Cholera-like enterotoxins and Regulatory T cells.
Cholera toxin (CT) and the heat-labile enterotoxin of E. coli (LT), as well as their non toxic mutants, are potent mucosal adjuvants of immunization eliciting mucosal and systemic responses against unrelated co-administered antigens in experimental models and in humans (non toxic mutants). These enterotoxins are composed of two subunits, the A subunit, responsible for an ADP-ribosyl transferase activity and the B subunit, responsible for cell binding. Paradoxically, whereas the whole toxins have adjuvant properties, the B subunits of CT (CTB) and of LT (LTB) have been shown to induce antigen specific tolerance when administered mucosally with antigens in experimental models as well as, recently, in humans, making them an attractive strategy to prevent or treat autoimmune or allergic disorders. Immunomodulation is a complex process involving many cell types notably antigen presenting cells and regulatory T cells (Tregs). In this review, we focus on Treg cells and cholera-like enterotoxins and their non toxic derivates, with regard to subtype, in vivo/in vitro effects and possible role in the modulation of immune responses to coadministered antigens.


Postintervention duration of anticoagulation in venous surgery.
For a substantial proportion of patients with deep venous thrombosis (DVT), current treatment strategies are suboptimal and new treatment options are needed. Especially for the group of patients who are at the highest risk for post-thrombotic syndrome, new treatment modalities such as catheter-directed thrombolysis and additional stenting are being investigated. With current clinical studies addressing new technical options, the medical management of patients following these interventions deserves attention. The duration of anticoagulant treatment following surgical or radiological interventions for DVT seems not to be influenced by the presence of a venous stent. According to recent ACCP 2012 guidelines the anticoagulant management in patients who have had any method of thrombus removal performed, the same intensity and duration of anticoagulant therapy as in comparable patients who do not undergo thrombosis removal is recommended (Grade 1B). In the acute phase of thrombosis, irrespective of the technique and whether or not stenting is applied, immediate anticoagulation following the procedure is pertinent to reduce the risk of recurrent thrombosis and thrombus propagation. The long-term treatment duration after venous interventions therefore may be tailored based on common risk factors for recurrent thrombosis and the individual risk for bleeding. Selected thrombophilia factors, d-dimer assessment and residual venous thrombosis provide markers for recurrent DVT. Currently, vitamin K antagonists) provide the main anticoagulants for (prolonged) anticoagulation, while the new oral anticoagulants emerge as promising alternatives. In case prolonged anticoagulation after unprovoked DVT is not indicated, cardiovascular risk management is warranted because of an increased rate of arterial thrombotic events after DVT; aspirin may be indicated as secondary prevention against recurrent thrombosis (while providing primary prevention against arterial thrombosis).


Objectively measured physical activity and obesity prevention in children, adolescents and adults: a systematic review of prospective studies.
This study aimed at synthesizing the prospective associations between measured physical activity (PA) and change in adiposity in children, adolescents and adults following from two previous reviews. Search terms were adapted and a systematic literature search was conducted (January 2000-September 2008) and later updated (up to October 2009), considering observational and intervention studies of weight gain that measured both PA and body composition. Sixteen observational studies (six comprising adults) and five trials (one comprising adults) were eligible. For consistency, whenever possible either baseline PA energy expenditure or accelerometer output (counts min(-1) ) and change in per cent body fat were the extracted exposure and outcome measures. Results of observational studies suggest that PA is not strongly prospectively related with adiposity: five studies on children and three on adults reported no association between baseline PA and change in adiposity, one study found a weak positive association and the other studies observed a weak negative association. Negative associations were more frequently observed in studies that analysed the association between change in the exposure and outcome. Intervention studies show generally no effect on either PA or adiposity. In conclusion, despite the well-established health benefits of PA, it may not be a key determinant of excessive gain in adiposity.


Protein complexes in bacteria.
Large-scale analyses of protein complexes have recently become available for Escherichia coli and Mycoplasma pneumoniae, yielding 443 and 116 heteromultimeric soluble protein complexes, respectively. We have coupled the results of these mass spectrometry-characterized protein complexes with the 285 "gold standard" protein complexes identified by EcoCyc. A comparison with databases of gene orthology, conservation, and essentiality identified proteins conserved or lost in complexes of other species. For instance, of 285 "gold standard" protein complexes in E. coli, less than 10% are fully conserved among a set of 7 distantly-related bacterial "model" species. Complex conservation follows one of three models: well-conserved complexes, complexes with a conserved core, and complexes with partial conservation but no conserved core. Expanding the comparison to 894 distinct bacterial genomes illustrates fractional conservation and the limits of co-conservation among components of protein complexes: just 14 out of 285 model protein complexes are perfectly conserved across 95% of the genomes used, yet we predict more than 180 may be partially conserved across at least half of the genomes. No clear relationship between gene essentiality and protein complex conservation is observed, as even poorly conserved complexes contain a significant number of essential proteins. Finally, we identify 183 complexes containing well-conserved components and uncharacterized proteins which will be interesting targets for future experimental studies.


New dual-energy X-ray absorptiometry equipment in the assessment of vertebral fractures: technical limits and software accuracy.
The aim of this study was to investigate software accuracy and influence of body mass index on image quality of Lunar iDXA (Lunar, Madison, WI, USA; software enCORE 12.0) in vertebral fracture (VFs) assessment. We enrolled 65 normal or overweight patients (group 1) and 64 obese patients (group 2) with indication for morphometric evaluation of the spine. Patients underwent iDXA, with scans performed in the standard manner by an expert technologist. Lateral images of the spine were subsequently evaluated by a musculoskeletal radiologist as the gold standard. Our analysis considered five points: vertebral bodies missed or not assessable or wrongly labeled on T4-L4 segment, diagnostic performance of the automatic morphometric point-positioning system in the detection of VFs, upgrading and downgrading of fractures, radiologist intervention rate, and BMI influence. In group 1, 57/845 (6.7%) vertebral bodies and 34/832 (4.1%) in group 2 were not assessable-the upper thoracic spine. enCORE failed to recognize vertebral levels in 5.4% of the patients (7.7% in group 1 vs. 3.1% in group 2). On a lesion-based analysis sensitivity, specificity and accuracy of the software were 81.4, 93.8, and 93.1% in group 1 and 69.1, 88.3, and 86.7% in group 2, respectively. For 52.7% of the vertebrae in group 1 (51/8 upgraded/downgraded) and 70.0% in group 2 (96/26 upgraded/downgraded), a point correction was necessary and this changed the diagnosis respectively in 29.2 and 50.0% of the patients. Differences in diagnostic performance and point correction rate were significantly different between the two groups; however, BMI did not significantly affect vertebral level labeling and was correlated with a better visualization of the whole T4-L4 spine segment. This study provides new and interesting information about the accuracy, reliability, and imaging quality provided by iDXA in the assessment of VFs.


The antioxidant effect of wheat germ oil on subchronic coumaphos exposure in mice.
Forty-eight male Balb/C mice, allocated to 4 equal groups, constituted the material of the study. The first group was maintained as the control group and was administered solely with a vehicle, which was used to dissolve coumaphos in the third and fourth groups. The second group was administered with 1.5 ml/kg.bw/day (∼1400 mg/kg.bw/day) of wheat germ oil. The third group received 5.5mg/kg.bw/day (1/10 LD50(oral)) of coumaphos. Finally, the fourth group was given both coumaphos and wheat germ oil at the doses indicated above. In all groups, the compounds were given directly into the stomach using a gastric tube, and treatment was continued for a period of 45 days. At the end of the 45th day, the liver, lungs, kidneys, brain, heart and spleen were extirpated in all of the animals. Tissue homogenates prepared from the tissue specimens were analysed for malondialdehyde (MDA) levels and catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities. In conclusion, it was determined that coumaphos led to adverse alterations in the majority of the oxidative stress markers investigated. The administration of wheat germ oil alleviated the coumpahos-induced adverse effects detected in the tissues examined.


Does the presence of coronary artery disease impact perioperative outcomes following partial hepatectomy?
Coronary artery disease (CAD) is often considered a contraindication to hepatectomy despite a lack of data to support this practice. The purpose of this study is to evaluate the impact of CAD on postoperative outcomes in patients undergoing hepatectomy. A total of 1,206 consecutive patients undergoing hepatectomy from August 1995 to June 2009 were included. Propensity matching was performed to identify differences in morbidity and mortality between patients with and without CAD. Subgroup analyses were performed to stratify patients based on the severity of CAD and the interval between coronary intervention and hepatectomy. Of all patients, 138 (11.4%) had a diagnosis of CAD and were more likely to have a malignant diagnosis and other comorbid conditions including renal insufficiency, COPD, and diabetes. Matched patients with CAD had no significant differences in complication rates, with 2.2 and 5.8% of CAD patients experiencing a postoperative myocardial infarction or arrhythmia, respectively. Propensity matching failed to identify differences in mortality or morbidity. Subgroup analysis revealed similar rates of mortality and complications regardless of the severity of CAD or the time interval between coronary intervention and hepatectomy. Despite the increased prevalence of major medical comorbidities, selected patients with CAD can safely undergo hepatectomy with acceptable rates of postoperative morbidity and mortality.


Investigating regional mobility in the southern hinterland of the Wari Empire: biogeochemistry at the site of Beringa, Peru.
Empires have transformed political, social, and environmental landscapes in the past and present. Although much research on archaeological empires focuses on large-scale imperial processes, we use biogeochemistry and bioarchaeology to investigate how imperialism may have reshaped regional political organization and regional migration patterns in the Wari Empire of the Andean Middle Horizon (ca. AD 600-1000). Radiogenic strontium isotope analysis of human remains from the site of Beringa in the Majes Valley of southern Peru identified the geographic origins of individuals impacted by the Wari Empire. At Beringa, the combined archaeological human enamel and bone values range from (87)Sr/(86)Sr = 0.70802 - 0.70960, with a mean (87)Sr/(86)Sr = 0.70842 ± 0.00027 (1σ, n = 52). These data are consistent with radiogenic strontium isotope data from the local fauna in the Majes Valley and imply that most individuals were local inhabitants, rather than migrants from the Wari heartland or some other locale. There were two outliers at Beringa, and these "non-local" individuals may have derived from other parts of the South Central Andes. This is consistent with our understanding of expansive trade networks and population movement in the Andean Middle Horizon, likely influenced by the policies of the Wari Empire. Although not a Wari colony, the incorporation of small sites like Beringa into the vast social and political networks of the Middle Horizon resulted in small numbers of migrants at Beringa.


