Positive and negative viral associations in patients with acute respiratory tract infections in primary care: the ECOVIR study.
Acute respiratory infections (ARIs) are the most common viral infections encountered in primary care settings. The identification of causal viruses is still not available in routine practice. Although new strategies of prevention are being identified, knowledge of the relationships between respiratory viruses remains limited. ECOVIR was a multicentric prospective study in primary care, which took place during two pre-pandemic seasons (2018-2019 and 2019-2020). Patients presenting to their General practitioner (GP) with ARIs were included, without selecting for age or clinical conditions. Viruses were detected on nasal swab samples using a multiplex Polymerase Chain Reaction test focused on 17 viruses [Respiratory Syncytial Virus-A (RSV-A), RSV-B, Rhinovirus/Enterovirus (HRV), human Metapneumovirus (hMPV), Adenovirus (ADV), Coronaviruses (CoV) HKU1, NL63, 229E, OC43, Influenza virus (H1 and H3 subtypes), Influenza virus B, Para-Influenza viruses (PIVs) 1-4, and Bocavirus (BoV)]. Among the 668 analyzed samples, 66% were positive for at least one virus, of which 7.9% were viral codetections. The viral detection was negatively associated with the age of patients. BoV, ADV, and HRV occurred more significantly in younger patients than the other viruses (p < 0.05). Codetections were significantly associated with RSV, HRV, BoV, hMPV, and ADV and not associated with influenza viruses, CoV, and PIVs. HRV and influenza viruses were negatively associated with all the viruses. Conversely, a positive association was found between ADV and BoV and between PIVs and BoV. Our study provides additional information on the relationships between respiratory viruses, which remains limited in primary care.


[Function of flow cytometry on the dosage of antibodies against double stranded DNA in systemic lupus erythematosus].
Among the diverse number of antibodies observed in systemic lupus erythematosus, antibodies against double stranded DNA (anti-dsDNA) represent important serologic markers for the disease diagnosis and the follow-up of the disease activity. To evaluate the role of a new quantitative methodology to detect antibodies against double stranded DNA in systemic lupus erythematosus and its association with the disease activity. The performance of the indirect immunofluorescence flow cytometry with Crithidia luciliae as substrate was compared with the Crithidia luciliae indirect immunofluorescence assay and the ELISA technique in order to detect antibodies against double stranded DNA in 54 sera from 47 patient with systemic lupus erythematosus and 100 sera from normal controls. The new method showed a sensitivity of 78% and a specificity of 81% when the Crithidia luciliae indirect immunofluorescence assay was the gold standard. Compared with the ELISA technique, the flow cytometry showed a sensitivity of 78% and a specificity of 86%. No correlation was found among antibodies against double stranded DNA values detected with flow cytometry and the MEX-SLEDAI activity scores. However, the flow cytometry showed a sensitivity of 70% and a specificity of 42% to distinguish patients with systemic lupus erythematosus with and without activity (MEX-SLEDAI score > or = 5). The Rho intra-observer coefficient was 0.61 (p < 0.0001). In spite of the fact that this new method might represent an interesting advance for antibodies against double stranded DNA quantitative testing, a clear superiority does not emerge when it was compared with more traditional assays. Difficulties related with its reproducibility might represent a limitation in the routine use of this new method.


[Mineral metabolism and aluminum burden with hydrotalcit. A placebo-controlled randomized double-blind study].
In a randomized, double-blind study, the influence of hydrotalcit (aluminium-magnesium hydroxide carbonate hydrate) on the mineral metabolism was investigated. No significant and clinically relevant changes in calcium, phosphate, magnesium or aluminium concentrations in the serum were observed. Nor were these substances eliminated in greater amounts in the urine. Merely the elimination of magnesium was higher in the group receiving the test substance than in the placebo group; after discontinuation of the medication, no difference in the elimination rates was found. Thus, provided that renal function is intact, the use of hydrotalcit does not lead to any disturbance in the mineral balance, or, in particular, to any additional aluminium burden.


Integrated Akt/PKB signaling in immunomodulation and its potential role in cancer immunotherapy.
T cell development and maturation involve a variety of defined and coordinated developmental stages under the control of a variety of signaling networks. They function as the major mediator in cell-based immunity that defends against pathogen infections and executes immune surveillance against tumor cells. Protein kinase B (PKB, also called Akt) is central to multiple signaling pathways and transduces extracellular signals to dictate cellular responses towards proliferation, migration, anti-apoptosis, and maintenance of metabolic homeostasis. Although the prosurvival function of PKB was thought to be responsible for most of the functions regulated by PKB, emerging evidence has started to dissect its role in immunomodulation. More importantly, hyperactivation of PKB in cancer stroma frequently occurs in patients treated clinically with targeted cancer therapies, where it acts as a key mediator involved in the trapping of host immune cells in the vicinity of tumors, which supports cancer cell invasion and the escape of cancer cells from host immune surveillance. Encouragingly, recent studies have shown that inhibition of PKB improves the recognition of cancer cells by the host immune system, indicating a potential clinical strategy to rekindle the suppressed host immune response through the specific targeting of PKB. In this review, we explore how PKB signaling contributes to T cell development and cellular immune responses and discuss the mechanistic roles that PKB plays in the creation of immunosuppressive conditions and the escaping of immune recognition in the microenvironment of cancer.


Characterization of small plaque mutants of mouse hepatitis virus, JHM strain.
Two small plaque mutants designated as 1a and 2c were isolated from DBT cells persistently infected with the JHM strain of mouse hepatitis virus. Unlike the wild type JHM, these two mutant viruses grew more slowly with no prominent cell fusion. The buoyant densities of the mutants were slightly lower and 2c was revealed to have fewer peplomers than JHM by electron microscopy. The purified JHM contained five polypeptides with molecular weights (M.W.) of 260,000, 105,000 (GP105), 65,000, 60,000 (P60), and 23,000 (GP23). In addition to two polypeptides, P60 and GP23, which were common to JHM and the mutants, 1a was found to contain three other specific polypeptides with M.W. of 180,000 (GP180), 110,000, and 95,000 (GP95), while 2c had GP180, GP105, GP95, and one with a M.W. of 175,000. All of these polypeptides were shown to be glycosylated except for P60. After bromelain treatment, all these viruses lost the peplomers and contained P60 and another new 18,000 dalton polypeptide.


Effectiveness of foot orthoses in patients with rheumatoid arthritis related to disability and pain: a systematic review and meta-analysis.
Epidemiological studies consistently report a 90% prevalence of foot pain. Mechanical and other non-pharmacological interventions such as orthoses and footwear can play an important role in managing foot pathology in patients whose systemic disease is controlled. The effectiveness of treatment with insoles has been examined in various randomised controlled trials, which have reported immediate clinical improvements, with reduced foot pain and disability and enhanced functionality. The aim of this systematic review is to determine the effectiveness of foot orthoses in patients with rheumatoid arthritis (RA), in comparison with other treatments, in terms of enhanced disability and reduced pain. A systematic review and meta-analysis was conducted of a number of randomised controlled trials focusing on patients with RA. The search was conducted in Cochrane, CINAHL, PubMed, EMBASE, SCOPUS and Cuiden, by means of an independent peer review. The Mesh terms and fields used were foot, ankle, joint, RA, foot, orthosis, insole and foot orthosis. Of the initial 118 studies considered, 5 were included in the final systematic review and meta-analysis. These five studies had enrolled a total of 301 participants, with follow-up periods ranging from 4 to 36 months. Although the use of orthoses seems to alleviate foot pain, our meta-analysis did not reveal statistically significant differences between control and intervention groups regarding long- and short-term pain relief and/or reduced disability. Foot orthoses can relieve pain and disability and enhance patients, but no significant differences were found between control and intervention groups.


Temperatibacter marinus gen. nov., sp. nov., a mesophilic bacterium isolated from surface seawater and description of Temperatibacteraceae fam. nov. in the class Alphaproteobacteria.
A Gram-stain-negative, motile, mesophilic, aerobic, rod-shaped bacterium, strain 5-11(T), was isolated from surface seawater at Muroto city, Kochi prefecture, Japan. The strain exhibited a narrow growth temperature range of 20-30 °C. Phylogenetic analyses based on 16S rRNA gene sequences showed that the strain fell within the order Kordiimonadales in the class Alphaproteobacteria and was related most closely to the genus Kordiimonas (up to 91.2 % similarity to the type strains of species of the genus) but branched deeply from species of Kordiimonas. The major fatty acids were iso-C17 : 1ω9c, iso-C15 : 0, and C16 : 1ω7c and/or iso-C15 : 0 2-OH. Ubiquinone-10 (Q-10) was detected as the sole isoprenoid quinone. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol and one unidentified aminolipid. Although strains of Kordiimonas have been shown to contain unidentified glycolipids, they were not detected from strain 5-11(T). The DNA G+C content of strain 5-11(T) was 44.3 mol%, a value that was lower than those of strains of Kordiimonas (50-58 mol%) and was relatively low for the members of the class Alphaproteobacteria. On the basis of phenotypic, genotypic and chemotaxonomic data, it is proposed that strain 5-11(T) represents a novel species of a new genus, Temperatibacter marinus gen. nov., sp. nov., within a new family Temperatibacteraceae fam. nov. The type strain of Temperatibacter marinus is 5-11(T) ( = NBRC 110045(T) = LMG 28278(T)).


