidation signature'.


The role of diagnosis in a psychiatric emergency setting.
A sample of 253 psychiatric emergency patients consecutively evaluated in a general hospital was studied to determine the role of psychiatric diagnosis in disposition decisions and the possible influences of patient and staff variables on diagnoses. Except for patients with organic brain syndrome, age and sex were not significantly associated with diagnostic grouping; some racial differences were found. Diagnosis was strongly associated with disposition decisions: schizophrenic and manic patients were more frequently hospitalized, while patients with substance abuse disorders, adjustment and neurotic disorders were more often referred to outpatient treatment. The authors stress the importance of a reliable diagnostic system and the recruitment of diagnosis-oriented staff in improving the quality of psychiatric emergency care.


Detecting the order of population dynamics from time series: nonlinearity causes spurious diagnosis.
Partial autocorrelation and partial rate correlation functions are frequently used to detect the order of the endogenous process generating an observed population time series. Here we uncover a problem with this approach: the diagnosis of spurious second order autocorrelation due to strong nonlinearity in a first order endogenous process, as exemplified by time series data from a population of Soay sheep. Causes and a possible solution are discussed.


Epidemiology of infrequent voiding and associated symptoms.
In an attempt to study the epidemiology of infrequent voiding and its associated symptoms, 1613 women aged 20-25, 30-35 or 40-45 years randomly selected among the ordinary female population in Northern Jutland in Denmark were sent a questionnaire. It was to be answered anonymously. The women were asked about voiding frequency, frequency of nocturnal voidings, urinary infections, problems in initiating voiding and urinary leaking symptoms. The response rate was 65.0%. Overall, 7.7% of the women in the 3 groups had a voiding frequency of 3 or less per day. We found that women aged 20-25 had a higher rate of this low voiding frequency than women in the two older groups, (p < 0.001). Women aged 40-45 had a higher rate of urinary leaking symptoms than the two younger groups, (p < 0.02). In all 3 groups, women who voided 3 times or less per day had significantly more urinary infections than those with 4 or more voidings per day, (p < 0.01). The investigation has given some impression of the frequency of the infrequent voiding and the frequency of its associated symptoms.


Sodium nitrate alleviates functional muscle ischaemia in patients with Becker muscular dystrophy.
Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. BMD is caused by in-frame mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the sarcolemma. Among these is neuronal nitric oxide synthase mu (nNOSμ), which requires specific spectrin-like repeats (SR16/17) in dystrophin's rod domain and the adaptor protein α-syntrophin for sarcolemmal targeting. When healthy skeletal muscle is exercised, sarcolemmal nNOSμ-derived nitric oxide (NO) attenuates α-adrenergic vasoconstriction, thus optimizing perfusion. In the mdx mouse model of dystrophinopathy, this protective mechanism (functional sympatholysis) is defective, resulting in functional muscle ischaemia. Treatment with a NO-donating non-steroidal anti-inflammatory drug (NSAID) alleviates this ischaemia and improves the murine dystrophic phenotype. In the present study, we report that, in 13 men with BMD, sympatholysis is defective mainly in patients whose mutations disrupt sarcolemmal targeting of nNOSμ, with the vasoconstrictor response measured as a decrease in muscle oxygenation (near infrared spectroscopy) to reflex sympathetic activation. Then, in a single-arm, open-label trial in 11 BMD patients and a double-blind, placebo-controlled cross-over trial in six patients, we show that acute treatment with oral sodium nitrate, an inorganic NO donor without a NSIAD moiety, restores sympatholysis and improves post-exercise hyperaemia (Doppler ultrasound). By contrast, sodium nitrate improves neither sympatholysis, nor hyperaemia in healthy controls. Thus, a simple NO donor recapitulates the vasoregulatory actions of sarcolemmal nNOS in BMD patients, and constitutes a putative novel therapy for this disease.


A survey of Canadian gastroenterologists about the use of methotrexate in patients with Crohn's disease.
Methotrexate (MTX) is effective in remission induction and maintenance in steroid-dependent Crohn's disease (CD), but is often considered to be a second-line immunosuppressive agent, to be used in cases of failure or intolerance to azathioprine (AZA) or 6-mercaptopurine (6-MP). This may be related to concerns about hepatotoxicity, but this adverse effect is rare in monitored CD patients taking MTX. Still, there are no guidelines for monitoring patients with CD on MTX, and physicians must decide based on rheumatological literature about how to monitor their patients. To determine the patterns of MTX use in patients with CD by Canadian gastroenterologists, examining the reasons for choosing MTX versus AZA/6-MP, the doses and routes of administration of MTX, and how patients on MTX are monitored, including the use of liver biopsy. A self-report survey was sent to physician members of the Canadian Association of Gastroenterology, with a second mailing three months later to increase response rate. Of 490 surveys mailed, a 54.9% response rate was achieved. Of adult gastroenterologists, 60.7% stated they never use MTX as a first-line immunosuppressive agent, and 33.3% never use MTX at all. The most common reasons for choosing MTX were a contraindication to the use of AZA/6-MP (43.7%) and patient preference (22.5%). MTX is used intramuscularly in 41.5%, subcutaneously in 31.8%, and orally in 26.7% of patients. The most common dose used for remission induction was 25 mg/week (84.2%; range 7.5 mg/week to 50 mg/week; three responders used more frequent dosing than weekly) and for remission maintenance was 15 mg/week (55.4%; range 7.5 mg/week to 50 mg/week; three responders used more frequent dosing than weekly). Most responders checked a liver profile and complete blood count at baseline and serially. Of those who used MTX, 26.5% routinely performed liver biopsy after an accumulated dose of MTX had been taken (usually 1 g to 2 g), 57.7% sometimes performed liver biopsy, and 16.8% never performed liver biopsy. Of pediatric gastroenterologists, 17.6% never used MTX, but those who used it prescribed it subcutaneously (80.0%) more often than intramuscularly (17.5%) or orally (2.5%). MTX was used as a first-line immunosuppressive agent in patients with CD by a minority of Canadian gastroenterologists. When used, there is variability in how MTX is prescribed and monitored. Although hepatotoxicity is rare, liver biopsy was performed frequently and probably often unnecessarily.


Reduction of acute anterior shoulder dislocations: comparing intraarticular lignocaine with intravenous anesthesia.
Anterior shoulder dislocation is the most common dislocation in the body. Various methods of anesthesia are available for reduction. The objective of this study was to compare the application of intra-articular anesthesia with intravenous anesthesia for reduction of acute anterior shoulder dislocation. This study was conducted at Kathmandu Medical College Teaching Hospital (KMCTH) and Kathmandu Hospital and comprised of patients coming with anterior dislocation of shoulder from July 2001 to June 2005. Forty-five patients aged 17-55 years with no associated fractures of adjoining bones were included in the study. In twenty-three patients, reduction was done using intra-articular anesthesia and in 22 patients intravenous anesthesia was given. In five patients (three in intra-articular group and two in intravenous group) the reduction technique had to be changed to the Hippocratic method. In these three patients intravenous anesthesia had to be given after intra-articular anesthesia failed to relieve pain and spasm. In the intravenous group two patients had to be admitted overnight while in the intra-articular group none had to be admitted to the hospital. However, in the intra-articular group the average time taken from injection to reduction was significantly longer (<.001). The use of intra-articular lignocaine for reduction of shoulder dislocation is safe and effective especially when patients present early. In patients presenting late (more than 5 hours) intravenous anesthesia should be primarily considered as the method for shoulder reduction.