Chronic dietary oxalate nephropathy after intensive dietary weight loss regimen.
Hyperoxaluria has been associated with nephrolithiasis as well as acute and chronic kidney disease. We present a case of end stage renal failure caused by excessive dietary oxalate intake in a dietary weight loss regimen. A 51-year-old Caucasian male with the past medical history of type 2 diabetes mellitus, gout, hypertension and morbid obesity was referred to the primary care clinic after being found pale and easily fatigued. The patient had lost 36 kg over a 7-month period by implementing exercise and intense dietary measures that included 6 meals of spinach, kale, berries, and nuts. Physical examination revealed a blood pressure of 188/93 mm Hg with sunken eyes and dry mucus membranes. Laboratory workup was notable for blood urea nitrogen of 122 mg/dL, creatinine of 12 mg/dL, and estimated glomerular filtration rate (eGFR) of 4.4 mL/min/1.73m2. Patient denied any history of renal disease or renal stones, or taking herbal products, non-steroidal anti-inflammatory drugs, antifreeze (ethylene glycol), or any type of "diet pills." Family history was unremarkable for any renal diseases. After failing intravenous fluid resuscitation, patient was started on maintenance hemodialysis. Abdominal imaging was consistent with chronic renal parenchymal disease with no evidence of nephrolithiasis. Renal biopsy revealed numerous polarized oxalate crystal deposition and diabetic nephropathy class IIA. At this point the patient was instructed to adopt a low oxalate diet. A 24-hour urine collection was remarkable for pH 4.7, citrate <50 mg, and oxalate 46 mg. Importantly, serum oxalate level was undetectable. Repeat renal biopsy 5 months later while patient was still on maintenance hemodialysis revealed persistence of extensive oxalate crystal deposition. Patient has been referred for evaluation for renal transplantation. Clinicians need to maintain a high index of suspicion for dietary hyperoxaluria as a potential etiology for acute or chronic kidney failure, particularly in patients pursuing intensive dietary weight loss intervention.


Identification of a structural glycoprotein of an RNA virus as a ribonuclease.
One of the three structural glycoproteins of classical swine fever virus (CSFV) is E0, a disulfide-bonded homodimer that induces virus-neutralizing antibodies and occurs in a virion-bound as well as a secreted form. E0 was shown to be similar to a family of fungal and plant ribonucleases. Purified E0 from CSFV-infected cells was a potent ribonuclease specific for uridine and inhibitable by zinc ions.


The free-viewing matrix task: A reliable measure of attention allocation in psychopathology.
Aberrant attention allocation has been implicated in the etiology and maintenance of a range of psychopathologies. However, three decades of research, relying primarily on manual response-time tasks, have been challenged on the grounds of poor reliability of its attention bias indices. Here, in a large, multisite, international study we provide reliability information for a new eye-tracking-based measure of attention allocation and its relation to psychopathology and age. Data from 1567 participants, across a wide range of psychiatric diagnoses and ages, were aggregated from nine sites around the world. Of these, 213 participants also provided retest data. Acceptable overall internal consistency and test-retest reliability were observed among adult participants (Cronbach's alpha = 0.86 and r(213) = 0.89, respectively), as well as across all examined psychopathologies. Youth demonstrated lower internal consistency scores (Cronbach's alpha = 0.65). Finally, the percent dwell time index derived from the task statistically differentiated between healthy participants and participants diagnosed with social anxiety disorder, major depression, and post-traumatic stress disorder. These results potentially address a long-standing reliability crisis in this research field. Aberrant attention allocation patterns in a variety of psychiatric disorders may be targeted with the hope of affecting symptoms. The attention allocation index derived from the matrix task offers reliable means to measure such cognitive target engagement in clinical contexts.


Factors associated with the consumption of chlorine dioxide to prevent and treat COVID-19 in the Peruvian population: a cross-sectional study.
Chlorine dioxide has been promoted as an alternative for the prevention and treatment of COVID-19, especially in Peru, despite the lack of evidence to support its efficacy. This study aimed to evaluate the factors associated with chlorine dioxide consumption in the Peruvian population. Analytical cross-sectional study. An adult Peruvian population was evaluated where chlorine dioxide consumption was divided into two groups according to the purpose of use: as prevention (individuals without COVID-19 history) and as treatment (individuals with COVID-19 history). The associated factors in each group were evaluated using Poisson regressions with the bootstrapping resampling method. Of 3610 participants included, 3213 reported no history of COVID-19, and 397 had been infected. The prevalence of chlorine dioxide consumption to prevent or treat COVID-19 was 8 and 16%, respectively. Factors either positively or negatively associated with chlorine dioxide consumption for prevention were male sex (aPR: 1.36; 95% CI: 1.09-1.71), being an adult or older adult (aPR: 0.54; 95% CI: 0.35-0.82), having a health sciences student within the family unit (aPR: 1.38; 95% CI: 1.02-1.87), using medical information as the main source of information of COVID-19 (aPR: 0.57; 95% CI: 0.40-0.80), having comorbidities for COVID-19 (aPR: 1.36; 95% CI: 1.01-1.82), considering COVID-19 dangerous and deadly (aPR: 0.57; 95% CI: 0.45-0.74), using medications (aPR: 1.59; 95% CI: 1.25-2.06) and plants to prevent COVID-19 (aPR: 1.69; 95% CI: 1.21-2.36), considering chlorine dioxide ineffective (aPR: 0.18; 95% CI: 0.18-0.24), and being uninformed of its efficacy (aPR: 0.21; 95% CI: 0.16-0.28). In addition, factors associated with chlorine dioxide consumption for treatment were considering COVID-19 dangerous and deadly (aPR: 0.56; 95% CI: 0.33-0.96), considering chlorine dioxide ineffective (aPR: 0.22; 95% CI: 0.12-0.42), and being uninformed of its efficacy (aPR: 0.15; 95% CI: 0.07-0.32). The prevalence of chlorine dioxide consumption to treat COVID-19 was higher than prevent. It is important to apply information strategies, prioritizing population groups with certain characteristics that are associated with a higher consumption pattern.


Randomized trial of essential oils to reduce perioperative patient anxiety: feasibility study.
This paper is a report of a feasibility study to examine the effectiveness of essential oils in reducing anxiety in thoracic patients awaiting the results of investigative and staging surgery. Patient anxiety is expected during the perioperative period. Anxiety places the patient at greater risk of adverse clinical outcomes. Nurses are limited in therapeutic options that can be used to address anxiety in the limited time available. Complementary therapies have been tested for therapeutic benefit but the evidence is weak. Patients admitted to a thoracic unit for bronchoscopy/mediastinoscopy in 2005 and 2006 were invited to participate in this double-blind controlled trial and randomized to receive study oil (A), neutral oil (B) or no intervention (C). Intervention was controlled by the patient at home after the procedure. The State Trait Anxiety Inventory and the Hospital Anxiety and Depression Scale were used to measure baseline and periodic anxiety status (days 3, 21). Of the 142 patients approached to participate, 71 (50%) agreed to take part. There were high and fluctuating levels of perioperative anxiety in the thoracic patient group, but no evidence that this was reduced by the absorption and inhalation of essential oils. The study did not provide evidence that the essential oils could reduce anxiety in this group of patients. Both recruitment rates and compliance rates were lower than anticipated. Logistic factors in the setting of diagnostic process for an acute condition may have contributed to these results. More stable settings would be better suited to evaluating such interventions.


Experimental syphilis vaccines in rabbits. I. Differential protection with an adjuvant spectrum.
This study shows that 1 per cent. glutaraldehyde fixation of unwashed Treponema pallidum, Nichols pathogen, preserves the integrity of the outer envelope as well as the ruthenium-red (RR) staining extracellular slime layer. Since other researchers wash their treponemal suspensions before preparing their vaccines, it is likely that the vaccine preparations used in this study contain antigens not tested elsewhere. In an attempt to eliminate the requirement of large numbers of injections to achieve any protection, the rabbits in this study were injected with glutaraldehyde-fixed T. pallidum (GFTP) only once, with or without one of a spectrum of adjuvants, and 5 months later were challenged intradermally or intratesticularly with freshly harvested pathogenic treponemes. Data of time of lesion appearance and severity of lesions reveal a differential protective effect of the various vaccine preparations when compared to the response of non-vaccinated controls. Vaccines which included phytohaemagglutinin (PHA) or alumina C gel (ALC) as adjuvants provided some degree of protection, whereas vaccines which contained the adjuvants incomplete Freund's, zymosan, complete Freund's, polyadenylic-polyuridylic acid, or no adjuvant at all produced enhanced infections. The differential protection data indicate that various portions of the immune mechanism are either suppressed or are not stimulated by T. pallidum antigens alone, but can be made to respond with a minimum of vaccine injections.


Dual effect of adenosine triphosphate on the apical small conductance K+ channel of the rat cortical collecting duct.
We used the patch-clamp technique to study the effects of ATP on the small-conductance potassium channel in the apical membrane of rat cortical collecting duct (CCD). This channel has a high open probability (0.96) in the cell-attached mode but activity frequently disappeared progressively within 1-10 min after channel excision (channel "run-down"). Two effects of ATP were observed. Using inside-out patches, low concentrations of ATP (0.05-0.1 mM) restored channel activity in the presence of cAMP-dependent protein kinase A (PKA). In contrast, high concentrations (1 mM) of adenosine triphosphate (ATP) reduced the open probability (Po) of the channel in inside-out patches from 0.96 to 0. 1.2 mM adenosine diphosphate (ADP) also blocked channel activity completely, but 2 mM adenosine 5'-[beta,gamma-imido]triphosphate (AMP-PNP), a nonhydrolyzable ATP analogue, reduced Po only from 0.96 to 0.87. The half-maximal inhibition (Ki) of ATP and ADP was 0.5 and 0.6 mM, respectively, and the Hill coefficient of both ATP and ADP was close to 3. Addition of 0.2 or 0.4 mM ADP shifted the Ki of ATP to 1.0 and 2.0 mM, respectively. ADP did not alter the Hill coefficient. Reduction of the bath pH from 7.4 to 7.2 reduced the Ki of ATP to 0.3 mM. In contrast, a decrease of the free Mg2+ concentration from 1.6 mM to 20 microM increased the Ki of ATP to 1.6 mM without changing the Hill coefficient; ADP was still able to relieve the ATP-induced inhibition of channel activity over this low range of free Mg2+ concentrations. The blocking effect of ATP on channel activity in inside-out patches could be attenuated by adding exogenous PKA catalytic subunit to the bath. The dual effects of ATP on the potassium channel can be explained by assuming that (a) ATP is a substrate for PKA that phosphorylates the potassium channel to maintain normal function. (b) High concentrations of ATP inhibit the channel activity; we propose that the ATP-induced blockade results from inhibition of PKA-induced channel phosphorylation.