Dynamics of the immune response in rabbits immunized with spreptococcal extracellular antigens: comparison of the Streptozyme agglutination test with three specific neutralization tests.
The dynamics of the immune response to streptococcal extracellular antigens as measured by the streptozyme agglutination test have been defined in experimental animals andcompared with the dynamics of the immune response as determined by three established neutralization tests for streptococcal antibodies (ASO, anti-DNase B,and anti-NADase). In rabbits immunized with streptococcal extracellular Streptozyme-measured antibodies rose more quickly and peaked earlier than did antibodies to streptolysin O, streptococcal DNase-B, and streptococcal NADase. Additional studiesrevealed that the early peak was primarily due to 2-mercaptoethanol-sensitive (19S) antibody and that the later rise in Streptozyme-measured antibodies was due to 2-mercaptoethanol-resistant (7S) antibody. Preliminary observations using sucrose gradient ultracentrifugation tended to confirm this interpretation. These data provide a possible explanation for the early detection of a streptococcal antibody response by the Streptozyme test which has also been described in humans. The data suggest a theoretical advantage for the Streptozyme agglutination test in patients with streptococcal infections and their sequealae. However, the complexity of the Streptozyme reagent suggests that more extensive studies are needed to assure the consistent reproductivity of results with different lots of the test reagent.


Dental and Temporomandibular Joint Pathology of the North American Brown Bear (Ursus arctos horribilis, Ursus arctos middendorffi and Ursus arctos sitkensis).
Museum specimens (maxillae and mandibles) from 393 North American brown bears (Ursus arctos) from Alaska were examined macroscopically according to predefined criteria and 204 specimens were included in this study. The specimens were acquired between 1905 and 2012. There were 99 specimens (48.5%) from male animals, 87 (42.7%) from female animals and 18 (8.8%) from animals of unknown sex. The ages of the animals ranged from neonate to adult, with 92 adults (45.1%) and 112 young adults (54.9%) included and neonates/juveniles excluded from the study. The number of teeth available for examination was 6,525 (76.2%); 8.6% of teeth were absent artefactually, 0.8% were deemed absent due to acquired tooth loss and 14.5% were absent congenitally. None of the brown bears had supernumerary teeth, persistent deciduous teeth or abnormally formed crowns. Only four of the specimens in the present population were affected by enamel hypoplasia and one specimen contained two mandibular fourth premolar teeth with one root instead of two. All 204 specimens displayed at least some degree of attrition/abrasion, affecting 63% of all teeth, ranging from mild wear of the enamel to deep abrasion associated with pulp exposure. Ten-times more adult than young adult specimens had abrasion causing pulp exposure, while more young adults showed mild attrition/abrasion. Dental fractures were noted in one-third of brown bears and in 3.0% of the total number of present teeth. More adult brown bears had dental fractures than young adults. There were 11 specimens (5.4%) that displayed overt periapical disease, affecting a total of 20 dental alveoli (0.22%), with adults significantly more affected than young adults. Some degree of periodontitis was seen in 145 specimens (71.1%), affecting 13.6% of all dental alveoli. Nearly one-third (29.9%) of skulls displayed skeletal and/or dental malocclusion, most commonly a level bite. Lesions consistent with temporomandibular joint (TMJ) osteoarthritis were found in 27 specimens (13.2%). Caries lesions were discovered in four specimens (2.0%), affecting eight teeth in total. Although the clinical significance of dental and TMJ pathology in the brown bear remains elusive, the occurrence and severity of some of these lesions may play an important role in the morbidity of this species.


The role of compression in large scale data transfer and storage of typical biomedical signals at hospitals.
In modern hospitals, monitoring patients' vital signs and other biomedical signals is standard practice. With the advent of data-driven healthcare, Internet of medical things, wearable technologies, and machine learning, we expect this to accelerate and to be used in new and promising ways, including early warning systems and precision diagnostics. Hence, we see an ever-increasing need for retrieving, storing, and managing the large amount of biomedical signal data generated. The popularity of standards, such as HL7 FHIR for interoperability and data transfer, have also resulted in their use as a data storage model, which is inefficient. This article raises concern about the inefficiency of using FHIR for storage of biomedical signals and instead highlights the possibility of a sustainable storage based on data compression. Most reported efforts have focused on ECG signals; however, many other typical biomedical signals are understudied. In this article, we are considering arterial blood pressure, photoplethysmography, and respiration. We focus on simple lossless compression with low implementation complexity, low compression delay, and good compression ratios suitable for wide adoption. Our results show that it is easy to obtain a compression ratio of 2.7:1 for arterial blood pressure, 2.9:1 for photoplethysmography, and 4.1:1 for respiration.


The pain imaging revolution: advancing pain into the 21st century.
The great advances in brain imaging techniques over the last few decades have determined a shift in our understanding of chronic pain conditions and opened the door for new opportunities to develop better diagnoses and perhaps better drug treatments. Neuroimaging has helped shape the concept of chronic pain from a disease affecting mainly the somatosensory system, to a condition in which emotional, cognitive, and modulatory areas of the brain are affected, in addition to degenerative processes. All these contribute to the development and maintenance of pain symptoms and comorbid features, including alterations in anxiety, depression, and cognitive processes. In this article the authors review the current understanding of the brain changes in chronic pain and the developments made possible by the use of various brain imaging techniques. They also discuss the possible applications of brain imaging to developing a "pain phenotype" that could aid in diagnostic and treatment choices of chronic pain conditions.


Metabolic requirements of pulmonary fibrosis: role of fibroblast metabolism.
Fibrosis is a pathologic condition characterized by excessive deposition of extracellular matrix and chronic scaring that can affect every organ system. Organ fibrosis is associated with significant morbidity and mortality, contributing to as many as 45% of all deaths in the developed world. In the lung, many chronic lung diseases may lead to fibrosis, the most devastating being idiopathic pulmonary fibrosis (IPF), which affects approximately 3 million people worldwide and has a median survival of 3.8 years. Currently approved therapies for IPF do not significantly extend lifespan, and thus, there is pressing need for novel therapeutic strategies to treat IPF and other fibrotic diseases. At the heart of pulmonary fibrosis are myofibroblasts, contractile cells with characteristics of both fibroblasts and smooth muscle cells, which are the primary cell type responsible for matrix deposition in fibrotic diseases. Much work has centered around targeting the extracellular growth factors and intracellular signaling regulators of myofibroblast differentiation. Recently, metabolic changes associated with myofibroblast differentiation have come to the fore as targetable mechanisms required for myofibroblast function. In this review, we will discuss the metabolic changes associated with myofibroblast differentiation, as well as the mechanisms by which these changes promote myofibroblast function. We will then discuss the potential for this new knowledge to lead to the development of novel therapies for IPF and other fibrotic diseases.


[Antiphospholipid antibody: laboratory, pathogenesis and clinical manifestations].
Antiphospholipid antibodies (aPL) represent a heterogeneous group of antibodies that recognize various antigenic targets including beta2 glycoprotein I (beta2GPI), prothrombin (PT), activated protein C, tissue plasminogen activator, plasmin and annexin A2. The most commonly used tests to detect aPL are: lupus anticoagulant (LAC), a functional coagulation assay, anticardiolipin antibody (aCL) and anti-beta2GPI antibody (anti-beta2GPI), which are enzyme-linked immunoassay (ELISA). Clinically aPL are associated with thrombosis and/or with pregnancy morbidity. Apparently aPL alone are unable to induce thrombotic manifestations, but they increase the risk of vascular events that can occur in the presence of another thrombophilic condition; on the other hand obstetrical manifestations were shown to be associated not only to thrombosis but mainly to a direct antibody effect on the trophoblast.


EDS1 in tomato is required for resistance mediated by TIR-class R genes and the receptor-like R gene Ve.
In tobacco and other Solanaceae species, the tobacco N gene confers resistance to tobacco mosaic virus (TMV), and leads to induction of standard defense and resistance responses. Here, we report the use of N-transgenic tomato to identify a fast-neutron mutant, sun1-1 (suppressor of N), that is defective in N-mediated resistance. Induction of salicylic acid (SA) and expression of pathogenesis-related (PR) genes, each signatures of systemic acquired resistance, are both dramatically suppressed in sun1-1 plants after TMV treatment compared to wild-type plants. Application of exogenous SA restores PR gene expression, indicating that SUN1 acts upstream of SA. Upon challenge with additional pathogens, we found that the sun1-1 mutation impairs resistance mediated by certain resistance (R) genes, (Bs4, I, and Ve), but not others (Mi-1). In addition, sun1-1 plants exhibit enhanced susceptibility to TMV, as well as to virulent pathogens. sun1-1 has been identified as an EDS1 homolog present on chromosome 6 of tomato. The discovery of enhanced susceptibility in the sun1-1 (Le_eds1-1) mutant plant, which contrasts to reports in Nicotiana benthamiana using virus-induced gene silencing, provides evidence that the intersection of R gene-mediated pathways with general resistance pathways is conserved in a Solanaceous species. In tomato, EDS1 is important for mediating resistance to a broad range of pathogens (viral, bacterial, and fungal pathogens), yet shows specificity in the class of R genes that it affects (TIR-NBS-LRR as opposed to CC-NBS-LRR). In addition, a requirement for EDS1 for Ve-mediated resistance in tomato exposes that the receptor-like R gene class may also require EDS1.


Dynamic Arctangent Center-Tracking Method for Respiratory Displacement Monitoring of Subjects in Arbitrary Positions.
Accurate continuous measurement of respiratory displacement using continuous wave Doppler radar requires rigorous management of dc offset which changes when a subject changes distance from the radar measurement system. Effective measurement, therefore, requires robust dynamic calibration which can recognize and compensate for changes in the nominal position of a subject. In this paper, a respiratory displacement measurement algorithm is proposed which can differentiate between sedentary and non-sedentary conditions and continuously adapt to provide long-term monitoring of a subject's sedentary respiration. Arctangent demodulation is an effective means of quantifying continuous displacement using a quadrature Doppler radar, yet it depends on accurate identification of dc offset and dc information contributions in the radar I-Q arc with the subject in a particular position. The dynamic calibration method proposed here is demonstrated to differentiate between sedentary and non-sedentary conditions for six subjects to produce accurate sedentary respiration measurements even when the subject arbitrarily changes position, once the appropriate thresholds are established for the measurement environment.