MicroRNA-Related Polymorphisms in PI3K/Akt/mTOR Pathway Genes Are Predictive of Limited-Disease Small Cell Lung Cancer Treatment Outcomes.
The phosphoinositide-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays an important role in cancer progression and treatment, including that of small cell lung cancer (SCLC), a disease with traditionally poor prognosis. Given the regulatory role of microRNA (miRNA) in gene expression, we examined the association of single nucleotide polymorphisms (SNPs) at miRNA-binding sites of genes in the mTOR pathway with the prognosis of patients with limited-disease SCLC. A retrospective study was conducted of 146 patients with limited-disease SCLC treated with chemoradiotherapy. Nine SNPs of six mTOR pathway genes were genotyped using blood samples. Cox proportional hazard regression modeling and recursive partitioning analysis were performed to identify SNPs significantly associated with overall survival. Three SNPs, MTOR: rs2536 (T>C), PIK3R1: rs3756668 (A>G), and PIK3R1: rs12755 (A>C), were associated with longer overall survival. Recursive partitioning analysis based on unfavorable genotype combinations of the rs2536 and rs3756668 SNPs classified patients into three risk subgroups and was internally validated with 1000 bootstrap samples. These findings suggest that miRNA-related polymorphisms in the PI3K/Akt/mTOR pathway may be valuable biomarkers to complement clinicopathological variables in predicting prognosis of limited-disease SCLC and to facilitate selection of patients likely to benefit from chemoradiotherapy.


[Survival benefits of chemotherapy for unresectable biliary tract cancer--a multicenter retrospective analysis].
There is no agreement on the standard chemotherapeutic regimen for biliary tract cancer(BTC), although multi-drug regimens such as gemcitabine and/or S-1 have been tested in clinical trials. This study retrospectively reviewed data from patients with BTC who were seen at hospitals in the Kitakyushu and Fukuoka areas between 2005 and 2006, and examined the effect of systemic chemotherapy regimen on survival benefits in patients with unresectable BTC. Chemotherapy may benefit patients with BTC any age group, regardless of the primary site.


Seeking evidence to support efforts to increase use of antenatal care: a cross-sectional study in two states of Nigeria.
Antenatal care (ANC) attendance is a strong predictor of maternal outcomes. In Nigeria, government health planners at state level and below have limited access to population-based estimates of ANC coverage and factors associated with its use. A mixed methods study examined factors associated with the use of government ANC services in two states of Nigeria, and shared the findings with stakeholders. A quantitative household survey in Bauchi and Cross River states of Nigeria collected data from women aged 15-49 years on ANC use during their last completed pregnancy and potentially associated factors including socio-economic conditions, exposure to domestic violence and local availability of services. Bivariate and multivariate analysis examined associations with having at least four government ANC visits. We collected qualitative data from 180 focus groups of women who discussed the survey findings and recommended solutions. We shared the findings with state, Local Government Authority, and community stakeholders to support evidence-based planning. 40% of 7870 women in Bauchi and 46% of 7759 in Cross River had at least four government ANC visits. Women's education, urban residence, information from heath workers, help from family members, and household owning motorized transport were associated with ANC use in both states. Additional factors for women in Cross River included age above 18 years, being married or cohabiting, being less poor (having enough food during the last week), not experiencing intimate partner violence during the last year, and education of the household head. Factors for women in Bauchi were presence of government ANC services within their community and more than two previous pregnancies. Focus groups cited costly, poor quality, and inaccessible government services, and uncooperative partners as reasons for not attending ANC. Government and other stakeholders planned evidence-based interventions to increase ANC uptake. Use of ANC services remains low in both states. The factors related to use of ANC services are consistent with those reported previously. Efforts to increase uptake of ANC should focus particularly on poor and uneducated women. Local solutions generated by discussion of the evidence with stakeholders could be more effective and sustainable than externally driven interventions.


The POP1 gene encodes a protein component common to the RNase MRP and RNase P ribonucleoproteins.
Two forms of the yeast 5.8S rRNA are generated from a large precursor by distinct processing pathways. Cleavage at site A3 is required for synthesis of the major, short form, designated 5.8S(S), but not for synthesis of the long form, 5.8S(L). To identify components required for A3 cleavage, a bank of temperature-sensitive lethal mutants was screened for those with a reduced ratio of 5.8S(S):5.8S(L). The pop1-1 mutation (for processing of precursor RNAs) shows this phenotype and also inhibits A3 cleavage. The pre-rRNA processing defect of pop1-1 strains is similar to that reported for mutations in the RNA component of RNase MRP; we show that a mutation in the RNase MRP RNA also inhibits cleavage at site A3. This is the first site shown to require RNase MRP for cleavage in vivo. The pop1-1 mutation also leads to a block in the processing of pre-tRNA that is identical to that reported for mutations in the RNA component of RNase P. The RNA components of both RNase MRP and RNase P are underaccumulated in pop1-1 strains at the nonpermissive temperature, and immunoprecipitation demonstrates that POP1p is a component of both ribonucleoproteins. The POP1 gene encodes a protein with a predicted molecular mass of 100.5 kD and is essential for viability. POP1p is the first protein component of the nuclear RNase P or RNase MRP for which the gene has been cloned.


Changes in Salivary Oxytocin Level of Term Pregnant Women after Aromatherapy Footbath for Spontaneous Labor Onset: A Non-Randomized Experimental Study.
Aromatherapy is usually used to stimulate labor. However, its specific physiological effects have been scarcely examined. We evaluated whether an aromatherapy footbath increases oxytocin levels in term pregnant women. In this quasi-experimental study, low-risk term pregnant women in Japan underwent aromatherapy using a footbath (1) infused with clary sage and lavender essential oils, (2) infused with jasmine oil, or (3) with no infused oils (control group). The primary outcome was the salivary oxytocin level. The secondary outcomes were uterine contractions and cortisol levels. In the clary sage and lavender group (n = 28), the oxytocin level increased significantly after the footbath (p = 0.035). The jasmine group (n = 27) and control group (n = 27) exhibited trends toward a respective increase and decrease in the oxytocin level; however, the changes in the oxytocin levels between the clary sage and lavender group and the control group showed no significance difference. There were no significant differences in the changes in the uterine contractions and cortisol levels between the experiment and control groups. The changes in the oxytocin levels in the clary sage and lavender group did not differ significantly with those in the control group, possibly because of the small sample size. Further studies are required to examine the effects of repeated aromatherapy footbaths to stimulate labor.


Partial splenectomy for a splenic cyst.
Partial splenectomy for a large splenic cyst was performed in a seven-year-old girl referred for splenomegaly. The increased risk of sepsis in splenectomized patients induced the successful attempt at partial splenectomy. The surgical procedure described involved removal of the cyst while preserving as much of the spleen as possible. In view of the planocellular epithelial lining, the pathological diagnosis was of a rare congenital, intrasplenic cyst.


A novel nuclear trafficking module regulates the nucleocytoplasmic localization of the rabies virus interferon antagonist, P protein.
Regulated nucleocytoplasmic transport of proteins is central to cellular function and dysfunction during processes such as viral infection. Active protein trafficking into and out of the nucleus is dependent on the presence within cargo proteins of intrinsic specific modular signals for nuclear import (nuclear localization signals, NLSs) and export (nuclear export signals, NESs). Rabies virus (RabV) phospho (P) protein, which is largely responsible for antagonising the host anti-viral response, is expressed as five isoforms (P1-P5). The subcellular trafficking of these isoforms is thought to depend on a balance between the activities of a dominant N-terminal NES (N-NES) and a distinct C-terminal NLS (C-NLS). Specifically, the N-NES-containing isoforms P1 and P2 are cytoplasmic, whereas the shorter P3-P5 isoforms, which lack the N-NES, are believed to be nuclear through the activity of the C-NLS. Here, we show for the first time that RabV P contains an additional strong NLS in the N-terminal region (N-NLS), which, intriguingly, overlaps with the N-NES. This arrangement represents a novel nuclear trafficking module where the N-NLS is inactive in P1 but becomes activated in P3, concomitant with truncation of the N-NES, to become the principal targeting signal conferring nuclear accumulation. Understanding this unique switch arrangement of overlapping, co-regulated NES/NLS sequences is vital to delineating the critical role of RabV P protein in viral infection.