Effect of outdoor fungus concentrations on symptom severity of children with asthma and/or rhinitis monosensitized to molds.
Although the relationship between asthma severity and exposure to airborne fungi has been well studied, little is known about the contribution of outdoor molds to the symptoms of children monosensitized to molds. In this study, we aimed to investigate the effect of outdoor mold spore concentrations on daily asthma and/or rhinitis scores in children monosensitized to molds. Nineteen children with asthma and/or rhinitis sensitized only to molds recorded their daily symptoms and PEF values to the diaries, from February 2005 to January 2006. Additionally, mold spores were measured daily using a Burkard 7-day recording volumetric spore trap in city atmosphere and compared with meteorological data. Total number of mold spores in atmosphere was found to be 352,867 spore/m3 during the study period. Cladosporium (53%) was the most common encountered outdoor fungi, followed by Altemaria (29%) and 1-septate Ascospore (3%). Outdoor fungi concentrations were significantly correlated with mean monthly rhinitis score (r = 0.877, p < 0.001) and mean monthly asthma score (r = 0.831, p = 0.001), and mean monthly morning PEF (r = -0.741, p = 0.006) and evening PEF (r = -0.720, p = 0.008), and climatic conditions. The effect of outdoor fungi was highly evident on the symptoms of our patients with asthma and/or rhinitis monosensitized to molds.


Furosemide-sensitive sodium and potassium fluxes in human neonatal erythrocytes.
During the course of incubation, in vitro, in a saline medium, we found an increase of cell volume and Na+ content in human neonatal erythrocytes (NNE), from the umbilical cord. The increased cell volume was dependent on the major anion in the medium in that replacement of Cl- by NO-3 abolished the cell volume increase. In erythrocytes from adults neither the cell volume nor the sodium content were altered under similar incubation conditions. Furosemide-sensitive Na+ and K+ fluxes were at variance from those reported from adult erythrocytes. The differences here presented between both cell types would be another instance of changes observed to occur in erythrocytes during the postnatal period.


Hexameric storage proteins during metamorphosis and egg production in the diamondback moth, Plutella xylostella (Lepidoptera).
As in many Lepidoptera, Plutella xylostella adults do not feed on protein and females must use accumulated reserves to supply vitellogenin synthesis. Storage proteins were quantified in females and males from the late larval stage through day 4 of adult life. The level of storage protein peaked in the early pupal stage, with females having about twice as much as males. In males, the level fell through pupal development and dropped to a trace by one day after eclosion. In females, level of storage proteins fell until eclosion, and then rose dramatically within four hours after the molt to about 2/3 of the original peak level. This post-eclosion increase, which has not been reported previously in insects, suggests that adult females synthesize hexamerins to resequester amino acids. Subsequently, the level of storage proteins fell as vitellogenin appeared and eggs were laid. The ability to synthesize and sequester amino acids as storage proteins during the adult stage has wide-ranging implication for protein management in insects, particularly those that are long-lived and have flexible schedules of reproduction.


Drug-dependent cellular cytotoxicity mediated by polymorphonuclear leukocytes.
Several anticancer drugs were tested for induction of cytolysis mediated by polymorphonuclear leukocytes (PMNs). Among them, actinomycin D and vincristine sulfate induced tumor lysis mediated by PMNs (drug-dependent cellular cytotoxicity). The cell-free supernatant of PMNs incubated with actinomycin D in vitro could lyse various murine tumor cells, although normal spleen cells and sheep red blood cells were not lysed. The cytolytic activity of the supernatant was resistant to treatment with superoxide dismutase, catalase, trypsin inhibitor or arginine. However, the cytolytic activity was labile to heat treatment at 56 degrees (30 min) or trypsin treatment, suggesting a protein nature. These results suggest that PMNs can lyse tumor cells in the presence of certain anticancer drugs and that a factor(s) from PMNs may participate in the killing of tumor cells.


Targeted sequencing library preparation by genomic DNA circularization.
For next generation DNA sequencing, we have developed a rapid and simple approach for preparing DNA libraries of targeted DNA content. Current protocols for preparing DNA for next-generation targeted sequencing are labor-intensive, require large amounts of starting material, and are prone to artifacts that result from necessary PCR amplification of sequencing libraries. Typically, sample preparation for targeted NGS is a two-step process where (1) the desired regions are selectively captured and (2) the ends of the DNA molecules are modified to render them compatible with any given NGS sequencing platform. In this proof-of-concept study, we present an integrated approach that combines these two separate steps into one. Our method involves circularization of a specific genomic DNA molecule that directly incorporates the necessary components for conducting sequencing in a single assay and requires only one PCR amplification step. We also show that specific regions of the genome can be targeted and sequenced without any PCR amplification. We anticipate that these rapid targeted libraries will be useful for validation of variants and may have diagnostic application.


Transmission of human T-lymphotropic virus types I and II by blood transfusion. A retrospective study of recipients of blood components (1983 through 1988). The American Red Cross HTLV-I/II Collaborative Study Group.
We studied results of a "lookback" program involving laboratory testing and interviews of 133 recipients of prior donations from blood donors seropositive for human T-lymphotropic virus types I and II (HTLV-I/II) identified at 28 American Red Cross blood centers. The study was designed to explore the natural course of posttransfusion HTLV-I/II infection among individuals who received blood components from donors subsequently identified as being HTLV-I/II seropositive. Seventeen recipients were seropositive, an apparent transmission rate of 12.8%. Red blood cells and platelets were the implicated components, and red blood cells that were less than 6 days old had a transmission efficiency of 80%. Virus typing enabled documentation of primary and secondary transfusion transmission of HTLV-I and HTLV-II, including the direct transmission of HTLV-II by a donor with a history of intravenous drug use. We conclude that transfusion transmission of HTLV-I/II to approximately 700 recipients per year occurred in the United States before routine donor testing began in 1988.


An indexing and price movement model for managing pension funds.
A model for the investment of pension funds has been created that combines passive and active portfolio management strategies. The model uses a passive index fund to reduce the amount spent in transaction costs. It applies a percentage band that identifies the portion of the portfolio that should be committed to equity investments at various stages of the market movement cycle. Finally, it uses price movement trigger points to dictate when pension funds should be moved into and withdrawn from stock market investments.


How to make rules and regulations for the states in accordance with the Mental Healthcare Act 2017.
Mental Healthcare Act (MHCA) 2017 was gazetted on April 7, 2017. It repeals the Mental Health Act, 1987, and it can be implemented only after the state rules are formed. The central government has already published three sets of rules. This article was written with an objective to review how to make rules and regulations for the state as per MHCA, 2017. All sections of MHCA 2017 and the mental health rules previously made by different states according to the Mental Health Act 1987 were reviewed. Google and PubMed searches were done to review the implementation of their respective mental health acts by different countries and states in the past. Go through Central/State Mental Health Rules, 2018, framed by the central government. Try to adapt it for the state. A meeting on MHCA 2017 should be conducted, including all stakeholders who will give their suggestions about changes to be made. Frame an initial draft and discuss it with the stakeholders and finalize the draft. Discuss the draft in state mental health authority meetings and submit the draft to the government. The Department of Legislation and Parliamentary Affairs can be consulted. The draft should be sent to the central government's Ministry of Health and Family Welfare for approval. According to MHCA 2017, state rules can be formed in relation to the aspects mentioned under Sections 121 and 123. The state government should make notification of the rules and then implement them.


Muscle energy metabolism, nuclear magnetic resonance spectroscopy and their potential in the study of fibromyalgia.
The fields of muscle physiology and biochemistry have already identified some of the key components of ATPase hydrolysis products that are involved in muscle fatigue. The concentration of the relevant chemical species can be readily measured by nuclear magnetic resonance techniques in muscle. Now the question is: is alteration of cellular energy balance and the normal balance between supply and demand disturbed in fibromyalgia? Since these chemical events account for a very large amount of muscle reduced performance as well as reduction in both velocity and force, at the very least one ought to identify how large these changes are in any patient in whom we are trying to assess the degree to which these chemical changes might be associated with muscle fatigue. An objective chemical criteria for muscle performance is possible with modern noninvasive phosphorus magnetic resonance spectroscopy.


Efficacy of an app-based multimodal lifestyle intervention on body weight in persons with obesity: results from a randomized controlled trial.
Despite an increasing number of smartphone applications (apps) addressing weight management, data on the effect of app-based multimodal obesity treatment approaches on weight loss is limited. This study aimed to examine the effect of a digital multimodal weight loss intervention program delivered by an app on body weight in persons with obesity. For this single-centre randomized controlled study, 168 adults with a body mass index (BMI) between 30.0 and 40.0 kg/m2 without severe comorbidities were recruited in the region of Munich and randomized into two intervention groups. The ADHOC group received an app-based multimodal weight loss program from baseline on for 12 weeks plus 12 weeks of follow-up. The EXPECT group received the app-based intervention for 12 weeks after 12 weeks of "waiting" (no intervention). Anthropometric data, data on quality of life (EuroQol, EQ-5D-5L), and app usage data were collected. 64.3% of study participants were women, mean age was 46.8 ± 11.0 years, and mean BMI was 34.2 ± 2.8 kg/m2. The completers analysis resulted in a weight loss of 3.2 ± 3.2 kg (3.2 ± 3.0%) in the ADHOC group and 0.4 ± 2.6 kg (0.3 ± 2.6%) in the EXPECT group after 12 weeks, with a significant difference between the groups (β [95% CI] = -2.9 [-3.8; -1.9], p < 0.001). Completers in the ADHOC group showed weight maintenance after 24 weeks. The time spent on the app was associated with weight reduction (β [95% CI] = -0.10 [-0.18; -0.01], p = 0.03). Application of a multimodal app-based weight loss program results in moderate weight loss in persons with obesity. This study was registered in the German Clinical Trials Register (Registration number: DRKS00025291).