Standardized 11-color flow cytometry panel for the functional phenotyping of human T regulatory cells.
T regulatory cells (Tregs) are a cell subset that can suppress immune responses to maintain homeostasis and self-tolerance. In some scenarios, the immunosuppressive nature could be associated to other pathological developments such as autoimmune diseases and cancers. Due to the importance of Tregs in disease pathogenesis, we developed and validated an 11-color flow cytometry panel for phenotypic and functional detection of Treg markers using healthy human donor peripheral blood mononuclear cells (PBMCs). Our panel contains 4 Treg surface proteins and 2 functional cytokines as well as T-lymphocyte lineage markers CD3, CD4, and CD8. Our data shows an increase in expression of markers CD25, FoxP3, CTLA4, GITR and intracellular cytokines IL4 and TGFβ when comparing unstimulated samples to CD3/CD28 bead stimulated samples. This 11-color panel can be used to functionally evaluate immunosuppressive Tregs in human PBMC samples.


Effects of Telephone Follow-Up Intervention on %Body Fat, Inflammatory Cytokines, and Oxidative Stress in Obese Hispanic Children.
This study investigated whether 10 month telephone follow-up intervention effectively stabilizes reductions in %body fat, and markers of inflammation and oxidative stress obtained from summer camp in obese Hispanic children. Fifty-six obese children (19 SUTI: summer camp and 10 months of follow-up telephone intervention, 18 SU: summer camp intervention only, and 19 CON: no intervention) completed this study. Anthropometric data and blood samples were obtained before (PRE), after 8 weeks of summer camp, and a 10month follow-up telephone intervention to measure markers of inflammation and oxidative stress. Eight weeks of summer camp significantly reduced %body fat, and levels of tumor necrosis factor-alpha, C-reactive protein and 8-hydroxydeoxyguanosine. It also elevated levels of adiponectin and total antioxidant status in SUTI and SU (p < 0.05). However, results of the 10month follow-up measurement were reverted back to PRE in SU, whereas the results for SUTI remained different to PRE (p < 0.05). Results confirm that levels of inflammation and oxidative stress are correlated to changes in %body fat, indicating that fat loss is effective in preventing and managing obesity-associated disorders. It is suggested that a telephone intervention is an effective follow-up tool for stabilizing reductions in %body fat as well as levels of inflammation and oxidative stress that were obtained from an intensive summer camp program in obese Hispanic children.


Thrombocytosis and immunohistochemical expression of connexin 43 at diagnosis predict survival in advanced non-small-cell lung cancer treated with cisplatin-based chemotherapy.
Patients with advanced non-small-cell lung cancer (NSCLC) have poor survival, and platinum-based chemotherapy agents are the standard first-line chemotherapy agents for advanced NSCLC. This study aimed to identify predictive factors associated with the response to chemotherapy and survival in 258 patients with advanced NSCLC treated with platinum-based chemotherapy. Stage IIIA-IV NSCLC patients diagnosed in Kaifeng second people's hospital (Henan, China) between March 2002 and September 2011 were retrospectively reviewed. All of the patients had received platinum-based chemotherapy, and patients were followed up to date of death or last follow-up to obtain data of response to chemotherapy and survival. Potential prognostic factors such as gender, age, tumor size, tumor type, histologic stage, anemia, calcium levels, ECOG performance status (PS), thrombocytosis, TTF-1, p63, and connexin 43 were analyzed. Response to chemotherapy, overall survival (OS) and progression-free survival (PFS) were calculated by the Kaplan-Meier method and Cox regression model. A univariate analysis indicated that thrombocytosis and connexin 43 were found to be significant prognostic factors (p < 0.001) and ECOG PS, Hb levels, and p63 presented a tendency toward association with survival. Kaplan-Meier survival showed that the mean OS and PFS in chemotherapy responders with connexin 43 ≥ +2 were significantly longer than in chemotherapy responders with connexin 43 ≤ 1+. In contrast, thrombocytosis was associated with increased mortality and resistance to chemotherapy in chemotherapy responders. In addition, all 21 patients of the 5-year OS were from chemotherapy responders with connexin 43 ≥ +2 or non-thrombocytosis. Thrombocytosis and connexin 43 absence may be reliable surrogate markers for the prediction of chemotherapy response and prognosis for patients with advanced NSCLC, and assessment of these factors may identify a population of patients with advanced NSCLC that is likely to have a prolonged life expectancy.


A histomorphometric study on age-related changes in selected lymphoid structures of Chukar partridge (Alectoris chukar).
Chukar partridge (Alectoris chukar) is raised for its highly nutritional and relatively expensive meat. This study evaluates selected lymphoid organs of juvenile and peripubertal Chukar partridges using a histomorphometric approach. Thirty one-day-old male and female Chukar partridges were included in the study. Samples were taken from cloacal bursa, thymus, spleen and the caecal tonsil (CT) as well as oesophageal and pyloric tonsils at 80, 100, and 120 days (peripuberty) of age. Ten transverse sections were then taken from each sample of each bird and stained with haematoxylin and eosin (H&E) in order to measure plicae height and follicular width as well as thickness of follicular cortex and medulla in cloacal bursa, villus height and nodular unit (ND) width and height in CT, lobular width as well as lobular cortex and medullar width in thymus, white pulp width in spleen and follicular width in oesophageal and pyloric tonsils, a linear graticule was used, the number of follicles in each plicae in cloacal bursa and the number of follicles in each ND in CT were determined under a light microscope. Drastic changes in histomorphometrical parameters of lymphoid tissues were observed in peripuberty, prominently in cloacal bursa and thymus as demonstrated by the significant decrease in all assayed parameters. Involutionary changes were also observed in oesophageal and pyloric tonsils. Involution occurs in bursa and thymus of partridges around puberty rather than their juvenile stages. These changes are also appreciable in CT, oesophageal and pyloric tonsils, whereas the spleen keeps the same histological features before and around puberty.


Decision-making flexibility in New Caledonian crows, young children and adult humans in a multi-dimensional tool-use task.
The ability to make profitable decisions in natural foraging contexts may be influenced by an additional requirement of tool-use, due to increased levels of relational complexity and additional work-effort imposed by tool-use, compared with simply choosing between an immediate and delayed food item. We examined the flexibility for making the most profitable decisions in a multi-dimensional tool-use task, involving different apparatuses, tools and rewards of varying quality, in 3-5-year-old children, adult humans and tool-making New Caledonian crows (Corvus moneduloides). We also compared our results to previous studies on habitually tool-making orangutans (Pongo abelii) and non-tool-making Goffin's cockatoos (Cacatua goffiniana). Adult humans, cockatoos and crows, but not children and orangutans, did not select a tool when it was not necessary, which was the more profitable choice in this situation. Adult humans, orangutans and cockatoos, but not crows and children, were able to refrain from selecting non-functional tools. By contrast, the birds, but not the primates tested, struggled to attend to multiple variables-where two apparatuses, two tools and two reward qualities were presented simultaneously-without extended experience. These findings indicate: (1) in a similar manner to humans and orangutans, New Caledonian crows and Goffin's cockatoos can flexibly make profitable decisions in some decision-making tool-use tasks, though the birds may struggle when tasks become more complex; (2) children and orangutans may have a bias to use tools in situations where adults and other tool-making species do not.


[Less ventilator-associated pneumonia after oral decontamination with chlorhexidine; a randomised trial].
To determine the effect of oral decontamination with either chlorhexidine (CHX, 2%) or the combination chlorhexidine-colistin (CHX-COL, 2%-2%) on the frequency and the time to onset of ventilator-associated pneumonia in Intensive Care patients. Double blind, placebo-controlled, multicentre, randomised trial. Consecutive ICU patients needing at least 48 h of mechanical ventilation were enrolled in a randomized trial with 3 arms: CHX, CHX-COL, and placebo (PLAC). The trial medication was administered in the oral cavity every 6 h. Oropharyngeal swabs were obtained daily and analysed quantitatively for Gram-positive and Gram-negative microorganisms. Endotracheal colonisation was monitored twice weekly. Ventilator-associated pneumonia was diagnosed on the basis of a combination of clinical, radiological and microbiological criteria. Of 385 patients included, 130 received PLAC, 127 CHX and 128 CHX-COL. Baseline characteristics in the three groups were comparable. The daily risk of ventilator-associated pneumonia was reduced in both treatment groups compared to PLAC: 65% (HR= 0.352; 95% CI: 0.160-0.791; p = 0.012) for CHX and 55% (HR= 0.454; 95%/ CI: 0.224-0.925; p = 0.030) for CHX-COL. CHX-COL provided a significant reduction in oropharyngeal colonisation with both Gram-negative and Gram-positive microorganisms, whereas CHX significantly affected only colonisation with Gram-positive microorganisms. There were no differences in the duration of mechanical ventilation, ICU-stay or ICU-survival. Oral decontamination of the oropharyngeal cavity with chlorhexidine or the combination chlorhexidine-colistin reduced the incidence and the time to onset ofventilator-associated pneumonia.


Ubiquilin 2 is not associated with tau pathology.
Accumulation of aberrant proteins in inclusion bodies is a hallmark of many neurodegenerative diseases. Impairment of proteolytic systems is a common event in these protein misfolding diseases. Recently, mutations in the UBQLN 2 gene encoding ubiquilin 2 have been identified in X-linked amyotrophic lateral sclerosis (ALS). Furthermore, ubiquilin 2 is associated with inclusions in familial and sporadic ALS/dementia, synucleinopathies and polyglutamine diseases. Ubiquilin 2 exerts a regulatory role in proteostasis and thus it has been suggested that ubiquilin 2 pathology may be a common event in neurodegenerative diseases. Tauopathies, a heterogenous group of neurodegenerative diseases accompanied with dementia, are characterized by inclusions of the microtubule-binding protein tau. In the present study, we investigate whether ubiquilin 2 is connected with tau pathology in Alzheimer's disease (AD), supranuclear palsy (PSP) and Pick's disease (PiD) and familial cases with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We show that ubiquilin 2 positive inclusions are absent in these tauopathies. Furthermore, we find decreased ubiquilin 2 protein levels in AD patients, but our results do not indicate a correlation with tau pathology. Our data show no evidence for involvement of ubiquilin 2 and indicate that other mechanisms underly the proteostatic disturbances in tauopathies.