A Call to Action for a Programmatic Approach to Addressing Health Disparities and Cultural Competency in Pharmacy Education.
Pharmacy has recognized the importance of education in health disparities and cultural competency (HDCC) for two decades. More recently, there has been emphasis on incorporating equity, diversity, and inclusion (EDI) in pharmacy programs. While many institutions identify a need to incorporate a programmatic approach to HDCC education to meet the growing needs of a diverse population, pharmacy curricula continue to lack a holistic, programmatic approach. More than ever, Doctor of Pharmacy (PharmD) students should graduate with the knowledge, values, and skills to provide culturally appropriate care for a diverse patient population. This commentary advocates for a holistic, programmatic approach to integrating HDCC education and serves as a call to action for curricular development. It is hoped that this commentary will also set the foundation for additional scholarly work and recommendations regarding a programmatic approach.


[Cardial fibrosis and the functional activity of leukocytes in patients with essential arterial hypertension].
The study revealed an increase in the serum levels of TGF-beta1 and the N-terminal peptide procollagen type III in patients with essential arterial hypertension (EAH), as well as an association between this increase and the duration of the disease, mean day arterial pressure profile, and left ventricular hypertrophy. An increased leukocyte functional activity is associated with disturbances in left ventricular diastolic function and an increase in TGF-beta1 serum concentration in EAH. The authors conclude that leukocytes participate in the development of myocardial hypertrophy and cardial fibrosis through the secretion of pro-inflammatory cytokines and peptide growth factors within the process of their activation.


Commentary: The Effect of Words on Health and Diabetes.
This article discusses the effect of words on diabetes. People with diabetes are exposed to the language health care professionals (HCPs) use, in both speaking and writing, and those words may contribute to an already stressful illness experience. Language is a significant part of every person's context, and context shapes experience. There is evidence that words can affect responses to health-related situations and may even lead to a stress response. HCPs often discuss delivering diabetes care in an empowerment model, and so far that has not included using language that is consistent with the approach. Awareness is the first step toward identifying and changing the words HCPs use with people who have diabetes.


[Global health--the ethical responsibility of the pharmaceutical industry].
Health is a global concern and all stakeholders in society--including the pharmaceutical industry--have an ethical responsibility to contribute to promote health. At Novo Nordisk, we have decided to focus on defeating diabetes since this is the area where the company can make the biggest difference. Financial viability goes hand in hand with environmental and social responsibility, not only in the external stakeholder dialogue, but also in the quest for attraction and retention of the best possible staff. Examples of the ethical obligations of a pharmaceutical company are presented, as are classical dilemmas faced by the industry.


Genome-Wide Association Study of Pericarp Color in Rice Using Different Germplasm and Phenotyping Methods Reveals Different Genetic Architectures.
Pericarp colors (PC) in rice are determined by the types and content of flavonoids in the pericarp. The flavonoid compounds have strong antioxidant activities and are beneficial to human health. However, the genetic basis of PC in rice is still not well-understood. In this study, a genome-wide association study (GWAS) of PC was performed in a diverse rice collection consisting of 442 accessions using different phenotyping methods in two locations over 2 years. In the whole population consisting of white and colored pericarp rice, a total of 11 quantitative trait loci (QTLs) were identified using two phenotyping methods. Among these QTLs, nine were identified using the phenotypes represented by the presence and absence of pigmentation in pericarp, while 10 were identified using phenotypes of the degree of PC (DPC), in which eight are common QTLs identified using the two phenotyping methods. Using colored rice accessions and phenotypes based on DPC, four QTLs were identified, and they were totally different from the QTLs identified using the whole population, suggesting the masking effects of major genes on minor genes. Compared with the previous studies, 10 out of the 15 QTLs are first reported in this study. Based on the differential expression analysis of the predicted genes within the QTL region by both RNA-seq and real-time PCR (RT-PCR) and the gene functions in previous studies, LOC_Os01g49830, encoding a RAV transcription factor was considered as the candidate gene underlying qPC-1, a novel QTL with a large effect in this study. Our results provide a new insight into the genetic basis of PC in rice and contribute to developing the value-added rice with optimized flavonoid content through molecular breeding.


Renal replacement therapy in acute kidney injury: which method to use in the intensive care unit?
Over the last three decades the treatment options for patients with acute kidney injury (AKI) requiring renal replacement therapy (RRT) have expanded from basic acute peritoneal dialysis and intermittent hemodialysis (IHD), to now include a variety of continuous modalities (CRRT), ranging from hemofiltration, dialysis and/or hemodiafiltration, and a variety of hybrid therapies, variously described as extended daily dialysis and/or hemodiafiltration, with the possibility of additional adjunct therapies encompassing plasma separation and adsorption techniques. Current evidence does not support that one modality is superior to any other in terms of patients' survival in the intensive care unit, or at discharge. There have been two prospective audits, which have reported improved renal recovery in the survivors who were treated by CRRT rather than IHD, but this has not been confirmed in randomized controlled trials. Thus the choice of RRT modality should be guided by the individual patients' clinical status, the medical and nursing expertise in the local intensive care unit, and the availability of RRT modality.


Structural genomics of the Epstein-Barr virus.
Epstein-Barr virus is a herpesvirus that causes infectious mononucleosis, carcinomas and immunoproliferative disease. Its genome encodes 86 proteins, which provided targets for a structural genomics project. After updating the annotation of the genome, 23 open reading frames were chosen for expression in Escherichia coli, initially selecting for those with known enzyme activity and then supplementing this set based on a series of predicted properties, in particular secondary structure. The major obstacle turned out to be poor expression and low solubility. Surprisingly, this could not be overcome by modifications of the constructs, changes of expression temperature or strain or renaturation. Of the eight soluble proteins, five were crystallized using robotic nanolitre-drop crystallization trials, which led to four solved structures. Although these results depended on individual treatment rather than standardized protocols, a high-throughput miniaturized crystallization screening protocol was a key component of success with these difficult proteins.


Autocrine growth induced by the insulin-related factor in the insulin-independent teratoma cell line 1246-3A.
An insulin-independent teratoma-derived cell line, called 1246-3A, has been isolated from the adipogenic cell line 1246, which stringently requires insulin for proliferation. The 1246-3A cell line, which can proliferate in the absence of exogenous insulin, produces in its conditioned medium a growth factor similar to pancreatic insulin by its biological and immunological properties. This factor, called "insulin-related factor" (IRF), was purified and iodinated to study its binding to cell surface receptors. 125I-labeled IRF binding to intact 1246-3A cells is lower than to 1246 cells. Cell surface binding can be restored by culturing the 1246-3A cells in the presence of an anti-porcine insulin monoclonal antibody or by acid prewash of the cells prior to performing the binding. Scatchard analysis of binding indicates that IRF secreted by the 1246-3A cells partially occupies high-affinity binding sites on the producer cells. Moreover, insulin monoclonal antibody inhibits the proliferation of the IRF-producing 1246-3A cells, suggesting that these cells are dependent on the secreted IRF for growth in culture. We conclude that the insulin-related factor secreted by the insulin-independent 1246-3A cells stimulates their proliferation in an autocrine fashion.