Identification and characterization of ErbB-3-binding protein-1 as a target for immunotherapy.
Based on immune reactivity in response to a whole-cell colon tumor vaccine and using serological identification of Ags by recombinant cDNA expression cloning, we here describe the molecular and functional identification of a novel human tumor Ag. By screening a cDNA expression library derived from the coloncarcinoma cell line HT-29 with pooled colorectal cancer patients' sera, 26 clones reactive with IgG Abs could be identified. Characterization of these cDNA clones by sequence analysis and alignment, and detailed serological analysis revealed cancer-related immunoreactivity for the ErbB-3-binding protein-1 (Ebp1). Immunohistochemical staining of colorectal tumors and neighboring normal colon tissue indicated the observed cancer-related immunogenicity of Ebp1 to be related to overexpression. Via reverse immunology, five potential HLA-A2-restricted T cell epitopes were identified, of which two (Ebp1(45-54) and Ebp1(59-67)) bound HLA-A2 with intermediate and high affinity, respectively. Analysis of their immunogenicity in vitro indicated that only the high-affinity Ebp1(59) epitope gave rise to CD8(+) T cells capable of recognizing both exogenously loaded Ebp1 peptide and endogenously expressed Ebp1 on target cells. In addition, in vivo CD8(+) T cell responsiveness against the Ebp1(59) epitope could be detected in two of nine and three of six cancer patients PBMC and tumor draining lymph nodes, respectively, but not in nine of nine healthy donors tested. These data confirm that Ebp1 is an immunogenic protein, capable of eliciting CD8-mediated responses in vivo and in vitro, providing a rationale for further exploration of Ebp1 as a possible target for anticancer immunotherapy.


Soil water repellency and the five spheres of influence: A review of mechanisms, measurement and ecological implications.
Soil water repellency (SWR) is a widespread phenomenon that influences patterns of soil wetting, runoff, evapotranspiration and availability of water for plants. In natural ecosystems there is emerging evidence that some plants can take advantage of non-uniform wetting patterns, leading to the emergence of co-evolutionary behaviour. In this review, SWR is considered in terms of five spheres of influence. Given the presence of hydrophobic organic material in the biosphere, the strength, severity and persistence of SWR is influenced by properties at the surface of the lithosphere and prevailing conditions in the atmosphere and hydrosphere. These in turn, can be modified by activities in the anthroposphere. This review thus examines the strength, severity and persistence of non-wetting behaviour with reference to these five spheres of influence and also the interactions between the spheres. It is focused on (i) how SWR is characterised to provide insight into how different measurement techniques have specific operational ranges, (ii) how SWR has developed as an indirect consequence of evolution in natural ecosystems and (iii) how feedbacks across the different spheres have emerged. It demonstrates that management and restoration of natural ecosystems with water repellent soils is very different from management of productive crops in monocultural agricultural systems, controlled in the anthroposphere.


Stress-related anhedonia is associated with ventral striatum reactivity to reward and transdiagnostic psychiatric symptomatology.
Early life stress (ELS) is consistently associated with increased risk for subsequent psychopathology. Individual differences in neural response to reward may confer vulnerability to stress-related psychopathology. Using data from the ongoing Duke Neurogenetics Study, the present study examined whether reward-related ventral striatum (VS) reactivity moderates the relationship between retrospectively reported ELS and anhedonic symptomatology. We further assessed whether individual differences in reward-related VS reactivity were associated with other depressive symptoms and problematic alcohol use via stress-related anhedonic symptoms and substance use-associated coping. Blood oxygen level-dependent functional magnetic resonance imaging (fMRI) was collected while participants (n = 906) completed a card-guessing task, which robustly elicits VS reactivity. ELS, anhedonic symptoms, other depressive symptoms, coping behavior, and alcohol use behavior were assessed with self-report questionnaires. Linear regressions were run to examine whether VS reactivity moderated the relationship between ELS and anhedonic symptoms. Structural equation models examined whether this moderation was indirectly associated with other depression symptoms and problematic alcohol use through its association with anhedonia. Analyses of data from 820 participants passing quality control procedures revealed that the VS × ELS interaction was associated with anhedonic symptoms (p = 0.011). Moreover, structural equation models indirectly linked this interaction to non-anhedonic depression symptoms and problematic alcohol use through anhedonic symptoms and substance-related coping. These findings suggest that reduced VS reactivity to reward is associated with increased risk for anhedonia in individuals exposed to ELS. Such stress-related anhedonia is further associated with other depressive symptoms and problematic alcohol use through substance-related coping.


Recurrent episodes of esophageal candidiasis without dysphagia post-Guillain-Barré syndrome: an unusual presentation of achalasia.
Here, we present a case of a 50-year-old male with a history of a Guillain-Barré-syndrome, who was referred to our clinic with recurrent esophageal candidiasis and long-standing intermittent retrosternal cramps for further evaluation. Other symptoms such as dysphagia, regurgitations and weight loss were denied, and prior repeated endoscopy was otherwise unremarkable. Using high resolution impedance manometry, we could demonstrate a panesophageal pressure increase on water swallows and complete aperistalsis of the tubular esophagus, indicating achalasia type II. However, due to the patient's extraordinary body height and resulting length of the esophagus, endoluminal functional lumen imaging probe analysis supplementary to high resolution impedance manometry needed to be used to assess distensibility of the esophagogastral junction and to secure the diagnosis of achalasia before appropriately treating the patient with pneumatic dilation.


Differentiation between basal cell carcinoma and trichoepithelioma by immunohistochemical staining of the androgen receptor: an overview.
Clinical and histopathological differentiation between basal cell carcinoma (BCC) and trichoepithelioma (TE) is a frequent problem. Attempts have been made to identify immunohistochemical markers helpful in differentiating them. A correct diagnosis is important because the tumours are treated differently. Recent studies showed the absence of androgen receptor (AR) expression in benign hair follicle tumours like TE. This study examines whether AR immunostaining is a useful diagnostic test to differentiate between BCC and TE. We randomly selected 75 cases with histological diagnoses of either BCC (subtypes: superficial, nodular or infiltrative) or TE (subtypes: classic or desmoplastic) from the database of the pathology department of Maastricht University Medical Centre. The available haematoxylin & eosin (H&E) slides were reviewed by three independent investigators using predetermined characteristics. Fifty-six slides (38 BCC and 18 TE) with unequivocal histological characteristics of either tumour were used for immunohistochemistry with AR antibodies. Any nuclear expression within the tumour was considered positive. AR expression was present in 5/8 classic TE, 0/10 desmoplastic TE, 22/23 superficial or nodular BCC and in 10/15 infiltrative BCC. Immunohistochemical stain for AR is useful to differentiate between TE and BCC; particularly in desmoplastic TE versus infiltrative BCC (specificity and positive predictive value of 100%).


A guardian residue hinders insertion of a Fapy•dGTP analog by modulating the open-closed DNA polymerase transition.
4,6-Diamino-5-formamidopyrimidine (Fapy•dG) is an abundant form of oxidative DNA damage that is mutagenic and contributes to the pathogenesis of human disease. When Fapy•dG is in its nucleotide triphosphate form, Fapy•dGTP, it is inefficiently cleansed from the nucleotide pool by the responsible enzyme in Escherichia coli MutT and its mammalian homolog MTH1. Therefore, under oxidative stress conditions, Fapy•dGTP could become a pro-mutagenic substrate for insertion into the genome by DNA polymerases. Here, we evaluated insertion kinetics and high-resolution ternary complex crystal structures of a configurationally stable Fapy•dGTP analog, β-C-Fapy•dGTP, with DNA polymerase β. The crystallographic snapshots and kinetic data indicate that binding of β-C-Fapy•dGTP impedes enzyme closure, thus hindering insertion. The structures reveal that an active site residue, Asp276, positions β-C-Fapy•dGTP so that it distorts the geometry of critical catalytic atoms. Removal of this guardian side chain permits enzyme closure and increases the efficiency of β-C-Fapy•dG insertion opposite dC. These results highlight the stringent requirements necessary to achieve a closed DNA polymerase active site poised for efficient nucleotide incorporation and illustrate how DNA polymerase β has evolved to hinder Fapy•dGTP insertion.


Guidelines for judicious use of electrocardiography. A summary of recommendations from the ACC/AHA Task Force Report.
Electrocardiography continues to be a cornerstone in the management of an array of cardiac and noncardiac disorders. However, the ease with which an electrocardiogram can be obtained, as well as its low cost, has led to widespread use--and possible overuse--of this technology. A joint committee of the American College of Cardiology and the American Heart Association recently published guidelines for appropriate use of electrocardiography in patients with known heart disease; in persons suspected of having, or who are at risk for, heart disease; and in persons with no apparent or suspected cardiac disease. These guidelines can help clinicians determine when, and for which patients in the intensive care unit, an electrocardiogram is warranted.


Characterization of an N-Allylglyoxylamide-Based Bioorthogonal Nitrone Trap.
Aldehydes are attractive bioorthogonal coupling partners. The ease of manipulation of aldehydes and their orthogonality to other classes of bioorthogonal reactions have inspired the exploration of chemistries, which generate irreversible conjugates. Similarly, nitrones have been shown to be potent 1,3-dipoles in bioorthogonal reactions when paired with strained alkynes. Here, we combine the reactivity of nitrones with the simplicity of aldehydes using an N-allylglyoxylamide, in a cascade reaction with an N-alkylhydroxylamine to produce a bicyclic isoxazolidine. The reaction is found to be catalyzed by 5-methoxyanthranilic acid and proceeds at pH 7 with favorable kinetics. Using the HaloTag7 protein bearing an N-alkylhydroxylamine, we show the reaction to be bioorthogonal in a complex cell lysate and to proceed well at the surface of a HEK293 cell. Furthermore, the reaction is compatible with a typical strain-promoted alkyne-azide click reaction. The characteristics of this reaction suggest it will be a useful addition to the pallet of bioorthogonal reactions that have revolutionized chemical biology.