1-Deamino-8-D-arginine vasopressin and cryoprecipitate in variant von Willebrand disease.
The effect of infusing DDAVP and cryoprecipitate either singly or in combination was studied in a patient with variant von Willebrand disease. Both DDAVP and cryoprecipitate caused only partial correction in the hemostatic defect when used as a single agent. A combination of DDAVP and cryoprecipitate induced a complete correction of the hemostatic defect as well as factor VIII related properties.


[Specific immune response and immunoglobulin production in intestinal infections. II. Methodological aspects of studying immunoglobulins in digestive tract secretions].
Application of radial immunodiffusion for the study of immunoglobulins in the digestive tract secretion is described. Sensitivity of the method is increased by high dilution of antisera; precipitation rings should be recorded in the stained plates. To quantitate both serum and secretory IgA it is suggested that the secretions should be studied in parallel with two antisera--against the alpha-chain (to determine the total IgA) and against SC (to determine the secretory IgA). It is recommended to calculate the amount of immunoglobulins per 1 mg of high-molecular protein precipitable by trichloracetic acid.


Computer Vision Tool and Technician as First Reader of Lung Cancer Screening CT Scans.
To implement a cost-effective low-dose computed tomography (LDCT) lung cancer screening program at the population level, accurate and efficient interpretation of a large volume of LDCT scans is needed. The objective of this study was to evaluate a workflow strategy to identify abnormal LDCT scans in which a technician assisted by computer vision (CV) software acts as a first reader with the aim to improve speed, consistency, and quality of scan interpretation. Without knowledge of the diagnosis, a technician reviewed 828 randomly batched scans (136 with lung cancers, 556 with benign nodules, and 136 without nodules) from the baseline Pan-Canadian Early Detection of Lung Cancer Study that had been annotated by the CV software CIRRUS Lung Screening (Diagnostic Image Analysis Group, Nijmegen, The Netherlands). The scans were classified as either normal (no nodules ≥1 mm or benign nodules) or abnormal (nodules or other abnormality). The results were compared with the diagnostic interpretation by Pan-Canadian Early Detection of Lung Cancer Study radiologists. The overall sensitivity and specificity of the technician in identifying an abnormal scan were 97.8% (95% confidence interval: 96.4-98.8) and 98.0% (95% confidence interval: 89.5-99.7), respectively. Of the 112 prevalent nodules that were found to be malignant in follow-up, 92.9% were correctly identified by the technician plus CV compared with 84.8% by the study radiologists. The average time taken by the technician to review a scan after CV processing was 208 ± 120 seconds. Prescreening CV software and a technician as first reader is a promising strategy for improving the consistency and quality of screening interpretation of LDCT scans.


[Mechanism of strengthening of the contractile activity in the duodenum and in the jejunum in psychogenic stress in rabbits].
In experiments on unanaesthetized rabbits myoelectric activity (contractile activity index) of proximal (postpyloric) and distal sites of duodenum, and proximal part of jejunum was studied under stress induced by fastening a rabbit to a table in supine position. In both sites of duodenum, the stress impact induced a short-time decrease of contractile activity which was followed by its increase that exceeded the initial level. In the proximal part ofjejunum, the increase of contractile activity took place only during the second part of stress response. The strengthening of the contractile activity of the proximal part of duodenum was preserved after muscarinic or nicotinic cholinoceptor blockage, and after beta-receptor blockage. It was concluded that the contractile response of the proximal part of duodenum did not result from the contribution of central or local neurogenic mechanism, including excitatory cholinergic one, but was humoral in origin. The strengthening of the contractile activity of the distal part of duodenum and proximal part ofjejunum was abolished by muscarinic cholinoceptor and beta-receptor blockage, and resulted from the action of circulating catecholamines on the excitatory beta-adrenoceptor, localized on the cholinergic neurones of the enteric nervous system.


[Characteristics of the energy metabolism in the kidneys in analgesic nephropathy].
Effect of prolonged treatment with acetyl salicylic acid (100 mg/kg) on energy metabolism was studied in dog kidney. Functional conditions of kidney were altered, which was manifested by an increase in excretion of sodium and by impairement is osmotic concentrating of urine. Studies of energy metabolism revealed uncoupling of oxidation and phosphorylation and also some decrease in the activity of glycolytic processes. The observed alterations in bioenergetics of kidney tissue are considered as important factors in development of analgetic nephropathy.


Examining Whistleblowing Intention: The Influence of Rationalization on Wrongdoing and Threat of Retaliation.
Whistleblowers who expose wrongdoing often face several concerns, pressures, and threats of retaliation before reaching a final decision. Specifically, this study examines the effects of perceived seriousness of wrongdoing (PSW) and perceived threat of retaliation (PTR), as well as the impact of rationalization (RNL), comparing perceived seriousness of wrongdoing, perceived threat of retaliation and whistleblowing intention. Furthermore, this study aims to determine the mediating effect of anticipated regret (AR) on the relationship between perceived seriousness of wrongdoing and whistleblowing intention. We validated our model by analyzing data gathered across three stages from employees in the telecom sector in Pakistan. The key findings of our research may be summarized as follows: (i) individuals' willingness to 'blow the whistle' increases as a result of perceived seriousness of wrongdoing; (ii) whistleblowers are more likely to opt to remain silent if they anticipate a greater threat of retaliation, and (iii) our study establishes a positive connection between perceived seriousness of wrongdoing and whistleblowing intention, indicating that perceived seriousness of wrongdoing enhances people's willingness to blow the whistle, and whistleblowers are more likely to choose to emerge if the behaviour is more serious in nature; (iv) the data we have uncovered indicates a moderating role of rationalization in regulating the connections between perceived seriousness of wrongdoing, perceived threat of retaliation, and whistleblowing intention; and (v) the findings demonstrate that anticipated regret mediates the connection between perceived seriousness of wrongdoing and the intention to report wrongdoing. Additionally, the results are discussed in terms of their significance for corporate ethics researchers and managers, as well as for end-users who are interested in whistleblowing.


Reproductive organ and vascular specific promoter of the rice plasma membrane Ca2+ATPase mediates environmental stress responses in plants.
Plasma membrane Ca(2+)ATPase is a transport protein in the plasma membrane of cells and helps in removal of calcium (Ca(2+)) from the cell, hence regulating Ca(2+) level within cells. Though plant Ca(2+)ATPases have been shown to be involved in plant stress responses but their promoter regions have not been well studied. The 1478 bp promoter sequence of rice plasma membrane Ca(2+)ATPase contains cis-acting elements responsive to stresses and plant hormones. To identify the functional region, serial deletions of the promoter were fused with the GUS sequence and four constructs were obtained. These were differentially activated under NaCl, PEG cold, methyl viologen, abscisic acid and methyl jasmonate treatments. We demonstrated that the rice plasma membrane Ca(2+)ATPase promoter is responsible for vascular-specific and multiple stress-inducible gene expression. Only full-length promoter showed specific GUS expression under stress conditions in floral parts. High GUS activity was observed in roots with all the promoter constructs. The -1478 to -886 bp flanking region responded well upon treatment with salt and drought. Only the full-length promoter presented cold-induced GUS expression in leaves, while in shoots slight expression was observed for -1210 and -886 bp flanking region. The -1210 bp deletion significantly responded to exogenous methyl viologen and abscisic acid induction. The -1210 and -886 bp flanking region resulted in increased GUS activity in leaves under methyl jasmonate treatments, whereas in shoots the -886 bp and -519 bp deletion gave higher expression. Salicylic acid failed to induce GUS activities in leaves for all the constructs. The rice plasma membrane Ca(2+)ATPase promoter is a reproductive organ-specific as well as vascular-specific. This promoter contains drought, salt, cold, methyl viologen, abscisic acid and methyl jasmonate related cis-elements, which regulated gene expression. Overall, the tissue-specificity and inducible nature of this promoter could grant wide applicability in plant biotechnology.


[Calorimetric studies of the effect of amino acid replacements 16Gln-Leu and 26Tyr-Asp on the structural organization and stability of the Cro-repressor from phage lambda].
The scanning calorimetry technique has been used to study the influence of amino acid substitutions on thermodynamic parameters of formation and stabilization of a cooperative structure of Cro repressor of bacteriophage lambda molecule. It is shown that substitutions 16Gln-Leu and 26Tyr-Asp enhances the protein molecule stability by 32 degrees C as compared with the wild-type protein. It is also demonstrated that the denaturation enthalpy of the mutated Cro differs slightly from that of the wild-type protein at the same temperature, while the effective enthalpy value is significantly lower. The analysis of excess heat capacity of the mutated protein shows that this complex function determined experimentally is approximated by two functions, which is indicative of the presence of two quasi-independent transitions. Thus, the stabilization and redistribution of intermolecular interactions evoked by the above substitutions leads to disintegration of the single cooperative repressor molecule in two interacting cooperative domains. The plausible mechanism of formation of such a domain structure is discussed on the basis of the available calorimetric data.


Marinimicrobium alkaliphilum sp. nov., an alkaliphilic bacterium isolated from soil and emended description of the genus Marinimicrobium.
Two Gram-stain-negative, rod-shaped bacterial strains, designated SW121T and W12, were isolated from a soil sample collected from Shanxi Province, China. The two strains were strictly aerobic, catalase-positive and oxidase-positive. Both strains grew at 6-42 °C (optimum, 30 °C), at pH 5.5-11.0 (optimum, pH 9.0) and in the presence of 0-15.0 % (w/v) NaCl (optimum, 2.0-3.0 %). The predominant cellular fatty acids of strain SW121T were C16 : 0, C18 : 1ω7c and summed feature 3 (comprising C16 : 1ω7c and/or C16 : 1ω6c). Strain SW121T contained ubiquinone-8 as the sole respiratory quinone. Diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol were major polar lipids. The genomic DNA G+C content of strain SW121T was 58.5 mol%. Comparative analysis of 16S rRNA gene sequences revealed that strains SW121T and W12 showed the highest similarities to Marinimicrobium koreense DSM 16974T(95.7 and 95.5 %, respectively). On the basis of phylogenetic inference and phenotypic characteristics, it is proposed that the two strains represent a novel species of the genus Marinimicrobium, for which the name Marinimicrobiumalkaliphilum sp. nov. is proposed. The type strain is SW121T (=CGMCC 1.16166T=KCTC 62651T).