Crystal structure of the catalytic domain of a human thioredoxin-like protein.
Thioredoxin is a ubiquitous dithiol oxidoreductase found in many organisms and involved in numerous biochemical processes. Human thioredoxin-like protein (hTRXL) is differentially expressed at different development stages of human fetal cerebrum and belongs to an expanding family of thioredoxins. We have solved the crystal structure of the recombinant N-terminal catalytic domain (hTRXL-N) of hTRXL in its oxidized form at 2.2-A resolution. Although this domain shares a similar three-dimensional structure with human thioredoxin (hTRX), a unique feature of hTRXL-N is the large number of positively charged residues distributed around the active site, which has been implicated in substrate specificity. Furthermore, the hTRXL-N crystal structure is monomeric while hTRX is dimeric in its four crystal structures (reduced, oxidized, C73S and C32S/C35S mutants) reported to date. As dimerization is the key regulatory factor in hTRX, the positive charge and lack of dimer formation of hTRXL-N suggest that it could interact with the acidic amino-acid rich C-terminal region, thereby suggesting a novel regulation mechanism.


[Amphicrine adenoma of the middle ear: three cases reports and a review of the literature].
Amphicrine adenoma is an extremely rare tumor of the middle ear. We report three cases obtained over a twenty year period. is to discuss our clinical cases and review the literature. Three cases of middle ear amphicrine tumour were reviewed. During a 10 year period (1986-2006) three cases of middle ear amphicrine tumour were treated at our unit (2 male, 1 female). The presenting complaint was hearing loss in all 3 cases. Amphicrine adenoma is diagnosed by an immuno-histological examination of pathological specimens. Differential diagnosis can be difficult and one individual was initially treated as an adenocarcinoma by radiotherapy. This patient succumbed to cerebral mycosis two years post-radiotherapy. The other two patients have no evidence of recurrence eight and nine years post treatment. Historically, differential diagnosis between amphicrine adenoma and adenocarcinoma of the middle ear has been very difficult. Carcinoid tumour is considered to be a more agressive form of amphicrine adenoma. Tumour progression is through loco regional invasion. Complete excision by surgical management with long term follow up is the treatment of choice.


Improved PNIPAAm-Hydrogel Photopatterning by Process Optimisation with Respect to UV Light Sources and Oxygen Content.
Poly-N-isopropylacrylamide (PNIPAAm) hydrogels, known for their sensor and actuator capabilities, can be photolithographically structured for microsystem applications. For usage in microsystems, the preparation, and hence the characteristics, of these hydrogels (e.g., degree of swelling, size, cooperative diffusion coefficient) are key features, and have to be as reproducible as possible. A common method of hydrogel fabrication is free radical polymerisation using a thermally-initiated system or a photoinitiator system. Due to the reaction quenching by oxygen, the polymer solution has to be rinsed with protective inert gases like nitrogen or argon before the polymerisation process. In this paper, we focus on the preparation reproducibility of PNIPAAm hydrogels under different conditions, and investigate the influence of oxygen and the UV light source during the photopolymerisation process. The flushing of the polymer solution with inert gas is not sufficient for photostructuring approaches, so a glove box preparation resulting in better quality. Moreover, the usage of a wide-band UV light source yields higher reproducibility to the photostructuring process compared to a narrow-band UV source.


[Treatment efficacy of Solitaire stent- and LVIS stent-assisted coil embolization for intracranial wide-neck carotid aneurysm].
To compare the safety, efficacy and complications of LVIS stent-assisted coil embolization and Solitaire stent-assisted coil embolization for management of intracranial wide-neck carotid aneurysms. We retrospectively analyzed the data of 86 patients with intracranial wide-neck carotid aneurysm treated in our hospital between June, 2016 and June, 2019. Forty-three of the patients received LVIS stent-assisted coil tamponade and the other 43 received Solitaire stentassisted coil tamponade. Arteriography was performed during, immediately after, and at 3 months after the surgery. The immediate embolization rate, surgical complications (vascular spasm, acute thrombus, coil escape, and bleeding), and the recurrence rate were compared between the two groups. In the LVIS stent group, 37 aneurysms were completely embolized, 5 were nearly fully embolized, and 1 was partially embolized, as compared with the numbers of 35, 6, and 2 in the Solitaire stent group, respectively. Surgery-related complications occurred in 5 patients in LVIS stent group and 3 in Solitaire stent group. Follow-up digital subtraction angiography (DSA) at 3 months after the operation revealed 4 recurrent aneurysms, including 1 in LVIS group and 3 in Solitaire stent group. All the patients had favorable outcomes that did not differ significantly between the two groups. Stent-assisted spring coils can achieve a high rate of complete and near-total embolization for intracranial aneurysms and is associated with a low incidence of neurological complications and favorable prognosis of the patients. The embolization rate, complications and recurrence rate are comparable between LVIS stent and Solitaire stent.


Thallium-205 nuclear magnetic resonance study of the thallium(I)-gramicidin A association in trifluoroethanol.
Association of the thallous ion with gramicidin in 2,2,2-trifluoroethanol has been investigated by thallium-205 NMR spectroscopy. The data obtained suggest that the gramicidin dimer has two strong binding sites and one or more weak binding sites. Association constants for the strong binding sites were found to have the same value. From the temperature dependence of the strong binding site association constants, values for the association enthalpy and entropy of -2.13 +/- 0.12 kcal/mol and +5.45 +/- 0.04 eu, respectively, were obtained.


Magnesium sulfate and calcium channel blocking drugs as antidotes for acute organophosphorus insecticide poisoning - a systematic review and meta-analysis.
Treatment of acute organophosphorus or carbamate insecticide self-poisoning is often ineffective, with tens of thousands of deaths occurring every year. Researchers have recommended the addition of magnesium sulfate or calcium channel blocking drugs to standard care to reduce acetylcholine release at cholinergic synapses. We aimed to review systematically the evidence from preclinical studies in animals exposed to organophosphorus or carbamate insecticides concerning the efficacy of magnesium sulfate and calcium channel blocking drugs as therapy compared with placebo in reducing mortality or clinical features of poisoning. We also systematically reviewed the evidence from clinical studies in patients self-poisoned with organophosphorus or carbamate insecticides concerning the efficacy of magnesium sulfate and calcium channel blocking drugs as therapy compared with placebo, in addition to standard therapy, in reducing mortality, atropine requirement, need for intubation and ventilation, and intensive care unit and hospital stay. We performed a systematic review for articles on magnesium sulfate and calcium channel blocking drugs in organophosphorus or carbamate insecticide poisoning using PubMed and China Academic Journals Full-text (Medicine/Hygiene Series) databases and keywords: "organophosphorus or organophosphate poisoning", "cholinesterase inhibitor poisoning" OR "carbamate poisoning" AND "magnesium", "calcium channel blocker", or generic names of different calcium channel blocking drugs. Review of titles and abstracts revealed 2262 papers of potential relevance. After review of the full papers, a total of 19 papers relevant to the question were identified: five preclinical studies, nine case reports or small case series, and five clinical studies and trials. We also obtained primary data from three unpublished clinical trials of magnesium sulfate, providing data from a total of eight clinical studies and trials for analysis. All studies were of organophosphorus insecticides; no studies of carbamates were found. No pre-clinical or clinical studies of calcium channel blocking drugs and magnesium sulfate in combination were found. We extracted data on study type, treatment regimens, outcome, and side effects. Pre-clinical studies: Two rodent studies indicated a benefit of calcium channel blocking drugs treatment on mortality if given before or soon after organophosphorus exposure, in addition to atropine and/or oxime. In poisoned minipigs, treatment with magnesium sulfate after organophosphorus insecticide poisoning reduced cholinergic stimulation and hypertension. Of note, magnesium sulfate further suppressed serum butyrylcholinesterase activity in one rat study. Observational clinical studies: Calcium channel blocking drugs and magnesium sulfate have been used to treat cardiac dysrhythmias and hypertonic uterine contractions in organophosphorus poisoned patients. A small neurophysiological study of magnesium sulfate reported reversion of neuromuscular junction effects of organophosphorus insecticide exposure. Comparative clinical studies: Only four of eight studies were randomized controlled trials; all studies were of magnesium sulfate, of small to modest size, and at substantial risk of bias. They included 441 patients, with 239 patients receiving magnesium sulfate and 202 control patients. The pooled odds ratios for magnesium sulfate for mortality and need for intubation and ventilation for all eight studies were 0.55 (95% confidence interval [CI] 0.32-0.94) and 0.52 (95% CI 0.34-0.79), respectively. However, there was heterogeneity in the results of higher quality phase III randomized controlled trials providing more conservative estimates. Although a small dose-escalation study suggested benefit from higher doses of magnesium sulfate, there was no evidence of a dose effect across the studies. Adverse effects were reported rarely, with 11.1% of patients in the randomized controlled trials receiving the highest dose of magnesium sulfate requiring their infusion to be stopped due to hypotension. Both preclinical and clinical data suggest that magnesium sulfate and calcium channel blocking drugs might be promising adjunct treatments for acute organophosphorus insecticide poisoning. However, evidence is currently insufficient to recommend their use. Mechanistic and large multi-center randomized controlled trials testing calcium channel blocking drugs and magnesium sulfate are required to provide the necessary evidence, with careful identification of the insecticides ingested and measurement of surrogate markers of toxicity, including butyrylcholinesterase activity.