Fever and health-seeking behaviour among migrants living along the Thai-Myanmar border: a mixed-methods study.
Fever is a common reason to seek healthcare in Southeast Asia, and the decline of malaria has complexified how is perceived, and what actions are taken towards it. We investigated the concept of fever and the determinants influencing health-seeking behaviours among migrants on the Thai-Myanmar border, where rapid economic development collides with precarious political and socio-economic conditions. We implemented a mixed-methods study between August to December 2019. Phase I used a qualitative approach, with in-depth interviews and focus group discussions. Phase II used a quantitative approach with a close-ended questionnaire based on Phase I findings. A conditional inference tree (CIT) model first identified geographic and socio-demographic determinants, which were then tested using a logistic regression model. Fever corresponded to a high diversity of conceptions, symptoms and believed causes. Self-medication was the commonest behaviour at fever onset. If fever persisted, migrants primarily sought care in humanitarian cost-free clinics (45.5%, 92/202), followed by private clinics (43.1%, 87/202), health posts (36.1%, 73/202), public hospitals (33.7%, 68/202) and primary care units (30, 14.9%). The qualitative analysis identified distance and legal status as key barriers for accessing health care. The quantitative analysis further investigated determinants influencing health-seeking behaviour: living near a town where a cost-free clinic operated was inversely associated with seeking care at health posts (adjusted odds ratio [aOR], 0.40, 95% confidence interval [95% CI] [0.19-0.86]), and public hospital attendance (aOR 0.31, 95% CI [0.14-0.67]). Living further away from the nearest town was associated with health posts attendance (aOR 1.05, 95% CI [1.00-1.10] per 1 km). Having legal status was inversely associated with cost-free clinics attendance (aOR 0.27, 95% CI [0.10-0.71]), and positively associated with private clinic and public hospital attendance (aOR 2.56, 95% CI [1.00-6.54] and 5.15, 95% CI [1.80-14.71], respectively). Fever conception and believed causes are context-specific and should be investigated prior to any intervention. Distance to care and legal status were key determinants influencing health-seeking behaviour. Current economic upheavals are accelerating the unregulated flow of undocumented migrants from Myanmar to Thailand, warranting further inclusiveness and investments in the public health system.


Influence of food acidulants and antioxidant spices on the bioaccessibility of beta-carotene from selected vegetables.
Four common food acidulants--amchur, lime, tamarind, and kokum--and two antioxidant spices--turmeric and onion--were examined for their influence on the bioaccessibility of beta-carotene from two fleshy and two leafy vegetables. Amchur and lime generally enhanced the bioaccessibility of beta-carotene from these test vegetables in many instances. Such an improved bioaccessibility was evident in both raw and heat-processed vegetables. The effect of lime juice was generally more pronounced than that of amchur. Turmeric significantly enhanced the bioaccessibility of beta-carotene from all of the vegetables tested, especially when heat-processed. Onion enhanced the bioaccessibility of beta-carotene from pressure-cooked carrot and amaranth leaf and from open-pan-boiled pumpkin and fenugreek leaf. Lime juice and the antioxidant spices turmeric and onion minimized the loss of beta-carotene during heat processing of the vegetables. In the case of antioxidant spices, improved bioaccessibility of beta-carotene from heat-processed vegetables is attributable to their role in minimizing the loss of this provitamin. Lime juice, which enhanced the bioaccessibility of this provitamin from both raw and heat-processed vegetables, probably exerted this effect by some other mechanism in addition to minimizing the loss of beta-carotene. Thus, the presence of food acidulants (lime juice/amchur) and antioxidant spices (turmeric/onion) proved to be advantageous in the context of deriving maximum beta-carotene from the vegetable sources.


Cold weather and GP consultations for respiratory conditions by elderly people in 16 locations in the UK.
Cold weather is associated with increases in mortality and demands on hospital services in the UK, particularly by the elderly. Less is known about the relationship with patterns of consultation in primary care. We wished to determine the magnitude and consistency of associations between cold temperature and consultations for respiratory conditions in primary care settings at different sites in the UK. Time series analysis of any short-term effects of temperature on daily general practitioner (GP) consultations made by elderly people (65+ years) for lower and upper respiratory tract infections (LRTI, URTI) over a 10-year period, 1992--2001. Practices were situated in 16 urban locations across the UK where a Met Office monitoring station was in operation. An association between low temperatures and an increase in LRTI consultations was observed in all 16 locations studied. The biggest increase was estimated for the Norwich practices for which a 19.0% increase in LRTI consultations (95% CI 13.6, 24.7) was associated with every 1 degrees C drop in mean temperature below 5 degrees C observed 0-20 days before the day of consultation. Slightly weaker relationships were observed in the case of URTI consultations. A north/south gradient, with larger temperature effects in the north, was in evidence for both LRTI and URTI consultations. An effect that was consistent and generally strongest in populations in the north was observed between cold temperature and respiratory consultations. Better understanding of the mechanisms by which cold weather is associated with increases in consultations for respiratory infections could lead to improved strategies for prevention and reduced burdens for health services.


Catalase: its effect on microbial enumeration.
The addition of catalase to the surface of selective medium plates permitted increased enumeration of physically or chemically injured (stressed) microorganisms. Catalase acted by preventing the accumulation of hydrogen peroxide in, or around, injured cells. Heat-injured Staphylococcus aureus cells had decreased catalase activity, and heat-inactivated catalase had no effect on enumeration.


Indicators for routine monitoring of effective mental healthcare coverage in low- and middle-income settings: a Delphi study.
High-quality information to measure the need for, and the uptake, cost, quality and impact of care is essential in the pursuit of scaling up mental health care in low- and middle-income countries (LMIC). The aim of this study was to identify indicators for the measurement of effective coverage of mental health treatment. We conducted a two-round Delphi study (n = 93 experts from primarily LMIC countries Ethiopia, India, Nepal, Nigeria, South Africa and Uganda), in order to generate and prioritize a set of indicators. First, 52 unique indicators were generated (based on a total of 876 responses from participants). Second, the selected indicators were then scored for significance, relevance and feasibility. Mean priority scores were calculated per indicator (score range, 1-5). All 52 indicators had a weighted mean score that ranged from 3.20 for the lowest ranked to 4.27 for the highest ranked. The 15 highest ranked indicators cover the different domains of measuring effective mental health treatment coverage. This set of indicators is highly stable between the different groups of experts, as well as between the different participating countries. This study provides data on how mental health service and financial coverage can be assessed in LMIC. This is an important element in the move to scale-up mental health care.


Vascular and cognitive effects of cocoa-rich chocolate in postmenopausal women: a study protocol for a randomised clinical trial.
The intake of polyphenols has certain health benefits. This study will aim to assess the effect of adding a daily amount of chocolate high in cocoa content and polyphenols to the normal diet on blood pressure, vascular function, cognitive performance, quality of life and body composition in postmenopausal women. Here we plan a randomised clinical trial with two parallel groups involving a total of 140 women between 50 and 64 years in the postmenopausal period, defined by amenorrhoea of at least 12 consecutive months. The main variable will be the change in blood pressure. Secondary variables will be changes in vascular function, quality of life, cognitive performance and body composition. The intervention group will be given chocolate containing 99% cocoa, with instructions to add 10 g daily to their normal diet for 6 months. The daily nutritional contribution of this amount of chocolate is 59 kcal and 65.4 mg of polyphenols. There will be no intervention in the control group. All variables will be measured at the baseline visit and 3 and 6 months after randomisation, except cognitive performance and quality of life, which will only be assessed at baseline and at 6 months. Recruitment is scheduled to begin on 1 June 2018, and the study will continue until 31 May 2019. This study was approved by the Clinical Research Ethics Committee of the Health Area of Salamanca, Spain ('CREC of Health Area of Salamanca'), in February 2018. A SPIRIT checklist is available for this protocol. The clinical trial has been registered at ClinicalTrials.gov provided by the US National Library of Medicine, number NCT03492983. The results will be disseminated through open access peer-reviewed journals, conference presentations, broadcast media and a presentation to stakeholders.


[DNA repair and its relation to cell division in E. coli].
In E. coli, lesions introduced by agents such as UV radiation, chemical agents, thymine starvation, lead to the induction of a series of bacterial fonctions called the "SOS response" (DNA reparation, mutagenesis, filamentation, prophages induction etc...). Genetics and biochemical study set up the evidences of a regulated mechanism. The central effector of this mechanism is the Rec A protéin. When a cell's DNA is damaged or its DNA replication is inhibited, an inducing signal is generated. The inducing signal reversebly activates a specific protease activity of Rec A which allows it to cleave the Lex A repressor. Thus inducing operons repressed by Lex A. These operons are implicated in DNA reparations and also in cellular division. A coordination between reparation and cellular division is thus established.


Antiplatelet agents versus control or anticoagulation for heart failure in sinus rhythm: a Cochrane systematic review.
Heart failure predisposes to stroke and thromboembolism, which in turn contribute to the high mortality and morbidity in heart failure. To determine the effect of antiplatelet agents, compared to placebo or anticoagulant therapy, on death and/or major thromboembolic events in adults with heart failure who are in sinus rhythm. Systematic review of randomized parallel group placebo or controlled trials comparing oral antiplatelet therapy with control or anticoagulation therapy in adults with chronic heart failure in sinus rhythm. Reference lists of papers resulting from this search, electronic database searching (MEDLINE, EMBASE, DARE), and abstracts from national and international cardiovascular meetings were studied to identify unpublished studies. Relevant authors of these studies were contacted to obtain further data. These included duration of treatment of at least 1 month, and adults with heart failure due to any underlying cause. To assess any adverse effects, cohort study and non-randomized controlled studies were assessed. Inclusion decisions were duplicated, disagreement resolved by discussion or a third party. No meta-analyses were performed, as no data were available from randomized comparisons. One randomized controlled trial of warfarin vs. aspirin vs. no antithrombotic therapy was found, but no definitive data have yet been published. Three retrospective, non-randomized cohort studies from large trials examining the role of ACE inhibitors have examined the role of aspirin therapy with and without anticoagulant therapy in patients with heart failure and/or left ventricular systolic dysfunction were identified, but the results from these trials were conflicting. A possible interaction with ACE inhibitors may reduce the efficacy of aspirin, although this evidence is from retrospective analyses of trial cohorts. At present there is no evidence from long term RCTs to recommend use of aspirin to prevent thromboembolism in patients with heart failure in sinus rhythm. There is also no evidence to indicate superior effects from oral anticoagulation, when compared to aspirin, in patients with heart failure in sinus rhythm.


Transcriptional activation of lck by retrovirus promoter insertion between two lymphoid-specific promoters.
p56lck, a member of the src family of cytoplasmic tyrosine protein kinases, is expressed primarily in lymphoid cells. Previous RNase protection data demonstrated the existence of at least two lck mRNAs (type I and type II) with different 5' untranslated regions in most T cells. These have been found here to arise from two separate promoters. S1 nuclease analysis and primer extension were used to locate the site of initiation of type I lck mRNA. The nucleotide sequence of the region upstream of this start site contains no classical promoter motifs. A cDNA clone of type II lck mRNA was isolated. The promoter of this mRNA must be more than 10 kilobases upstream of the type I promoter region. In two murine thymoma cell lines, LSTRA and Thy19, lck is expressed at elevated levels as a result of Moloney murine leukemia virus retrovirus promoter insertion. p56lck is encoded in these cells by a hybrid virus-lck mRNA containing the 5' untranslated region of Moloney virus mRNA. The structures and the sites of integration of the proviruses upstream of lck in these cells were examined by molecular cloning and Southern analysis. A truncated and rearranged provirus, flanked by 554 nucleotides (nt) of duplicated cellular sequences, was found 962 nt upstream of the start site for type I lck mRNA in LSTRA cells. What appears to be a Moloney mink cytopathic focus-forming provirus was found between 584 to 794 nt upstream of the start site for type I lck mRNA in Thy19 cells. Thus in both tumor cell lines, viral DNA is present between the promoters for type I and type II lck mRNAs. Comparison of the sequences of the 5' ends of the lck and c-src genes suggests that divergence of these two genes involved exon shuffling and that a homolog of the neuronal c-src(+) exon is not present in lck.