Portable Medical Suction and Aspirator Devices: Are the Design and Performance Standards Relevant?
Airway clearance refers to the clearing of any airway blockage caused due to foreign objects such as mud, gravel, and biomaterials such as blood, vomit, or teeth fragments using the technology of choice, portable suction devices. Currently available devices are either too heavy and bulky to be carried, or insufficiently powered to be useful despite being in accordance with the ISO 10079-1 standards. When applied to portable suction, the design and testing standards lack clinical relevancy, which is evidenced by how available portable suction devices are sparingly used in pre-hospital situations. Lack of clinical relevancy despite being in accordance with design/manufacturing standards arise due to little if any collaboration between those developing clinical standards and the bodies that maintain design and manufacturing standards. An updated set of standards is required that accurately reflects evidence-based requirements and specifications, which should promote valid, rational, and relevant engineering designs and manufacturing standards in consideration of the unique scenarios facing prehospital casualty care. This paper aims to critically review the existing standards for portable suction devices and propose modifications based on the evidence and requirements, especially for civilian prehospital and combat casualty care situations.


The influence of postoperative lymph node radiation therapy on overall survival of patients with stage III melanoma, a National Cancer Database analysis.
Recently, TROG 02.01 results showed that in stage III melanoma patients with nodal metastasis, adjuvant radiation to lymph node basin after nodal dissection improves lymph node field relapse without an overall survival (OS) benefit. However, this trial was neither designed nor powered to detect an OS difference. In the present study, we analyzed patients in the National Cancer Database (NCDB) with stage III melanoma with pathologically involved nodes and compared survival outcomes of adjuvant radiation and no-radiation cohorts. Inclusion criteria were as follows: age at least 18 years; diagnosed 2003-2011; surgery to regional lymph nodes; pathologically involved lymph nodes; and American Joint Committee on Cancer stage (IIIA-C). We used propensity score matching analysis to compare the OS of patients with similar baseline demographic, clinical, and pathologic characteristics who received adjuvant radiation and no adjuvant radiation. Overall, 912 patients were analyzed with an average age at diagnosis of 54.4 years and a median follow-up time of 5.5 years. In this cohort, the 5-year OS was 69.0, 51.1, and 30.6% for stage IIIA, IIIB, and IIIC, respectively. On propensity score-adjusted multivariate analysis, we found that adjuvant radiation had no statistically significant impact on OS (hazard ratio: 1.09, 95% confidence interval: 0.75-1.58, P=0.640). Furthermore, age older than 60 years, number of nodes, increasing pathologic stage, and absence of immunotherapy correlated with worse OS. In this NCDB analysis, we found that the adjuvant radiotherapy for node-positive, stage III melanoma patients did not improve OS. This is consistent with TROG 02.01; however, there may be patient selection bias not accounted for by the NCDB.


[Modern principles of prevention of human transmitted infections].
According to information about ecology of agents of parasitic diseases with lousy-flea mechanism of contamination, mite natural diseases and experience of battle with them, we can make a conclusion: elimination of spongers in their natural environment, lousies and fleas by washing and disinfection is not effective. Alternative is implementation of insectoacaricides of new class, based on permethrins. These insectoacaricides are secure for environment and very effective towards arthopods. Method of non-termal preventing suction of arthopods is probed in military practice and other treatment-prophylaxis institutes. It is proposed to implement new insectoacaricides in form of spray cans as part of individual contrebiological drug-locker of every service man, acting in difficult epidemiological situation, caused by virus threat of lousy or flea infection, or by beforehanded provision by impregnated uniform or clothes.


Altered TERT promoter and other genomic regulatory elements: occurrence and impact.
Study of genetic alterations, inherited or acquired, that increase the risk or drive cancers and many other diseases had remained mostly confined to coding sequences of the human genome. Data from genome wide associations studies, development of the Encyclopedia of DNA Elements (ENCODE), and a spurt in detection of driver somatic mutations have shifted focus towards noncoding regions of the human genome. The majority of genetic variants robustly associated with cancers and other syndromes identified through genome wide studies are located within noncoding regulatory regions of the genome. Genome wide techniques have put an emphasis on the role of three-dimensional chromosomal structures and cis-acting elements in regulations of different genes. The variants within noncoding genomic regions can potentially alter a number of regulatory elements including promoters, enhancers, insulators, noncoding long RNAs and others that affect cancers and various diseases through altered expression of critical genes. With effect of genetic alterations within regulatory elements dependent on other partner molecules like transcription factors and histone marks, an understanding of such modifications can potentially identify extended therapeutic targets. That concept has been augmented by the detection of driver somatic noncoding mutations within the promoter region of the telomerase reverse transcriptase (TERT) gene in different cancers. The acquired somatic noncoding mutations within different regulatory elements are now being reported in different cancers with an increased regularity. In this review we discuss the occurrence and impact of germline and somatic alterations within the TERT promoter and other genomic regulatory elements.


Cell death classification: A new insight based on molecular mechanisms.
Cells tend to disintegrate themselves or are forced to undergo such destructive processes in critical circumstances. This complex cellular function necessitates various mechanisms and molecular pathways in order to be executed. The very nature of cell death is essentially important and vital for maintaining homeostasis, thus any type of disturbing occurrence might lead to different sorts of diseases and dysfunctions. Cell death has various modalities and yet, every now and then, a new type of this elegant procedure gets to be discovered. The diversity of cell death compels the need for a universal organizing system in order to facilitate further studies, therapeutic strategies and the invention of new methods of research. Considering all that, we attempted to review most of the known cell death mechanisms and sort them all into one arranging system that operates under a simple but subtle decision-making (If \ Else) order as a sorting algorithm, in which it decides to place and sort an input data (a type of cell death) into its proper set, then a subset and finally a group of cell death. By proposing this algorithm, the authors hope it may solve the problems regarding newer and/or undiscovered types of cell death and facilitate research and therapeutic applications of cell death.


A new approach for determination of the selectively favoured kinetic design of enzyme reactions.
A new criterion is applied for characterization of the kinetic design of enzymes that should be favoured by a selective pressure in the direction of increased metabolic reaction flux. According to this criterion, the selectively favoured state of a metabolic sequence of enzyme reactions conforming to Michaelis-Menten kinetics is identical with the uniform one which is known to optimize reaction flux for a given average magnitude of enzyme concentrations and of true and apparent first-order rate constants in the reaction system. It is argued that presently observed values of on-velocity constants for metabolite binding to enzymes are unlikely to represent the upper limit for diffusion-controlled association process and are more likely to represent those corresponding to the selectively favoured kinetic design at the present stage of the evolutionary development of enzyme function.


Non-linear changes of electrocortical activity after antenatal betamethasone treatment in fetal sheep.
We determined the effects of betamethasone on the fetal sheep electrocorticogram (ECoG) using linear (power spectral) and non-linear analysis. For non-linear analysis we used an algorithm based on the Wolf algorithm for the estimation of the leading Lyapunov exponent which calculates a prediction error based on the course of the time series in the phase space. A high prediction error stands for low predictibility or low regularity and vice versa. After 48 h of baseline recordings, vehicle (n = 6) or betamethasone (n = 7) at 10 microg h(-1) was infused over 48 h to the sheep fetus at 128 days gestational age (0.87 of gestation). ECoG spectral analysis revealed no difference in power spectrum between vehicle- and betamethasone-treated fetuses. The prediction error of the ECoG during REM sleep was higher than during non-REM or quiet sleep in both groups (P < 0.0001) revealing lower causality of brain activity during REM sleep. During REM sleep, prediction error significantly decreased 18-24 h after onset of betamethasone treatment (P < 0.05) and returned to baseline values within the following 24 h of continued betamethasone treatment. No ECoG changes were found during quiet sleep. Non-linear ECoG changes during metabolically active REM sleep accompanied the previously described decrease in cerebral blood flow. These results suggest that betamethasone in doses used in perinatal medicine acutely alters complex neuronal activity.


Micro x-ray fluorescence analysis of trace element distribution in frozen hydrated HeLa cells at the P06 beamline at Petra III.
X-ray fluorescence analysis enables the study of trace element distributions in biological specimens. When this analysis is done under cryogenic conditions, cells are cryofixed as closely as possible to their natural physiological state, and the corresponding intracellular elemental densities can be analyzed. Details about the experimental setup used for analysis at the P06 beamline at Petra III, DESY and the used cryo-transfer system are described in this work. The system was applied to analyze the elemental distribution in single HeLa cells, a cell line frequently used in a wide range of biological applications. Cells adhered to silicon nitride substrates were cryoprotected within an amorphous ice matrix. Using a continuous scanning scheme and a KB x-ray focus, the distribution of elements in the cells was studied. We were able to image the intracellular potassium and zinc levels in HeLa cells as two key elements relevant for the physiology of cells.