Anxiety and depression in children with HFASDs: symptom levels and source differences.
The purpose of this study was to: (1) examine symptom levels of anxiety and depression in children with high-functioning autism spectrum disorders (HFASDs) compared with matched control children using child self-reports and parent ratings; and (2) examine source differences within the two condition groups. An overall multivariate effect indicated significantly elevated depression and anxiety symptoms for children with HFASDs based on parent reports; however no significant between-group differences based on child self-reports. Within-condition source comparisons (parent vs. child) revealed a significant multivariate effect indicating a significant difference in symptoms of depression and anxiety for the HFASD group but none for the control. Correlations between parent and child reports for the HFASD group suggested some positive association between child-reports and parent-reports for depressive symptoms only; however, the difference in average scores reflected a substantial discrepancy in the magnitude of symptoms by rater. Implications for clinical assessment and future research are provided.


Structural reorganization of the rat liver under cytotoxic effect of doxorubicin.
We studied structural reorganization of the liver after toxic injury caused by a single injection of doxorubicin in a sublethal dose (10 mg/kg). The morphogenesis of doxorubicin injury to the liver is determined by two main pathogenetic factors: cytotoxic effect of doxorubicin and its metabolites on liver cell populations (primarily hepatocytes) and pronounced hemodynamic disorders in the greater circulation resulting from the development of chronic cardiac insufficiency. Changes in hepatocyte caused by doxorubicin manifest by fatty degeneration in the periportal zones and by pronounced lytic changes in the pericentral zones, most pronounced by day 30 of the experiment. Doxorubicin in the studied dose exhibited no cytostatic effect on the hepatocyte population. Hepatocyte proliferation, observed during the entire experiment, leads to an appreciable increase in their count and liver weight.


Comparison Of Protective Effect Of Green Tea And Vitamin C Against Cypermethrin Induce Nephrotoxicity In Mice.
Insecticide toxicity is the problem of every person in under developed countries. It is necessary to counteract its effect by natural and cheap remedies like green tea and vitamin C. In this manner common man can also enjoy blessings of life. The current research was performed to compare the protective function of green tea and vitamin C on experimental cypermethrin provoked nephrotoxicity. Forty healthy Balb/C mice purchased from National Institute of Health, Islamabad, Pakistan and divided in to four groups (10 each). Group a was control which received only normal diet. Group B, group C and group D were experimental groups which were given Cypermethrin, Cypermethrin with green tea and Cypermethrin with vitamin C respectively. These groups were also given normal diet. After 1 month blood was drawn by intra-cardiac method to assess renal parameters. One month research showed increase in serum urea to 6.8±.48 m.mol/l (n=3.9±.44) while green tea and vitamin C normalize them to 4.0±.83m.mol/l and 3.4±.33m.mol/l respectively. Serum creatinine increased to 42.90±3.28m.mol/l (n=29.50±3.95) while green tea and vitamin C normalize them to 28.80±4.58m.mol/l and 22.60±2.06m.mol/l correspondingly. The results showed that green tea and vitamin C neutralized toxicity induced by Cypermethrin in mice and their effect is comparable.


Epigenetic/Genetic Mismatch: Using Transdifferentiation as a Potential Cancer Therapy to Exploit the Cell Type Specificity of Cancer.
Every cell type capable of proliferation can be malignantly transformed. However, there appears to be no naturally occurring universal set of genetic mutations capable of converting every cell type to a malignant state. Any specific cell type is generally resistant to transformation by the cancer mutations accumulated by cells of different lineages, presumably due to epigenetic differences. Evidence for this idea derives from experiments in which the developmental fates of cancer cells are altered to reduce malignancy. Reprogramming cancer cells to more primitive developmental states using pluripotency factors (IPS) or somatic nuclear transfer suppresses the malignant phenotype, as does subsequent directed differentiation to mature cells of lineages distinct from the originating cell. Direct transdifferentiation to an alternative cell fate also reduces tumorigenicity. In contrast, after reprogramming, cells induced to redifferentiate toward the original tumor cell type are tumorigenic. In these types of experiments an epigenetic/genetic mismatch often results in suppression of malignancy or cell death. Elucidating the specific transcription and cell signaling network incompatibilities will identify new targets for cancer therapy. Moreover, novel strategies to induce an incompatible transdifferentiated state, in which expression of thousands of genes are altered, will prove useful in controlling malignancies that otherwise easily evolve resistance to single target-based therapeutics. Engineering small molecules, genetic vectors, cytokines, growth factors, targeted extracellular vesicles, and cell fusion will help realize transdifferentiation-based therapeutics for cancer.


[Influence of prehospital response times in the survival of trauma patients in Navarre].
The relation between response times and mortality of polytrauma patients in the so-called "golden hour" continues to be a subject of debate. The purpose of this study is to determine the variables related to mortality in these patients and the influence of response times of the Emergency Medical Services in this mortality. To this end, the data in the "Major Trauma of Navarre" Register (retrospective cohort of polytrauma patients attended to by the Navarre Health Service) were analyzed for the four year period between 2010 and 2013. Of the 217 trauma cases available for the analysis, 42 (19%) died. No significant association was found in the multi-variate analysis between the different response times and mortality: arrival at the scene (odds ratio (OR) 1.0; 95% confidence interval (CI) from 0.99 to 1.01), in the scenario (OR 1.00; 95% CI from 0.98 to 1.02) and total time (OR 1.00; 95% CI from 0.99 to 1.01). The variables that influenced mortality are patient age and severity of injuries measured by the prehospital Triage-Revised Trauma Score (T-RTS) and the New Injury Severity Score (NISS). The mortality of polytrauma patients attended to by the emergency system in our region is influenced by age and by the intensity of the aggression suffered, determined by the prehospital T-RTS and by the NISS. The response times of the hospital do not have a significant influence.