Dynamics of the IFT machinery at the ciliary tip.
Intraflagellar transport (IFT) is essential for the elongation and maintenance of eukaryotic cilia and flagella. Due to the traffic jam of multiple trains at the ciliary tip, how IFT trains are remodeled in these turnaround zones cannot be determined by conventional imaging. Using PhotoGate, we visualized the full range of movement of single IFT trains and motors in Chlamydomonas flagella. Anterograde trains split apart and IFT complexes mix with each other at the tip to assemble retrograde trains. Dynein-1b is carried to the tip by kinesin-II as inactive cargo on anterograde trains. Unlike dynein-1b, kinesin-II detaches from IFT trains at the tip and diffuses in flagella. As the flagellum grows longer, diffusion delays return of kinesin-II to the basal body, depleting kinesin-II available for anterograde transport. Our results suggest that dissociation of kinesin-II from IFT trains serves as a negative feedback mechanism that facilitates flagellar length control in Chlamydomonas.


Identification, cloning, and expression of bolA, an ftsZ-dependent morphogene of Escherichia coli.
A newly found morphogene of Escherichia coli, bolA, mapping at min 10 of the genetic map, was cloned in a 7.2-kilobase BamHI fragment and identified by its ability to produce osmotically stable spherical cells when overexpressed. This gene codes for a polypeptide of 13 kilodaltons. Overexpression of bolA+ was achieved in low-copy-number vectors with operon fusions to the tet and lac promoters, indicating a clockwise direction of transcription. While no modification of any of the penicillin-binding proteins was observed, morphological effects due to overexpression of bolA+ were shown to be dependent on the presence of an active ftsZ gene product. Our results suggest the existence of a mechanism mediated by FtsZ for modifying the conformation of nascent murein in the early steps of septum formation.


The hyperoxic switch: assessing respiratory water loss rates in tracheate arthropods with continuous gas exchange.
Partitioning the relative contributions of cuticular and respiratory water loss in a tracheate arthropod is relatively easy if it undergoes discontinuous gas exchange cycles or DGCs, leaving its rate of cuticular water loss in primary evidence while its spiracles are closed. Many arthropods are not so obliging and emit CO(2) continuously, making cuticular and respiratory water losses difficult or impossible to partition. We report here that by switching ambient air from 21 to 100% O(2), marked spiracular constriction takes place, causing a transient but substantial - up to 90% - reduction in CO(2) output. A reduction in water loss rate occurs at the same time. Using this approach, we investigated respiratory water loss in Drosophila melanogaster and in two ant species, Forelius mccooki and Pogonomyrmex californicus. Our results - respiratory water loss estimates of 23%, 7.6% and 5.6% of total water loss rates, respectively - are reasonable in light of literature estimates, and suggest that the 'hyperoxic switch' may allow straightforward estimation of respiratory water loss rates in arthropods lacking discontinuous gas exchange. In P. californicus, which we were able to measure with and without a DGC, presence or absence of a DGC did not affect respiratory vs total water loss rates.


Thrombocytopenia associated with long-term levodopa therapy.
A 63-year-old man had severe thrombocytopenia after long-term levodopa therapy. Serologic studies and clinical features indicate that the thrombocytopenia was due to an autoimmune process, presumably similar to that induced by the chemically similar drug methyldopa. Direct allergy to levodopa was ruled out by controlled challenge of the patient receiving levodopa. Combined levodopa-prednisone therapy was then instituted, with good clinical response and no recurrence of thrombocytopenia.


Creating gradients of amyloid fibrils from the liquid-liquid interface.
We report a method to deposit amyloid fibrils on a substrate creating gradients in orientation and coverage on demand. For this purpose, we adapt a colloidal self-assembly method at liquid-liquid interfaces to deposit amyloid fibrils on a substrate from the water-hexane interface, while simultaneously compressing it. The amyloid fibril layers orient perpendicularly to the compression, ranging from isotropic to nematic distributions. We furthermore observe reproducible transitions from a monolayer to a bilayer and from a bilayer to multilayers with increasing surface pressures. The creation of each new layer is accompanied by a systematic drop in the structural order of the system, which is however regained upon further compression. This method shows great potential for overcoming the thin-film engineering challenges associated with the manipulation of sticky amyloid fibrils, and allows their ex situ visualisation under compression at the fluid-fluid interface, a situation relevant to understand the propagation of amyloid-related diseases, their functional role in biological systems, and their potential for technological applications.


Nuchal translucency of 3.0-3.4 mm an indication for NIPT or microarray? Cohort analysis and literature review.
Currently fetal nuchal translucency (NT) ≥3.5 mm is an indication for invasive testing often followed by chromosomal microarray. The aim of this study was to assess the risks for chromosomal aberrations in fetuses with an NT 3.0-3.4 mm, to determine whether invasive prenatal testing would be relevant in these cases and to assess the residual risks in fetuses with normal non-invasive prenatal test (NIPT) results. A retrospective study and meta-analysis of literature cases with NT between 3.0 and 3.4 mm and 2 cohorts of pregnant women referred for invasive testing and chromosomal microarray was performed: Rotterdam region (with a risk >1:200 and NT between 3.0 and 3.4 mm) tested in the period July 2012 to June 2019 and Central Denmark region (with a risk >1:300 and NT between 3.0 and 3.4 mm) tested between September 2015 and December 2018. A total of 522 fetuses were referred for invasive testing and chromosomal microarray. Meta-analysis indicated that in 1:7.4 (13.5% [95% CI 8.2%-21.5%]) fetuses a chromosomal aberration was diagnosed. Of these aberrant cases, 47/68 (69%) involved trisomy 21, 18, and 13 and would potentially be detected by all NIPT approaches. The residual risk for missing a (sub)microscopic chromosome aberration depends on the NIPT approach and is highest if NIPT was performed only for common trisomies-1:21 (4.8% [95% CI 3.2%-7.3%]). However, it may be substantially lowered if a genome-wide 10-Mb resolution NIPT test was offered (~1:464). Based on these data, we suggest that the NT cut-off for invasive testing could be 3.0 mm (instead of 3.5 mm) because of the high risk of 1:7.4 for a chromosomal aberration. If women were offered NIPT first, there would be a significant diagnostic delay because all abnormal NIPT results need to be confirmed by diagnostic testing. If the woman had already received a normal NIPT result, the residual risk of 1:21 to 1:464 for chromosome aberrations other than common trisomies, dependent on the NIPT approach, should be raised. If a pregnant woman declines invasive testing, but still wants a test with a broader coverage of clinically significant conditions then the genome-wide >10-Mb resolution NIPT test, which detects most aberrations, could be proposed.


One-stage biopsy, debridement, reconstruction, and stabilization of pyogenic vertebral osteomyelitis.
Study Design Retrospective cohort study. Objective To evaluate whether the proposed one-stage biopsy, culture, debridement, and reconstruction with stabilization strategy is a viable option for pyogenic vertebral osteomyelitis (PVO). PVO is increasing in frequency globally, particularly in immunologically compromised individuals. Typically, biopsy and culture sensitivity followed by staged surgery and long-term antibiotic therapy is the mainstay of therapy. Methods This is a study of a group of 32 consecutive cases of PVO (spondylodiskitis) treated in our institution from 2010 to 2012. All cases had one-stage biopsy, culture sensitivity, debridement, reconstruction with iliac bone graft, and stabilization with titanium implants. The mean age in this series was 51 years, and the male-to-female ratio was 2.2:1. Approximately 50% of the patients had impaired immunity status. The commonest organism isolated was Pseudomonas aeruginosa. Culture-specific antibiotics were given for a minimum of 6 weeks to all patients. The follow-up period ranged from 6 months to a maximum of 2 years. All patients were assessed for wound healing, recurrence of infection, deformity progression, pain, and healing by radiologic and biochemical parameters. No generic or disease-specific outcome tools were used for this study. Results All patients had good wound healing, although there was one case of superficial infection that was resolved with debridement. There were two implant failures with pseudarthrosis and one localized kyphosis in this series. Conclusions The one-stage technique of biopsy, debridement, bone grafting, and stabilization can be recommended for most cases of PVO.


First-Aid Treatment for Friction Blisters: "Walking Into the Right Direction?"
Blisters are common foot injuries during and after prolonged walking. However, the best treatment remains unclear. The aim of the study was to compare the effect of 2 different friction blister treatment regimens, wide area fixation dressing versus adhesive tape. A prospective observational cohort study. The 2015 Nijmegen Four Days Marches in the Netherlands. A total of 2907 participants (45 ± 16 years, 52% men) were included and received 4131 blister treatments. Blisters were treated with either a wide area fixation dressing or adhesive tape. Time of treatment application was our primary outcome. In addition, effectiveness and satisfaction were evaluated in a subgroup (n = 254). During a 1-month follow-up period, blister healing, infection and the need for additional medical treatment were assessed in the subgroup. Time of treatment application was lower (41.5 minutes; SD = 21.6 minutes) in the wide area fixation dressing group compared with the adhesive tape group (43.4 minutes; SD = 25.5 minutes; P = 0.02). Furthermore, the wide area fixation dressing group demonstrated a significantly higher drop-out rate (11.7% vs 4.0%, P = 0.048), delayed blister healing (51.9% vs 35.3%, P = 0.02), and a trend toward lower satisfaction (P = 0.054) when compared with the adhesive tape group. Wide area fixation dressing decreased time of treatment application by 2 minutes (4.5%) when compared with adhesive tape. However, because of lower effectiveness and a trend toward lower satisfaction, we do not recommend the use of wide area fixation dressing over adhesive tape in routine first-aid treatment for friction blisters.