Parental perceptions of the psychological adjustment of children with diabetes and their siblings.
This study examined the psychological adjustment of children with diabetes and their siblings. Data were collected for 41 diabetic children and their siblings between ages 6 and 11 yr who were followed in a large pediatric practice. The diabetic group was matched with 35 control children who were followed for routine pediatric care and their siblings. Diabetic families and the controls did not differ on divorce rate or level of marital adjustment. Behavior problems were measured through the use of the Achenbach Behavior Checklist for both sexes separately at the 6-11- and 12-16-yr-old age levels. Diabetic boys, aged 6-11 yr, were higher than nondiabetic boys on internalizing and externalizing symptom scales, particularly on measures of schizoid tendencies, obsessive compulsive symptoms, hyperactivity, and aggression. Neither female patients, male siblings, nor female siblings in the 6-11-yr-old age group differed from controls on emotional adjustment. Among the 12-16-yr-old males, diabetic patients were higher on internalizing symptoms than male siblings and their controls. Male siblings tended to be lower than diabetic patients and controls on school performance. Social class differences may have contributed to the differences at the 12-16-yr age levels. Female subjects in the 12-16-yr-old group did not differ on measures of adjustment. Level of control was unrelated to patients' or siblings' adjustment, but behavioral symptoms tended to increase for male diabetic patients with length of illness, and tended to decrease for male siblings. Results are interpreted according to social class effects and sex differences.


Detecting Changes in the Caenorhabditis elegans Intestinal Environment Using an Engineered Bacterial Biosensor.
Caenorhabditis elegans has become a key model organism within biology. In particular, the transparent gut, rapid growing time, and ability to create a defined gut microbiota make it an ideal candidate organism for understanding and engineering the host microbiota. Here we present the development of an experimental model that can be used to characterize whole-cell bacterial biosensors in vivo. A dual-plasmid sensor system responding to isopropyl β-d-1-thiogalactopyranoside was developed and fully characterized in vitro. Subsequently, we show that the sensor was capable of detecting and reporting on changes in the intestinal environment of C. elegans after introducing an exogenous inducer into the environment. The protocols presented here may be used to aid the rational design of engineered bacterial circuits, primarily for diagnostic applications. In addition, the model system may serve to reduce the use of current animal models and aid in the exploration of complex questions within general nematode and host-microbe biology.


Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis.
Notch signaling plays an important role in cell-fate specification in multicellular organisms by regulating cell-cell communication. The Drosophila deltex gene encodes a modulator of the Notch pathway that has been shown to interact physically with the Ankyrin repeats of Notch. We isolated four distinct cDNAs corresponding to mouse homologs of deltex - mouse Deltex1 (MDTX1), mouse Deltex2 (MDTX2), mouse Deltex2DeltaE (MDTX2DeltaE), and mouse Deltex3 (MDTX3). Deduced amino acid sequences of these four cDNAs showed a high degree of similarity to Drosophila Deltex and its human homolog, DTX1 throughout their lengths, even though they possess distinct structural features. MDTX proteins formed homotypic and heterotypic multimers. We found that these genes were expressed in the central, peripheral nervous system and in the thymus, overlapping with those of mouse Notch1. In mammalian tissue culture cells, overexpression of any of the four mouse deltex homologs suppressed the transcriptional activity of E47, a basic helix-loop-helix (bHLH) protein, in a manner similar to suppression by an activated form of human Notch1 or human DTX1. In addition, overexpression of MDTX2 and MDTX2DeltaE in C2C12 cells under differentiation-inducing conditions suppressed the expression of myogenin, one of the myogenic transcriptional factors; this was also similar to a previously reported activity of constitutively activated Notch. Furthermore, misexpression of any of the MDTX genes in Xenopus embryos resulted in an expansion of the region expressing the neural cell adhesion molecule (N-CAM) gene, a marker for the neuroepithelium. Collectively, our results suggest that these mouse deltex homologs are involved in vertebrate Notch signaling and regulation of neurogenesis.


Regeneration of myelin sheaths of normal length and thickness in the zebrafish CNS correlates with growth of axons in caliber.
Demyelination is observed in numerous diseases of the central nervous system, including multiple sclerosis (MS). However, the endogenous regenerative process of remyelination can replace myelin lost in disease, and in various animal models. Unfortunately, the process of remyelination often fails, particularly with ageing. Even when remyelination occurs, it is characterised by the regeneration of myelin sheaths that are abnormally thin and short. This imperfect remyelination is likely to have implications for the restoration of normal circuit function and possibly the optimal metabolic support of axons. Here we describe a larval zebrafish model of demyelination and remyelination. We employ a drug-inducible cell ablation system with which we can consistently ablate 2/3rds of oligodendrocytes in the larval zebrafish spinal cord. This leads to a concomitant demyelination of 2/3rds of axons in the spinal cord, and an innate immune response over the same time period. We find restoration of the normal number of oligodendrocytes and robust remyelination approximately two weeks after induction of cell ablation, whereby myelinated axon number is restored to control levels. Remarkably, we find that myelin sheaths of normal length and thickness are regenerated during this time. Interestingly, we find that axons grow significantly in caliber during this period of remyelination. This suggests the possibility that the active growth of axons may stimulate the regeneration of myelin sheaths of normal dimensions.


Delayed insulin transport across endothelium in insulin-resistant JCR:LA-cp rats.
Capillary endothelial cells are thought to limit the transport of insulin across the endothelium, resulting in attenuated insulin action at target sites. Whether endothelial insulin transport is altered in dysglycemic insulin-resistant states is not clear and was therefore investigated in the JCR:LA-cp corpulent male rat, which exhibits the metabolic syndrome of obesity, insulin resistance, hyperlipidemia, and hyperinsulinemia. Lean littermates that did not develop these alterations served as controls. Animals of both groups were normotensive (mean arterial pressure 136+/-2 mmHg). Hearts from obese and lean rats aged 7 (n = 6) or 18 (n = 8) weeks were perfused in vitro at 10 ml/min per gram wet wt over 51 min with Krebs-Henseleit buffer containing 0.1 or 0.5 U human insulin/l (equivalent to 0.6 and 3 nmol/l). Interstitial fluid was collected using a validated method, and interstitial insulin was determined with a radioimmunoassay. At 0.1 U/l, insulin transfer velocity was similar in both experimental groups (half-times of transfer: 11+/-0.2 min in obese and 18+/-4 min in lean rats; NS), but at 0.5 U/l, the respective half-times were 7+/-1 min in lean and 13+/-2 min in obese rats (P < 0.05). The steady-state level of insulin in the interstitium was 34+/-1% of the vascular level at 0.1 U/l and reached the vascular level (102+/-2%) at 0.5 U/l in both lean and obese rats. In rats aged 18 weeks, the half-times of insulin transfer were 31+/-2 and 14+/-l min in obese rats and 10+/-0.3 and 7+/-0.3 min in lean rats (P < 0.05). Again, interstitial steady-state levels were similar in both groups. Finally, postprandial insulin dynamics were simulated over a period of 120 min with a peak concentration of 0.8 U/l in rats aged 27 weeks (n = 4). The maximal interstitial level was 0.38+/-0.02 U/l in lean rats and 0.24+/-0.02 U/l in obese rats (P < 0.05), and a similar difference was noted throughout insulin infusion (areas under the transudate concentration-time curves: 17 and 11 U/min per 1, respectively). These data show, for the first time in a genetic animal model of insulin resistance, that transfer of insulin across the endothelium is substantially delayed in obese insulin-resistant rats and that it likely contributes to the postprandial alterations of glucose metabolism observed in the metabolic syndrome.


Effect of cytoarchitecture on the transport and localization of protein synthetic machinery.
The emerging picture of cytoarchitecture imposes constraints on the transport and localization of several components of the protein synthetic machinery. The range in which "free" polysomes can diffuse through the cytoplasm may be restricted to about 50 nm due to obstruction by cytoskeletal barriers. Individual ribosomes and large transcripts will diffuse at least 4-10 times slower in cytoplasm than in dilute aqueous solution and may be sterically excluded from some cytoplasmic domains. The transport of these components from the nucleus to the cell periphery may be restricted to microtubule-containing channels that traverse the excluding domains. In the peripheral cytoplasm, mitochondria, endoplasmic reticulum, and other membrane-bound organelles are found only in nonexcluding channels, while actin, nonmuscle filamin (ABP280), and fodrin are concentrated in excluding domains. This suggests that the cytoplasmic volume may be functionally compartmentalized by local differentiations of cytoarchitecture. Excluding compartments may play a structural role, while nonexcluding compartments are the site of vesicle traffic and protein synthesis.


Complexity As Key to Designing Cognitive-Friendly Environments for Older People.
The lived environment is the arena where our cognitive skills, preferences, and attitudes come together to determine our ability to interact with the world. The mechanisms through which lived environments can benefit cognitive health in older age are yet to be fully understood. The existing literature suggests that environments which are perceived as stimulating, usable and aesthetically appealing can improve or facilitate cognitive performance both in young and older age. Importantly, optimal stimulation for cognition seems to depend on experiencing sufficiently stimulating environments while not too challenging. Environmental complexity is an important contributor to determining whether an environment provides such an optimal stimulation. The present paper reviews a selection of studies which have explored complexity in relation to perceptual load, environmental preference and perceived usability to propose a framework which explores direct and indirect environmental influences on cognition, and to understand these influences in relation to aging processes. We identify ways to define complexity at different environmental scales, going from micro low-level perceptual features of scenes, to design qualities of proximal environments (e.g., streets, neighborhoods), to broad geographical areas (i.e., natural vs. urban environments). We propose that studying complexity at these different scales will provide new insight into the design of cognitive-friendly environments.


Comparison of three purse-string suture techniques for prevention of anal leakage during surgery.
To compare 3 anal purse-string suture techniques for resistance to leakage and to identify the suture technique requiring the fewest tissue bites to create a consistent leak-proof orifice closure. 18 large-breed canine cadavers. 3 purse-string suture techniques (3 bites with 0.5 cm between bites [technique A], 5 bites with 0.5 cm between bites [technique B], and 3 bites with 1.0 cm between bites [technique C]) were evaluated. Each technique involved 2-0 monofilament nylon suture that was placed in the cutaneous tissue around the anus and knotted with 6 square throws. Standardized 2.0-cm-diameter circular templates with the designated bite number and spacing indicated were used for suture placement. Leak-pressure testing was performed, and the pressure at which saline was first observed leaking from the anus was recorded. The median and interquartile (25th to 75th percentile) range (IQR) were compared among 3 techniques. Median leak pressure for technique A (101 mm Hg; IQR, 35 to 131.3 mm Hg) was significantly greater than that for technique C (19 mm Hg; IQR, 14.3 to 25.3 mm Hg). Median pressure did not differ between techniques A and B (50 mm Hg; IQR, 32.5 to 65 mm Hg) or between techniques B and C. Placement of an anal purse-string suture prevented leakage at physiologic colonic and rectal pressures, regardless of technique. Placement of 3 bites 0.5 cm apart (technique A) is recommended because it used the fewest number of bites and had the highest resistance to leakage.