Enzyme-linked immunosorbent assay-based detection of free trenbolone in bovine bile.
A rapid antibody-based detection system has been developed for the presence of free trenbolone in bovine samples. Polyclonal antibodies were produced that showed specificity toward epitopes located around the steroidal A-ring of the trenbolone molecule. These antibodies were shown to have little or no recognition for many closely related compounds. The antibodies were utilized as the specific biorecognition molecules in competitive and inhibitive enzyme-linked immunosorbent assay systems. While both assays were able to detect low nanogram concentrations of trenbolone in bovine bile, the competitive format was more sensitive (2.41 vs 17.15 ng/mL for TRAb2 and 3.31 vs 30.73 ng/mL for TRAb1). This format was also more accurate and the data produced by this assay fitted more closely to the four parameter equation used to calculate the standard curve. This was a common finding with both of the polyclonal antibodies, suggesting that this was a characteristic of the format used.


Flexible metal binding of the metallo-beta-lactamase domain: glyoxalase II incorporates iron, manganese, and zinc in vivo.
Glyoxalase II belongs to the metallo-beta-lactamase superfamily of proteins, possessing the characteristic dinuclear active site. Within this protein family, glyoxalase II from Arabidopsis thaliana is the first member to be isolated with significant amounts of iron, manganese, and zinc when being recombinantly produced in Escherichia coli. Enzyme preparations with different ratios of these three metals all yield k(cat)/K(M) values in the range of 1.5-1.9 s(-1) microM(-1) with the substrate S-d-lactoylglutathione. X-ray absorption spectroscopy reveals binding of all three metals to the dinuclear active site with 5-6-fold coordination consisting of 2.5 +/- 0.5 histidine and 2.5 +/- 0.5 oxygen ligands. This model does not distinguish site-specific or distributed binding. The metal-metal distance is determined to be 3.18 +/- 0.06 A. Electron paramagnetic resonance spectroscopy gives evidence for several different types of dimetal sites, including spin-coupled Fe(III)Fe(II), Fe(III)Zn(II), and Mn(II)Mn(II) centers. The metal-ligand distances measured by X-ray absorption spectroscopy vary depending on the metal type and comply with their element-specific, characteristic values. This reflects a high degree of structural flexibility within the glyoxalase II dinuclear active site, which is considered as the structural basis for its broad metal selectivity.


Reproductive history in women with lower limb ischemia.
The purpose of this study was to identify reproductive factors that may contribute to the development of arteriosclerosis in the leg arteries by comparing the reproductive history of women with lower limb ischemia to a reference group of women. All 173 female patients treated for chronic lower limb ischemia with surgical or endovascular procedures performed from 1994 to 1996 at a university clinic received a validated questionnaire to which 116 (67%) responded. The reference group, 348 women, 197 (57%) of whom responded, was recruited randomly from the hospital catchment area. The 2 groups were similar regarding age at menopause and menarche, pregnancies, salpingo-oophorectomies, and hormone replacement therapy. There was a higher number of women who had used oral contraceptives in the reference group than in the patient group (53% vs 16%, p < 0.001). The same results were found when comparing the subgroup of patients younger than 55 years to the references. No association between reproductive history and development of lower limb ischemia could be found. Our results support that use of oral contraceptives early in life is not associated with an increased risk for lower limb ischemia.


Study of risk perception consumption behavior of sports tourism in China.
In order to further implement the "Healthy China 2030 Planning Outline" and actively develop the sports tourism industry, this study analyzed the independent variables and dependent variables that affect the urban residents' sports tourism risk perception consumption behavior.Finally, the simultaneous regression, stepwise regression and hierarchical regression models of sports tourism risk perception consumption behavior of urban residents are constructed. The purpose is to help people effectively screen all kinds of risks in the process of sports tourism, promote the growth of sports consumption, and provide theoretical and practical guidance for the development of sports tourism.


Two new polyketides from the fungus Penicillium oxalicum MHZ153.
Two new polyketides, penicilloxalones A (1) and B (2), together with 13 known compounds (3-15), were isolated from the ethyl acetate extract of the solid substrate fermentation cultures of the fungus Penicillium oxalicum MHZ153. The structures of the isolates were determined by spectroscopic analysis and comparison of their spectroscopic and physicochemical data with the literature values. Compounds 7 and 11 showed inhibition of nitric oxide production in lipopolysaccharide-stimulated BV-2 microglial cells with IC50 values of 0.9 ± 0.2 μM and 87.9 ± 0.7 μM, respectively.


Making health insurance responsive to citizens: the management of members' complaints by mutual health organisations in Kinshasa, Democratic Republic of Congo.
In moving towards universal health coverage, a number of low-income and middle-income countries have adopted community-based health insurance (CBHI) as a means to reduce both the inequity in healthcare access and the burden of catastrophic health expenditures linked to user fees. However, organisations managing CBHIs face many challenges, including a poor relationship with their members. In the Democratic Republic of the Congo, CBHI schemes are managed by mutual health organisations (MHOs) and are in the process of enhancing their accountability and responsiveness to members' needs and expectations. This study assessed how MHOs have managed member complaints and their performance in grievance redressal. Using a sequential mixed-methods approach, we drew insights from four types of sources: review of approximately 50 relevant documents, 25 in-depth interviews (IDIs) with CBHI managers, 9 IDIs with health facility managers, 1063 surveys of MHO members and 15 focus group discussions (FGDs) comprising an additional 153 MHO members. MHO members in this study belonged to three different MHOs (Lisanga, La Borne and Mutuelle de santé des Enseignants de l'Enseignement Primaire, Secondaire et Professionnel) in the capital, Kinshasa. The document review showed that there were no clear administrative processes for the implementation of the grievance redressal arrangement measures resulting in low member awareness of these measures. These results were confirmed by the IDIs. Of 1044 members surveyed, only 240 (23%) were aware of the complaint measures, and 201 (84%) of these declared they had used the measures at some point in time, 181/201 (90%) users who had used the measures declared being satisfied with the response provided. The FGDs confirmed that most members lack knowledge on the grievance redressal procedures, but those who were aware had made use of them and were often satisfied with the response provided. MHOs should urgently improve communication with their members on the range of redressal measures put in place to address grievances. Attention should be given to properly monitor existing arrangements, and possibly adapt them with well-documented and communicated standard operating procedures.


Gamma Irradiation Upregulates B-cell Translocation Gene 2 to Attenuate Cell Proliferation of Lung Cancer Cells Through the JNK and NF-κB Pathways.
Gamma ray can promote cancer cell apoptosis and cell cycle arrest. It is often used in the clinical treatment of tumors, including lung cancer. In this study, we aimed to explore the role of gamma ray treatment and its correlation with BTG2 in cell proliferation, apoptosis, and cell cycle arrest regulation in a lung cancer cell line. A549 cell viability, apoptosis rate, and cell cycle were investigated after gamma ray treatment. We then used siRNA for BTG2 to detect the effect of BTG2 knockdown on the progress of gamma ray-treated lung cancer cells. Finally, we investigated the signaling pathway by which gamma ray might regulate BTG2. We found that gamma ray inhibited A549 cell viability and promoted apoptosis and cell cycle arrest, while BTG2 knockdown could relieve the effect caused by gamma ray on A549 cells. Moreover, we confirmed that the effect of BTG2 partly depends on p53 expression and gamma ray-promoting BTG2 expression through the JNK/NF-κB signaling pathway. Our study assessed the possible mechanism of gamma ray in tumor treatment and also investigated the role of BTG2 in gamma ray therapy. All these findings might give a deep understanding of the effect of gamma ray on the progression of lung cancer involving BTG2.