Characterization and physical mapping of Molluscum contagiosum virus DNA and location of a sequence capable of encoding a conserved domain of epidermal growth factor.
DNA from Molluscum contagiosum virus (MCV) isolates was analysed by restriction endonuclease cleavage, revealing two virus subtypes. Physical maps of cleavage sites for BamHI, ClaI and HindIII were constructed, and found to differ extensively between the two subtypes. MCV DNA was similar to Orthopoxvirus DNA with respect to size, terminal cross-linking and the presence of inverted terminal repetitions, but did not hybridize with vaccinia virus DNA. The genomes of the two MCV subtypes cross-hybridized and were colinear except for two small regions. There was sequence homology between DNA from corresponding map regions of the MCV subtypes but, in contrast to Orthopoxvirus DNA, no conservation of restriction sites. A synthetic oligonucleotide probe representing a conserved domain of epidermal growth factor, alpha-transforming growth factor and the vaccinia growth factor identified equivalent regions of both MCV genomes as having the potential to encode this domain. This locus is similar to the position of the vaccinia growth factor gene in vaccinia virus DNA. Thus MCV may induce epidermal cell proliferation and tumourigenesis by expression of an epidermal growth factor-like polypeptide.


Next-generation sequencing sheds light on intricate regulation of insect gut microbiota.
Next-generation sequencing (NGS) technologies are getting cheaper and easier and hence becoming readily accessible for many researchers in biological disciplines including ecology. In this issue of Molecular Ecology, Sudakaran et al. (2012) show how the NGS revolution contributes to our better and more comprehensive understanding of ecological interactions between gut symbiotic microbiota and the host organism. Using the European red firebug Pyrrhocoris apterus as a model system, they demonstrated that the gut microbiota consists of a small number of major bacterial phylotypes plus other minor bacterial associates. The major bacteria are localized in a specific anoxic section of the midgut and quantitatively account for most of the gut microbiota irrespective of host's geographic populations. The specific gut microbiota is established through early nymphal development of the host insect. Interestingly, the host feeding on different food, namely linden seeds, sunflower seeds or wasp larvae, scarcely affected the symbiont composition, suggesting homoeostatic control over the major symbiotic microbiota in the anoxic section of the midgut. Some of the minor components of the gut microbiota, which conventional PCR/cloning/sequencing approaches would have failed to detect, were convincingly shown to be food-derived. These findings rest on the robust basis of high-throughput sequencing data, and some of them could not be practically obtained by conventional molecular techniques, highlighting the significant impact of NGS approaches on ecological aspects of host-symbiont interactions in a nonmodel organism.


Head in the clouds: Re-imagining the experimental laboratory record for the web-based networked world.
The means we use to record the process of carrying out research remains tied to the concept of a paginated paper notebook despite the advances over the past decade in web based communication and publication tools. The development of these tools offers an opportunity to re-imagine what the laboratory record would look like if it were re-built in a web-native form. In this paper I describe a distributed approach to the laboratory record based which uses the most appropriate tool available to house and publish each specific object created during the research process, whether they be a physical sample, a digital data object, or the record of how one was created from another. I propose that the web-native laboratory record would act as a feed of relationships between these items. This approach can be seen as complementary to, rather than competitive with, integrative approaches that aim to aggregate relevant objects together to describe knowledge. The potential for the recent announcement of the Google Wave protocol to have a significant impact on realizing this vision is discussed along with the issues of security and provenance that are raised by such an approach.


Sustained antinociceptive effect of cannabinoid receptor agonist WIN 55,212-2 over time in rat model of neuropathic spinal cord injury pain.
A significant complaint associated with spinal cord injury (SCI) is chronic pain, which includes symptoms such as cutaneous hypersensitivity and spontaneous unevoked pain and is difficult to treat with currently available drugs. One complication with current analgesics is tolerance, a decrease in efficacy with repeated treatment over time. One promising class of pharmacological treatment is cannabinoid (CB) receptor agonists. The current study assessed the efficacy of the CB receptor agonist WIN 55,212-2 (WIN) in a rat model of neuropathic SCI pain. Brief spinal compression leads to significant hindpaw hypersensitivity to tactile stimulation. WIN dose-dependently increased withdrawal thresholds and continued to demonstrate efficacy over a twice-daily 7-day treatment regimen. By contrast, the efficacy of morphine in SCI rats decreased over the same treatment period. Similarly, the antinociceptive efficacy of WIN to acute noxious heat in uninjured rats diminished over time. These data suggest that the sustained efficacy of a CB receptor agonist for pain could depend on the pain state. Such agonists may hold promise for long-term use in alleviating chronic SCI pain.


Angiotensin II induces angiogenesis in the hypoxic adult mouse heart in vitro through an AT2-B2 receptor pathway.
Angiotensin II is a vasoactive peptide that may affect vascularization of the ischemic heart via angiogenesis. In this study we aimed at studying the mechanisms underlying the angiogenic effects of angiotensin II under hypoxia in the mouse heart in vitro. Endothelial sprout formation from pieces of mouse hearts was assessed under normoxia (21% O(2)) and hypoxia (1% O(2)) during a 7-day period of in vitro culture. Only under hypoxia did angiotensin II dose-dependently induce endothelial sprout formation, peaking at 10(-7) mol/L of angiotensin II. Angiotensin II type 1 (AT(1)) receptor blockade by losartan did not affect angiotensin II-induced sprouting in wild-type mice. Conversely, the angiotensin II type 2 (AT(2)) receptor antagonist PD 123319 blocked this response. In hearts from AT(1)(-/-) mice, angiotensin II-elicited sprouting was preserved but blocked again by AT(2) receptor antagonism. In contrast, no angiotensin II-induced sprouting was found in preparations from hearts of AT(2)(-/-) mice. Angiotensin II-mediated angiogenesis was also abolished by a specific inhibitor of the B2 kinin receptor in both wild-type and AT(1)(-/-) mice. Furthermore, angiotensin II failed to induce endothelial sprout formation in hearts from B2(-/-) mice. Finally, NO inhibition completely blunted sprouting in hearts from wild-type mice, whereas NO donors could restore sprouting in AT(2)(-/-) and B2(-/-) hearts. This in vitro study suggests the obligatory role of hypoxia in the angiogenic effect of angiotensin II in the mouse heart via the AT(2) receptor through a mechanism that involves bradykinin, its B2 receptor, and NO as a downstream effector.


A Novel LINS1 Truncating Mutation in Autosomal Recessive Nonsyndromic Intellectual Disability.
The large majority of cases with intellectual disability are syndromic (i.e. occur with other well-defined clinical phenotypes) and have been studied extensively. Autosomal recessive nonsyndromic intellectual disability is a group of genetically heterogeneous disorders for which a number of potentially causative genes have been identified although the molecular basis of most of them remains unexplored. Here, we report the clinical characteristics and genetic findings of a family with two male siblings affected with autosomal recessive nonsyndromic intellectual disability. Whole exome sequencing was carried out on two affected male siblings and unaffected parents. A potentially pathogenic variant identified in this study was confirmed by Sanger sequencing to be inherited in an autosomal recessive fashion. We identified a novel nonsense mutation (p.Gln368Ter) in the LINS1 gene which leads to loss of 389 amino acids in the C-terminus of the encoded protein. The truncation mutation causes a complete loss of LINES_C domain along with loss of three known phosphorylation sites and a known ubiquitylation site in addition to other evolutionarily conserved regions of LINS1. LINS1 has been reported to cause MRT27 (mental retardation, autosomal recessive 27), a rare autosomal recessive nonsyndromic intellectual disability, with limited characterization of the phenotype. Identification of a potentially pathogenic truncating mutation in LINS1 in two profoundly intellectually impaired patients also confirms its role in cognition.


Microbiology of bone and joint infections in injecting drug abusers.
The literature contains variable reports on the causative organisms of osteomyelitis and septic arthritis in patients with injecting drug abuse and on the rate of oxacillin-resistant S aureus. It is important to have a clear notion of the organisms to initiate empiric antimicrobial therapy. We therefore determined the spectrum of organisms in bone and joint infections in patients who were injecting drug users. We retrospectively reviewed the medical records of 215 patients (154 male, 61 female) with a history of injecting drug abuse and concurrent bone and/or joint infection from 1998 to 2005. The mean age was 43 years (range, 23-83 years). Osteomyelitis was present in 127 of the 215 patients (59%), septic arthritis in 53 (25%), and both in 35 (16%). The lower extremity was most commonly involved (141 cases, 66%), with osteomyelitis of the tibia present in 70 patients (33%) and septic knee arthritis in 30 patients (14%). Cultures yielded predominately Gram-positive bacteria: Staphylococcus aureus in 52% and coagulase-negative Staphylococcus in 20%. The proportion of oxacillin-resistant S aureus among S aureus infections increased from 21% in 1998 to 73% in 2005. Gram-negative organisms were present in 19% of infections and anaerobes in 13%. Patients with osteomyelitis had a higher prevalence of polymicrobial infections (46% versus 15%), infections due to Gram-negative organisms (24% versus 9%), and anaerobic infections (19% versus 6%) compared to patients with septic arthritis. These findings suggest broad-spectrum empiric antibiotic therapy, including vancomycin, should be considered for bone and joint infections in patients with injecting drug abuse. Level IV, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.


Short term results of endoscopic submucosal dissection in superficial esophageal squamous cell neoplasms.
To evaluate the efficacy of endoscopic submucosal dissection for superficial esophageal squamous cell neoplasms. Between July 2007 and March 2009, 27 consecutive superficial esophageal squamous cell neoplasms in 25 enrolled patients were treated by endoscopic submucosal dissection. The therapeutic efficacy, complications, and follow-up results were assessed. The mean size of the lesions was 21 ± 13 mm (range 2-55 mm); the mean size of the resection specimens was 32 ± 12 mm (range 10-70 mm). The en block resection rate was 100% (27/27), and en block resection with tumor-free lateral/basal margins was 88.9% (24/27). Perforation occurred in 1 patient who was managed by conservative medical treatments. None of the patients developed local recurrence or distant metastasis in the follow-up period. Endoscopic submucosal dissection is applicable to superficial esophageal squamous cell neoplasms with promising results.