Molecular Dynamics Simulations for Loading-Dependent Diffusion of CO2, SO2, CH4, and Their Binary Mixtures in ZIF-10: The Role of Hydrogen Bond.
The loading-dependent diffusion behavior of CH4, CO2, SO2, and their binary mixtures in ZIF-10 has been investigated in detail by using classical molecular dynamics simulations. Our simulation results demonstrate that the self-diffusion coefficient Di of CH4 molecules decreases sharply and monotonically with the loading while those of both CO2 and SO2 molecules initially display a slight increase at low uptakes and follow a slow decrease at high uptakes. Accordingly, the interaction energies between CH4 molecules and ZIF-10 remain nearly constant regardless of the loading due to the absence of hydrogen bonds (HBs), while the interaction energies between CO2 (or SO2) and ZIF-10 decease rapidly with the loading, especially at small amounts of gas molecules. Such different loading-dependent diffusion and interaction mechanisms can be attributed to the relevant HB behavior between gas molecules and ZIF-10. At low loadings, both the number and strength of HBs between CO2 (or SO2) molecules and ZIF-10 decrease obviously as the loading increases, which is responsible for the slight increase of their diffusion coefficients. However, at high loadings, their HB strength increases with the loading. Similar loading-dependent phenomena of diffusion, interaction, and HB behavior can be observed for CH4, CO2, and SO2 binary mixtures in ZIF-10, only associated with some HB competition between CO2 and SO2 molecules in the case of the CO2/SO2 mixture.


Coping Strategies and Social Support in a Mobile Phone Chat App Designed to Support Smoking Cessation: Qualitative Analysis.
Smoking is one of the most significant factors contributing to low life expectancy, health inequalities, and illness at the worldwide scale. Smoking cessation attempts benefit from social support. Mobile phones have changed the way we communicate through the use of freely available message-oriented apps. Mobile app-based interventions for smoking cessation programs can provide interactive, supportive, and individually tailored interventions. This study aimed to identify emotions, coping strategies, beliefs, values, and cognitive evaluations of smokers who are in the process of quitting, and to analyze online social support provided through the analysis of messages posted to a chat function integrated into a mobile app. In this descriptive qualitative study, informants were smokers who participated in the chat of Tobbstop. The technique to generate information was documentary through messages collected from September 2014 through June 2016, specifically designed to support a smoking cessation intervention. A thematic content analysis of the messages applied 2 conceptual models: the Lazarus and Folkman model to assess participant's experiences and perceptions and the Cutrona model to evaluate online social support. During the study period, 11,788 text messages were posted to the chat by 101 users. The most frequent messages offered information and emotional support, and all the basic emotions were reported in the chat. The 3 most frequent coping strategies identified were physical activity, different types of treatment such as nicotine replacement, and humor. Beliefs about quitting smoking included the inevitability of weight gain and the notion that not using any type of medications is better for smoking cessation. Health and family were the values more frequently described, followed by freedom. A smoke-free environment was perceived as important to successful smoking cessation. The social support group that was developed with the app offered mainly emotional and informational support. Our analysis suggests that a chat integrated into a mobile app focused on supporting smoking cessation provides a useful tool for smokers who are in the process of quitting, by offering social support and a space to share concerns, information, or strategies.


Ovulation, in vivo emotion regulation problems, and sexual risk recognition deficits.
To examine associations between menstrual cycle phase, negative mood, sexual risk recognition deficits (assessed via an analogue risk vignette), and in vivo emotion dysregulation. Participants were 714 college women recruited between February 2007 and December 2009. Participants were randomly assigned to a negative or neutral mood induction and instructed to identify sexual risk during an audiotaped sexual coercion vignette. Participants reported menstrual cycle information, in vivo emotional nonacceptance, and attention during the vignette. In the negative mood condition, ovulation was associated with longer risk recognition latencies relative to the luteal and follicular phases of the menstrual cycle. Increased in vivo emotional nonacceptance and decreased attention to the vignette mediated associations between ovulation and risk recognition deficits in the negative mood condition. Sexual assault risk reduction programs could provide psychoeducation regarding negative mood during ovulation and emphasize emotional acceptance and attention to external stimuli when distressed.


Insights into the consequences of co-polymerisation in the early stages of IAPP and Aβ peptide assembly from mass spectrometry.
The precise molecular mechanisms by which different peptides and proteins assemble into highly ordered amyloid deposits remain elusive. The fibrillation of human amylin (also known as islet amyloid polypeptide, hIAPP) and the amyloid-beta peptide (Aβ-40) are thought to be pathogenic factors in Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD), respectively. Amyloid diseases may involve co-aggregation of different protein species, in addition to the self-assembly of single precursor sequences. Here we investigate the formation of heterogeneous pre-fibrillar, oligomeric species produced by the co-incubation of hIAPP and Aβ-40 using electrospray ionisation-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS)-based methods. Conformational properties and gas-phase stabilities of amyloid oligomers formed from hIAPP or Aβ40 alone, and from a 1 : 1 mixture of hIAPP and Aβ40 monomers, were determined and compared. We show that co-assembly of the two sequences results in hetero-oligomers with distinct properties and aggregation kinetics properties compared with the homo-oligomers present in solution. The observations may be of key significance to unravelling the mechanisms of amyloid formation in vivo and elucidating how different sequences and/or assembly conditions can result in different fibril structures and/or pathogenic outcomes.


Single-stage management of choledocholithiasis: intraoperative ERCP versus laparoscopic common bile duct exploration.
Laparoscopic cholecystectomy (LC) is the criterion standard for treating patients with symptomatic gallstone disease; however, the optimal technique for extracting common bile duct stones remains unclear. Recent studies have noted improved outcomes with single-stage techniques, such as intraoperative endoscopic retrograde cholangiopancreatography (iERCP) and laparoscopic common bile duct exploration (LCBDE); however only few studies have directly compared those two single-stage techniques. Using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database, we retrospectively analyzed the postoperative outcomes of all patients who underwent single-stage LC for choledocholithiasis from 2005 to 2017. Using Current Procedural Terminology (CPT) codes, as well as International Classification of Diseases, Ninth Revision (ICD-9) and 10th Revision (ICD-10) codes, we stratified patients into two cohorts: those who underwent iERCP and LCBDE. Applying univariate techniques, we evaluated baseline characteristics and postoperative outcomes for both cohorts. Our primary outcomes of interest were 30-day morbidity and 30-day mortality; our secondary outcomes included rates of reoperation, readmission, operative time, and hospital length of stay. Of the 1814 single-stage LC patients during our 13-year study period, 1185 (65.3%) underwent LCBDE; 629 (34.6%) underwent iERCP. Our univariate analysis showed that the two cohorts were homogeneous in terms of baseline characteristics, including demographics, preoperative comorbidities, laboratory values, and American Society of Anesthesiologists (ASA) scores. 30-day postoperative morbidity (including infectious and noninfectious complications) and overall mortality between groups were low and comparable. The mean operative time was slightly longer with LCBDE (125.1 ± 62.0 min) than iERCP (113.5 ± 65.2 min; P < 0.001), however the mean hospital length of stay, readmission rate, and reoperation rate were similar. We found that both iERCP and LCBDE resulted in low, comparable rates of morbidity and mortality. Centers with readily available endoscopic expertise might favor iERCP for its ease of access and shorter operative time. However, LCBDE remains an appropriate technique for patients with choledocholithiasis, especially when immediate endoscopic intervention is unavailable.


A reliable and efficient first principles-based method for predicting pK(a) values. 1. Methodology.
We have developed an efficient and reliable protocol for the calculation of pK(a) values in aqueous solution from density functional calculations. We establish a standard linear regression fit using only calculated energies of deprotonation and experimental pK(a) values; all other factors, including most entropic effects, are absorbed into the fitting constants. In this article we fit a small training set of 34 experimentally well-characterized molecules to determine the best level of theory among those tested (i.e., the optimum compromise between efficiency and accuracy for the basis set, the exchange-correlation functional, the (continuum) solvation model and the level of geometry optimization). Our main findings are that a relatively modest basis set (6-311+G**) suffices for the calculation of the energy differences, with an even small basis set (3-21G*) sufficient for the preceding geometry optimization. Using a solvation model (COSMO in our case) throughout is essential to achieve reliable results. The exchange-correlation functional plays only a modest role; in particular, pure DFT functionals that allow the efficient calculation of the Coulomb term are perfectly adequate. The final protocol will be applied subsequently to data sets much larger than commonly used in such studies.


1H NMR study of the binding of bis(acridines) to d(AT)5.d(AT)5. 2. Dynamic aspects.
Measurements of the 1H NMR spectra and relaxation rates were used to study the dynamic properties of 9-aminoacridine (9AA) and four bis(acridine) complexes with d(AT)5.d(AT)5. The behavior of the 9AA (monointercalator) and that of C8 (bisintercalator containing an eight-carbon atom linker chain) are entirely similar. For both compounds, the lifetime of the drug in a particular binding site is 2-3 ms at approximately 20 degrees C, and neither affects the A.T base pair opening rates. The complex with C10 (bisintercalator containing a 10-carbon atom linker chain) is slightly more stable than the C8 complex since its estimated binding site lifetime is 5-10 ms at 29 degrees C. Base pairs adjacent to the bound C10 are destabilized, relative to free d(AT)5.d(AT)5, but other base pairs in the C10 complex are little affected. Bis(acridine) pyrazole (BAPY) and bis(acridine) spermine (BAS) considerably stabilize those base pairs that are sandwiched between the two acridine chromophores, but in the BAS complex proton exchange from the two flanking base pairs appears to be accelerated, relative to free d(AT)5.d(AT)5. The lifetime of these drugs in specific binding sites is too long (>10 ms) to be manifested in increased line widths, at least up to 41 degrees C. An important conclusion from this study is that certain bisintercalators rapidly migrate along DNA, despite having large binding constants (K>10(6) M-1). For C8 and C10 complexes, migration rates are little different from those deduced for 9AA. The rigid linker chain in BAPY and the charge interactions in BAS retard migration of these two bisintercalators. These results provide new parameters that are useful in understanding the biochemical and biological properties of these and other bisintercalating drugs.