Deciding on cystic fibrosis carrier screening: three citizens' juries and an online survey.
Health technology assessment and ethical issues have to be dealt with in deciding on national carrier screening for cystic fibrosis (CF)-the most frequent severe autosomal recessive disease in Caucasian populations and several stakeholders need to be involved. A citizens' jury is one way to ask citizens to deliberate on controversial topics in the interests of a society. The aims of this project were to gather opinions about CF carrier screening through citizens' jury deliberations and to match them with the findings of a large online consultation survey open to the general population, people with CF and families and health professionals. Three citizens' juries and an online survey were asked: 'Should the Health Service organize screening of the population with the aim of identifying healthy people who may have children with CF?' The jurors had no medical background and no personal or family CF history. The survey was open to people with CF, families, and healthcare professionals. Jurors and survey respondents were in favour of CF carrier screening, mainly considering the severity of CF, the value of informed reproductive choices and the equality of the screening. All the citizens' juries felt positively about the health service actively offer CF carrier screening to provide women and couples of reproductive age equal access and standardized information on the pros and cons. Considering the favourable attitude towards CF screening, the feasibility of CF screening, in terms of best setting, target age and healthcare professionals providing it, should be tested in a clinical trial.


Use of computerized ICU documentation to capture ICU core measures.
Intensive care unit (ICU) core measures that target the prevention of catheter-related bloodstream infections (CRBSIs) and ventilator-associated pneumonia (VAP) in ventilated ICU patients are underway across the United States. Implementation often requires additional personnel to educate providers and collect the data. We hypothesized that use of our current computerized ICU flowsheet could provide timely, accurate data on ICU core measures without additional personnel dedicated to data capture. In a 10-bed, closed surgical ICU with existing protocols for deep vein thrombosis (DVT) prophylaxis, stress ulcer bleeding prophylaxis (SUP), ventilator weaning parameters, and glucose control, we created a reporting tool that would document daily weaning parameters, head of bed (HOB) at 30 degrees , glucose levels, DVT prophylaxis, and SUP. Our glucose protocol targeted <150 mg/dL, with all daily glucose values reported rather than just the morning value. The results from the previous 12 am to 11:59 pm were available to the rounding team at 7 am. We examined compliance at the start and after education of medical staff (March/April for HOB up, DVT, and SUP; May/June for glucose control). During 2005, compliance with all protocols improved. Percent compliance for DVT prophylaxis, SUP, and HOB up rose from as low as 32% at the start of the documentation process to consistently higher than the target level of 95%. Compliance for glucose control increased after intensive education of nursing and physicians with the mean glucose falling from 144 to 122 mg/dL. There was increased nursing workload for checking glucose levels in which the mean number of glucose checks rose from a low of 1.5 per patient to as high as 8.2 per patient per day. CRBSI and VAP rates did not decrease during this period compared with the prior year. Length of stay and mortality were unchanged. Reporting of ICU core measures to treating staff can be done accurately and promptly with a computerized system. Education was effective in improving compliance levels. No additional personnel were required to create reports, capture data, or improve compliance after initial development and testing. Although compliance with core measures met target levels at the end of the year, we did not observe improved outcomes in terms of CRBSI, VAP, mortality, or length of stay.


Willingness to pay for social health insurance and its determinants among public servants in Mekelle City, Northern Ethiopia: a mixed methods study.
Owing to lack of adequate healthcare financing, access to at least the basic health services is still a problem in Ethiopia. With the intention of raising funds and ensuring universal health coverage, a mandatory health insurance scheme has been introduced. The Community Based Health Insurance has been implemented in all regions of the country, while implementation of social health insurance was delayed mainly due to resistance from public servants. This study was, therefore, aimed to assess willingness to pay for social health insurance and its determinant factors among public servants in Mekelle city, Northern Ethiopia. A concurrent mixed approach of cross-sectional study design using double bound dichotomous choice contingent valuation method and qualitative focus group discussions was employed. A total 384 public servants were recruited from randomly selected institutions and six focus group discussions (n = 36) were carried out with purposively selected respondents. Participants' mean willingness to pay (WTP) and independent predictors of WTP were identified using an interval data logit model. Qualitative data were analyzed using thematic analysis. From the 384 participants, 381 completed the interview, making a response rate of 99.2%. Among these respondents 85.3% preferred social health insurance and were willing to pay for the scheme. Their estimated mean WTP was 3.6% of their monthly salary. Lack of money to pay (42.6%) was the major stumbling block to enrolling in the scheme. Respondents' WTP was significantly positively associated with their level of income but their WTP decreased with increasing age and educational status. On the other hand, a majority of focus group discussion participants were not willing to pay the 3% premium set by the government unless some preconditions were satisfied. The amount of premium contribution, benefit package and poor quality of health service were the major factors affecting their WTP. The majority of the public servants were willing to be part of the social health insurance scheme, with a mean WTP of 3.6% of their monthly salary. This was greater than the premium proposed by the government (3%). This can pave the way to start the scheme but attention should focus on improving the quality of health services.


A physical map of the Myxococcus xanthus chromosome.
A physical map of the 9.2-Mbp Myxococcus xanthus DK1622 chromosome at a resolution of 25 kbp was constructed by using a strategy that is applicable to virtually all microorganisms. Segments of the chromosome were used as hybridization probes to subdivide a yeast artificial chromosome (YAC) library into groups of linked clones. The clones were aligned by comparing their EcoRI restriction patterns. The groups of YAC clones ("contigs") were oriented and aligned with the genomic restriction map by means of common genetic and physical markers such as rare restriction sites and transposon insertions. Over 95% of the genome is represented by cloned DNA. Sixty genetic loci including > 100 genes, many of which play a role in fruiting body development, have been mapped in this way. Additional genes can now be located on the chromosome map by hybridization of their sequences to the ordered set of YAC chromosomes. The mapped genetic loci account for approximately 2% of the genome.


Pain experienced during and after office hysteroscopy with and without intracervical anesthesia.
We designed this study to evaluate if intracervical anesthesia reduces pain experienced during and after office hysteroscopy (OH). Two hundred women undergoing OH were randomized into two groups. Group I received intracervical anesthesia (10 ml %2 prilocaine), group II did not receive any anesthesia before procedure. The intensity of pain during procedure, 30 and 60 minutes later on visual analog scale (VAS) was assessed. Groups were similar in age, parity, previous number of vaginal delivery, or presence of menopausal status. The mean of pain scores during OH was less in group I (0.82 ± 0.11) than in group II (0.86 ± 0.09) and the difference was statistically significant (p = 0.04). But, the difference of mean pain scores 30 and 60 minutes after procedure between the groups were not statistially significant. In conclusion, intracervical anesthesia reduces pain experienced during OH, but this effect does not last longer.


A self-administered device for cervical cancer screening in northeast Thailand.
To test a self-scraping device as a mass screening device against a routine scraping method and to evaluate the acceptance of the self-scraping device by a group of rural females from Northeast Thailand. From a rural area of Northeast Thailand, 552 women were trained and motivated, through primary health care structures, to participate in a cervical cancer screening exercise using a self-scraping device. After one week, the same females were reexamined by gynecologists using the routine scraping method. In both cases the specimens were stained according to Papanicolaou. Through questionnaires the acceptance of the self-scraping device was evaluated. Through the self-scraping method, 13 cases suspicious for malignancy were detected. Specimens obtained through examination by physicians confirmed 11 cases to be suspicious for malignancy. No false negative cases were found. In the detection of inflammation, the self-scraping method was not as accurate as examination by a physician. The device was accepted by the females who participated in the study. In the rural areas of developing countries, where physicians and other trained medical personnel are not often available to carry out regular screening tests on a population basis, the self-scraping method can be applied as an integral part of primary health care for mass screening for uterine cervical cancer.