[Treatment of postprandial discomfort syndrome in the elderly: a multi-centered prospective randomized controlled clinical study].
Objective: To evaluate the efficacy and safety of Oryz-Aspergillus enzyme and pancreatin tablets (Combizym(®)) in the treatment of postprandial distress syndrome (PDS) in the elderly, compared with gastrointestinal motility drugs. Methods: A prospective randomized controlled trial was designed and registered in the China Clinical Trials Registry (ChiCTR-IPR-16008185). The elderly patients with PDS were randomly divided into three groups, including Mosapride group with Mosapride citrate tablets 5 mg 3 times per day for 2 weeks; Combizym(®) group with Combizym tablets 244 mg 3 times per day for 2 weeks; combined treatment group with both drugs and same doses for 2 weeks. The modified Nepean dyspepsia index (NDSI) score, discomfort intensity score and PDS score were calculated on patients before treatment, at the end of first and second week of treatment, as well as 4 weeks after treatment finished, respectively. Adverse effects were evaluated. Results: A total of 323 patients from 16 tertiary hospitals in China were enrolled in this study. Among them, 105 patients were in Mosapride group, 109 in Combizym(®) group and 109 in combined treatment group. There were 148 males (45.8%) and 175 females (54.2%) with median age 71.4±9.0 years (60-100 years). Baseline characteristics of three groups were comparable. After treatment, the NDSI scores in three groups all decreased significantly (P<0.001), while they were similar between groups (P>0.05). The discomfort intensity score and PDS score in three groups showed a significant reduction after treatment (P<0.001), especially in the combined treatment group. Compared with Mosapride group, the scores in Combizym(®) group decreased significantly after one or two weeks [discomfort intensity score: after one week, 4.0(2.5, 8.0) vs. 6.0(3.0, 10.0); after two weeks, 3.0(0.0, 5.0) vs. 4.0(2.0, 6.0); all P<0.05. PDS score: after one week, 6.0(3.0, 9.0) vs. 7.0(3.5, 10.5); after two weeks, 3.0(0.0, 5.0) vs. 4.0(2.0, 7.0); all P<0.05]. The efficacy rate in all patients after first week of treatment was over 15.0%. The efficacy rates after two weeks were 55.2%, 68.8% and 73.4% in Mosapride group, Combizym(®) group and combined treatment group, respectively. After two week treatment, the efficacy rates in Combizym(®) group (P=0.041) and combined group (P=0.006) were higher than that of Mosapride group. The recurrence rate of Mosapride group was 9.5%, which was significantly higher than that of Combizym(®) group (1.8%, P<0.05) and combined treatment group (1.8%, P<0.05). There were no serious adverse effects in the three groups. Conclusions: The efficacy of Oryz-Aspergillus enzyme and pancreatin tablets is comparable with that of Mosapride in elderly PDS patients, with fewer adverse effects and low recurrence rate. Combination regimen indicates better efficacy than that of Oryz-Aspergillus enzyme and pancreatin tablets or Mosapride alone.


Caenorhabditis elegans has a phosphoproteome atypical for metazoans that is enriched in developmental and sex determination proteins.
In eukaryotic species, signal transduction is often mediated by posttranslational modifications that can serve as regulatory switches. Although nematodes have usually been studied by genetic rather than biochemical methods, PTMs such as phosphorylation are thought to control all aspects of biological functions including sex determination and development. Here, we apply high accuracy mass spectrometry and comprehensive bioinformatic analysis to determine and characterize the in vivo Caenorhabditis elegans phosphoproteome for the first time. We detect nearly 7000 phosphorylation sites on 2400 proteins, which are disproportionately involved in development and sex determination. Interestingly, the worm phosphoproteome turns out to be very distinct from phosphoproteomes of other multicellular eukaryotes as judged by its phylogenetic conservation, kinase substrate motifs and site analysis by a support vector machine. This result agrees with the large proportion of worm specific kinases previously discovered by genome sequencing. Furthermore, our data show that the C. elegans specific dosage complex can be phosphorylated on most subunits, suggesting its regulation by kinases. Availability of the C. elegans phosphoproteome should add a novel dimension to functional data obtained by genetic screens in this organism.


[Effect of electrostimulation of different brain structures on the motor activity of the digestive tract of the cod].
In acute experiments on immobilized unanesthetized cod, the effect of electrical stimulation of different brain structures on electrical activity of smooth muscle of the alimentary tract was investigated. Stimulation of the lateral telencephalon and tectum with trains of square pulses (0.1 - 0.5 mA, 2 msec, 300 Hz) depressed the tonic and peristaltic gastrointestinal motility. Stimulation of the rostral area of cerebellum and medulla oblongata intensified the gastric and intestinal emptying. The effect was found to depend on the level of spontaneous motor activity of the stomach and intestine.


Definitions of progression in chronic kidney disease--predictors and relationship to renal replacement therapy in a population cohort with a 6 year follow-up.
Chronic kidney disease (CKD) is common, important and associated with increased healthcare needs due to CKD progression. Definitions of renal disease progression are multiple, and not always comparable. A measure of 'progression' directly comparable with renal replacement therapy (RRT) initiation would identify 'progressors' in research and for healthcare planning. The Grampian Laboratory Outcomes Morbidity and Mortality Study (GLOMMS-I) is a community cohort with CKD from 2003, followed up to June 2009 for (i) RRT initiation and (ii) 'progression': sustained reduction in estimated glomerular filtration rate (eGFR) by 15 mL/min/1.73 m2 (equivalent to CKD stage change), or to <10 mL/min/1.73 m2, whichever occurs first. Predictors were baseline demographics and comorbidity. The use of the Kidney Disease: Improving Global Outcomes-2012 progression definition was also explored. Two thousand two hundred and eighty-nine and 1044 had Stage 3 and 4 CKD, 44% were males. Overall, RRT initiation and progression rates were 0.97 and 3.50 per 100 patient-years (py). Females had significantly lower progression and RRT initiation rates. The progression rate was not dependent on CKD stage [incidence rate ratio (IRR) for Stage 4 (versus Stage 3) 0.9 (95% CI 0.8-1.2)], whereas the RRT initiation rate was [IRR 5.6 (95% CI 3.8-8.2)]. Increased proteinuria was associated with both greater RRT initiation and progression rates. Progression and RRT initiation rate ratios allow comparison of predictors of these outcomes. Higher rates of both in males suggest that greater RRT initiation rate is biological rather than due to preferential treatment. Similar progression but very different RRT initiation rates in Stage 3 and 4 CKD suggests that CKD stage effect on RRT initiation is a function of endpoint proximity rather than faster renal function deterioration.


Prognostic significance of TRAIL death receptors in Middle Eastern colorectal carcinomas and their correlation to oncogenic KRAS alterations.
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumour necrosis factor cytokine family that induces apoptosis upon binding to its death domain containing receptors, TRAIL receptor 1 (DR4) and TRAIL receptor 2 (DR5). Expression of TRAIL receptors is higher in colorectal carcinoma (CRC) as compared to normal colorectal mucosa and targeted therapy with TRAIL leads to preferential killing of tumor cells sparing normal cells. We investigated the expression of TRAIL and its receptors in a tissue microarray cohort of 448 Middle Eastern CRC. We also studied the correlation between TRAIL receptors and various clinico-pathological features including key molecular alterations and overall survival. CRC subset with TRAIL-R1 expression was associated with a less aggressive phenotype characterized by early stage (p = 0.0251) and a histology subtype of adenocarcinomas (p = 0.0355). Similarly CRC subset with TRAIL-R2 expression was associated with a well-differentiated tumors (p < 0.0001), histology subtype of adenocarcinomas (p = 0.0010) and tumors in left colon (p = 0.0009). Over expression of pro apoptotic markers: p27KIP1 and KRAS4A isoforms was significantly higher in CRC subset with TRAIL-R1 and TRAIL-R2 expression; TRAIL-R1 expression was also associated with cleaved caspase-3(p = 0.0011). Interestingly, TRAIL-R2 expression was associated with a microsatellite stable (MS--S/L) phenotype (p = 0.0003) and with absence of KRAS mutations (p = 0.0481). TRAIL-R1 expression was an independent prognostic marker for better survival in all CRC samples and even in the CRC group that received adjuvant therapy. The biological effects of TRAIL in CRC models, its enhancement of chemosensitivity towards standard chemotherapeutic agents and the effect of endogenous TRAIL receptor levels on survival make TRAIL an extremely attractive therapeutic target.


Social functioning in patients with depressive and anxiety disorders.
Adaptive social functioning is severely impeded in depressive and anxiety disorders, even after remission. However, a comprehensive overview is still lacking. Using data from the Netherlands Study of Depression and Anxiety (NESDA), behavioural (network size, social activities, social support) and affective (loneliness, affiliation, perceived social disability) indicators of social functioning were analyzed in patients with anxiety (N = 540), depressive (N = 393), comorbid anxiety and depressive disorders ('comorbid', N = 748), remitted participants (N = 621), and healthy control subjects (N = 650). Analyses revealed an increasing trend of social dysfunction among patient groups, in patients with comorbid anxiety and depressive disorders, showing the most severe impairments, followed by depressed and anxious patients (P's < 0.001 for all social functioning indicators). Affective indicators showed the largest effect sizes (Cohen's d range from 0.13 to 1.76). We also found impairments in social functioning among remitted patients. Furthermore, perceived social disability among patients was predictive of still having a depressive and/or anxiety diagnosis 2 years later (P < 0.01). Behavioural but especially affective indicators of social functioning are impaired in patients with anxiety or depressive disorders and most in patients with comorbid disorders. After remission of affective psychopathology, residual impairments tend to remain, while social dysfunction in patients seems predictive of future psychopathology.


Paradoxical positive inotropic effect of K+ in the rat heart.
In cardiac muscle isolated from most mammalian species, an elevation of extracellular K+ concentration decreases developed tension. This is explained from stimulation of the Na pump. In rat myocardium, however, developed tension increased when K+ concentration was raised from 3.5 to 9.5 mM, seemingly inconsistent with the above explanation. Activation of isolated Na+,K+-adenosinetriphosphatase by K+ was not different in rat and guinea pig heart. The K+-induced increase in developed tension observed in left atrial muscle preparations obtained from rat heart was not blocked by phentolamine and propranolol or by reserpine pretreatment but attenuated by stimulation at higher frequency, incubation at a lower temperature, or by veratridine, all of which have been shown to increase Na+ loading of myocardial cells. K+ slightly prolonged action potential duration and partially depolarized resting membrane potential; however, K+-induced changes in electrophysiological parameters or possible inactivation of early outward current observed in myocytes isolated from rat heart are unlikely to be the primary cause of the positive inotropic effect. Caffeine or Cd2+ eliminated the inotropic effect of K+ but ryanodine was ineffective. An increase in extracellular K+ from 1 to 3.5 mM decreased developed tension. These results indicate that K+ has dual effects on developed tension in rat myocardium: a negative inotropic effect resulting from Na pump stimulation and a positive inotropic effect. The latter effect is due to a process that is either unique or more strongly expressed in the rat myocardium and masks the former effect in the range of physiological K+ concentrations.