From HDL-cholesterol to HDL-function: cholesterol efflux capacity determinants.
The validity of HDL-cholesterol (HDL-C) elevation as a therapeutic target has been questioned, in comparison to enhancing HDL functionality. Cholesterol efflux capacity (CEC) is an in-vitro assay that measures the ability of an individual's HDL to promote cholesterol efflux from cholesterol donor cells such as macrophages. CEC of HDL is a predictor of cardiovascular risk independent of HDL-C levels. However, molecular determinants of CEC and the effects of diseases and therapeutic interventions on CEC have not been completely defined. We review here recent findings on elevated HDL-C and disease risk, as well as determinants of CEC, from genetics and proteomics to pathophysiology and therapeutic interventions that contribute to our understanding of CEC as a biomarker of HDL functionality. Elevated HDL-C levels are not always protective against cardiovascular disease and mortality. CEC is a heritable trait, and genetic polymorphisms in genes involved in HDL and triglycerides metabolism are associated with CEC. Multiple HDL proteins correlate positively with CEC levels and inversely with noncalcified plaque burden. Differences in CEC assays that make comparisons between studies difficult are also emphasized. CEC should be measured in clinical trials of lipid-modifying and anti-inflammatory therapies to determine whether increases are cardioprotective.


[Can isoflurane be advised for controlled hypotension?].
Since 1983, many papers tell of the usefulness of isoflurane for induced hypotension. It can induce and maintain stable arterial hypotension during neurosurgery, or any other surgical procedure requiring induced hypotension. Its use has proved to be simple. Although other hypotensive techniques are possible, especially if only moderate hypotension is required, the mechanism of action of isoflurane is very appealing: it reduces arterial pressure by reducing the peripheral resistances, without reducing the output, unlike halothane or trinitrin. Moreover, as it is anaesthetic, it reduces the overall oxygen consumption, such that if there were a fall in output one could assume that it was related to the level of oxygen consumption. When there is no severe hypocapnia, isoflurane, quite unlike sodium nitroprusside, lowers cerebral oxygen consumption without affecting cerebral blood flow rate. It does however increase intracranial pressure, like all the other hypotensive agents used. It does not increase filling pressures and has no effect on blood gas movements, unlike sodium nitroprusside and trinitrin which increase filling pressures and the intrapulmonary shunt. It is not toxic either, unlike sodium nitroprusside. The expensiveness of the drug is balanced by its many advantages, all the more so as this cost can be reduced by using a filter-system for some cases (e.g. middle ear surgery), or by using some drug combinations which need yet to be defined. However, there exist some disadvantages which may, in fact, be due to experimental conditions: failure of induced hypotension, coronary ischaemia, doubtful cerebral protection in case of focal areas of ischemia, different degrees of organ vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)


Detection of a serum DNA-binding protein associated with cancer.
An accompanying report describes the purification and partial characterization of a unique DNA-binding protein (Mr 64,000; pI 5.9) that is present in human sera. This report gives the results of assays of sera from patients for the bleomycin inhibitor protein (BIP) using the Pseudomonas bacteriophage covalently closed circular DNA fluorescence technique standardized for DNA breakage induced by bleomycin. The results of the BIP assays were expressed by values of specific activity of inhibition. One arbitrary unit of inhibitory activity was defined as equivalent to the amount of serum protein required to cause 50% inhibition of DNA degradation using standard conditions of the DNA breakage assay. The mean values of specific activity of inhibition (SAI) for groups of healthy individuals (n = 26), patients with nonmalignant diseases (n = 33), and patients with malignant diseases (n = 83) were 12.60 +/- 4.69 (S.E.), 12.53 +/- 3.17, and 2.40 +/- 0.84 units/mg, respectively. Mean SAI values for patients with cancers of various types were: solid tumors (n = 46), 2.44 +/- 0.86; leukemias (n = 24), 2.59 +/- 0.96; and lymphomas (n = 18), 2.07 +/- 0.64. The decrease in BIP activity was not correlated with sex, age, or prior chemotherapy. Mean SAI values of male (n = 29) and female (n = 59) patients with cancer were 2.61 +/- 0.87 and 2.30 +/- 0.83 units/mg, respectively. Mean SAI values for different age groups were: 0 to 40 years (n = 21), 2.05 +/- 0.68 units/mg; 41 to 70 years (n = 56), 2.59 +/- 0.68 units/mg; and greater than 70 years (n = 11), 2.12 +/- 0.67 units/mg. Cancer patients with and without prior chemotherapy had mean SAI values of 2.97 +/- 0.85 (n = 23) and 2.20 +/- 0.86 units/mg (n = 65), respectively. Linear regression analysis comparing SAI values and serum protein levels showed no correlation (r = 0.21). These results suggest the decrease of the BIP is associated with malignant disease. Additional controlled studies are required before the significance of this association can be adequately assessed.


[Improvement of management of hypertension by implementation of alcohol screening and subsequent interventions in primary practice].
Hypertension and alcohol use are both part of the five most important risk factors for burden of disease in Western Europe, mainly because of their impact on non-communicable diseases (NCD). Both risk factors are prevalent with high overlap among patients in primary care. Implementation of a screening for alcohol among patients of hypertension in primary care followed by brief intervention for problem alcohol use or formal treatment for people with alcohol dependence could constitute an important step to reach the goals of the Global WHO Action Plan for Prevention and Control of NCD. In addition, such an intervention could improve the management of hypertension. In a working group of experts from clinical practice and research the rationale and potential barriers for this intervention were discussed and steps for implementation in primary care were developed.


OX40 and Bcl-xL promote the persistence of CD8 T cells to recall tumor-associated antigen.
The molecular signals that allow primed CD8 T cells to persist and be effective are particularly important during cancer growth. With response to tumor-expressed Ag following adoptive T cell transfer, we show that CD8 effector cells deficient in OX40, a TNFR family member, could not mediate short-term tumor suppression. OX40 was required at two critical stages. The first was during CD8 priming in vitro, in which APC-transmitted OX40 signals endowed the ability to survive when adoptively transferred in vivo before tumor Ag encounter. The second was during the in vivo recall response of primed CD8 T cells, the stage in which OX40 contributed to the further survival and accumulation of T cells at the tumor site. The lack of OX40 costimulation was associated with reduced levels of Bcl-x(L), and retroviral expression of Bcl-x(L) in tumor-reactive CD8 T cells conferred greatly enhanced tumor protection following adoptive transfer. These data demonstrate that OX40 and Bcl-x(L) can control survival of primed CD8 T cells and provide new insights into both regulation of CD8 immunity and control of tumors.


[Transgenic mice as models to study the influence of polyunsaturated fatty acids on metabolism].
The mouse is a popular animal model employed for studying metabolic alterations. The generation of fat-1 transgenic mice by Professor Jing X. Kang and collaborators has revolutionised the omega-3 research. Fat-1 mice are able to convert omega-6 fatty acids to omega-3 fatty acids due to gene fat-1 from Caenorhabditis elegans that encodes an omega-3 fatty acids desaturase. This mice model can endogenously synthesize omega-3 PUFA without ALA intake and the balancing quantity and quality of various confounding factors of different diets. Next, novel transgenic mice - "Omega mice" with the expression of the fat-1 and fat-2 transgenes were created to produce both omega-6 and omega-3 PUFA from a diet containing saturated fat or carbohydrates with essential fatty acids deficiency. Both transgenic mice are utilities for studying molecular mechanisms of omega-3 fatty acids and their metabolites in tumorigenesis and inflammatory disorders.