Extracorporeal Pringle for laparoscopic liver resection.
A primary concern during laparoscopic liver resection (lapLR) is hemorrhage during parenchymal transection. Intermittent pedicle clamping is an effective method to minimize blood loss during open liver surgery; however, inflow occlusion techniques are challenging to reproduce during laparoscopy. The purpose of this study is to describe the safety and efficacy of a facile method for Pringle maneuver during lapLR. 154 patients who underwent lapLR from 2007 to 2013 were retrospectively reviewed. For Pringle, the hepatoduodenal ligament is encircled with an umbilical tape which is externalized through a flexible Rumel tourniquet running alongside a port used for the operation. The internal end of the catheter is close to the pedicle and the external end is extracorporeal, allowing for easy external occlusion. Patients who underwent Pringle Maneuver (PM, n = 88) were compared to patients who had "No Occlusion" (NO, n = 66) with respect to patient characteristics, operative outcomes, changes in postoperative liver function, and complications. Annual placement of the tourniquet and vascular occlusion increased from 35.7 to 82.8 % (p = 0.004) and 21.4 to 62.1 % (p = 0.02), respectively. Median occlusion time was 24 min (IQR 15-34.3, min 5, max 70). Peak transaminase levels were comparable between groups (AST 298 ± 32 vs 405 ± 47 U/L, p = 0.15; ALT 272 ± 27 vs 372 ± 34 U/L, p = 0.14, NO and PM, respectively). Postoperative transaminase and bilirubin levels for both groups were not significantly different with similar recovery to baseline. Subgroup analysis of cirrhotic patients who underwent Pringle demonstrated similar transaminase profiles compared to non-cirrhotic patients. There were two conversions (1.3 %) and postoperative 30-day mortality was 0.65 %. Extracorporeal tourniquet placement in lapLR is a quick and safe method of gaining control for inflow occlusion. Routine adoption of laparoscopic Pringle maneuver facilitates low conversion rates without liver injury.


Prevalence of high-risk HPV types and abnormal cervical cytology in American Indian/Alaska Native women, 2003-2005.
OBJECTIVES; We described prevalence estimates of high-risk human papillomavirus (HR-HPV), HPV types 16 and 18, and abnormal Papanicolaou (Pap) smear tests among American Indian/Alaska Native (AI/AN) women compared with women of other races/ethnicities. A total of 9,706 women presenting for cervical screening in a sentinel network of 26 clinics (sexually transmitted disease, family planning, and primary care) received Pap smears and HR-HPV type-specific testing. We compared characteristics of 291 women self-identified as AI/AN with other racial/ethnic minority groups. In our population, AI/AN and non-Hispanic white (NHW) women had similar age- and clinic-adjusted prevalences of HR-HPV (29.1%, 95% confidence interval [CI] 23.9, 34.3 for AI/AN women vs. 25.8%, 95% CI 24.4, 27.2 for NHW women), HPV 16 and 18 (6.7%, 95% CI 3.9, 9.6 for AI/AN women vs. 8.8%, 95% CI 7.9, 9.7 for NHW women), and abnormal Pap smear test results (16%, 95% CI 11.7, 20.3 for AI/AN women vs. 14.9%, 95% CI 13.7, 16.0 for NHW women). AI/AN women had a higher prevalence of HR-HPV than Hispanic women, and a similar prevalence of HPV 16 and 18 as compared with Hispanic and African American women. We could not demonstrate differences in the prevalence of HR-HPV, HPV 16 and 18, or abnormal Pap smear test results between AI/AN and NHW women. This finding should improve confidence in the benefit of HPV vaccine and Pap smear screening in the AI/AN population as an effective strategy to reduce rates of cervical cancer.


Slow continuous dilatation of oesophageal strictures using the Didcott dilator, with reference to its wider use.
Acute dilatation or bouginage of strictures gives only temporary relief, and slow continuous dilatation was therefore tried and found to give superior results in treating benign and malignant strictures, particularly of the oesophagus. Slow stretch methods are discussed and compared with other methods. Methods are described that were evolved for dilating both by the 'acute' and slow-continuous methods, including use of the Didcott dilator (DD), invented in 1956. For oesophageal cancer this, combined with brachytherapy, has resulted in increased longevity and quality of life. Mortality from the dilatation and introduction of a DD for a week, followed by its removal without anaesthesia, is less than 2%. Relief of dysphagia lasts 2-10 months. Thereafter the procedure can be repeated and finally, when the patient is obviously near-terminal, a permanent indwelling stent can be used. This can be a modified DD stent or a Livingstone or Celestin tube. These are also used in tracheo-oesophageal fistulas. Complete cure is often possible in benign strictures, especially if short.


Novel pipeline identifies new upstream ORFs and non-AUG initiating main ORFs with conserved amino acid sequences in the 5' leader of mRNAs in Arabidopsis thaliana.
Eukaryotic mRNAs contain a 5' leader sequence preceding the main open reading frame (mORF) and, depending on the species, 20%-50% of eukaryotic mRNAs harbor an upstream ORF (uORF) in the 5' leader. An unknown fraction of these uORFs encode sequence conserved peptides (conserved peptide uORFs, CPuORFs). Experimentally validated CPuORFs demonstrated to regulate the translation of downstream mORFs often do so in a metabolite concentration-dependent manner. Previous research has shown that most CPuORFs possess a start codon context suboptimal for translation initiation, which turns out to be favorable for translational regulation. The suboptimal initiation context may even include non-AUG start codons, which makes CPuORFs hard to predict. For this reason, we developed a novel pipeline to identify CPuORFs unbiased of start codon using well-annotated sequence data from 31 eudicot plant species and rice. Our new pipeline was able to identify 29 novel Arabidopsis thaliana (Arabidopsis) CPuORFs, conserved across a wide variety of eudicot species of which 15 do not initiate with an AUG start codon. In addition to CPuORFs, the pipeline was able to find 14 conserved coding regions directly upstream and in frame with the mORF, which likely initiate translation on a non-AUG start codon. Altogether, our pipeline identified highly conserved coding regions in the 5' leaders of Arabidopsis transcripts, including in genes with proven functional importance such as LHY, a key regulator of the circadian clock, and the RAPTOR1 subunit of the target of rapamycin (TOR) kinase.


Are we fully utilizing the functionalities of modern operating room ventilators?
The modern operating room ventilators have become very sophisticated and many of their features are comparable with those of an ICU ventilator. To fully utilize the functionality of modern operating room ventilators, it is important for clinicians to understand in depth the working principle of these ventilators and their functionalities. Piston ventilators have the advantages of delivering accurate tidal volume and certain flow compensation functions. Turbine ventilators have great ability of flow compensation. Ventilation modes are mainly volume-based or pressure-based. Pressure-based ventilation modes provide better leak compensation than volume-based. The integration of advanced flow generation systems and ventilation modes of the modern operating room ventilators enables clinicians to provide both invasive and noninvasive ventilation in perioperative settings. Ventilator waveforms can be used for intraoperative neuromonitoring during cervical spine surgery. The increase in number of new features of modern operating room ventilators clearly creates the opportunity for clinicians to optimize ventilatory care. However, improving the quality of ventilator care relies on a complete understanding and correct use of these new features. VIDEO ABSTRACT: http://links.lww.com/COAN/A47.


Predictive value of tumor mutation burden (TMB) with targeted next-generation sequencing in immunocheckpoint inhibitors for non-small cell lung cancer (NSCLC).
Background: To evaluate the clinical predictive value of tumor mutation burden (TMB) for immune checkpoint inhibitor (ICI) therapy in patients with non-small cell lung cancer (NSCLC). Method: As of 15 February 2020, PubMed, PMC and EMBASE databases as well as the American society of clinical oncology (ASCO) and European society of medical oncology (ESMO) databases were searched. The Mantel-Haenszel or inverse variance weighted fixed-effects model (I2 ≤ 50%) or random-effects model (I2 > 50%) were used to evaluate OR and its 95% CI of objective response rate (ORR) and disease control rate (DCR) , as well as HR and its 95% CI of progression-free survival (PFS) and overall survival (OS). In addition, we did publication bias, heterogeneity analysis, sensitivity analysis and subgroup analysis. And quality of the studies included and the level of evidence for outcome measures were evaluated. Results: 14 studies involving 2872 patients were included. The ORR (OR 3.52, 95%CI 2.32-5.35, p < 0.00001), DCR (OR 3.26, 95%CI 1.91-5.55, p < 0.0001), PFS (HR 0.81, 95%CI 0.74-0.89, p < 0.00001) and OS (HR 0.83, 95%CI 0.74-0.94, p = 0.002) of ICI therapy in the high TMB group were all superior to those in the low TMB group. Conclusions: TMB is a promising biomarker, which can predict the efficacy of ICI therapy in advanced NSCLC patients, included ORR, DCR, PFS and OS.


Left Ventricle Hypertrophy, Dilatation and Ejection Fraction Changes Before and After Kidney Transplantation.
Patients with end stage renal disease (ESRD) are at risk of complications in different organs including cardiovascular system. Renal transplantation is the best choice in these patients which diminishes these complications. It is observed that after renal transplantation, cardiac parameters have appropriate improvement. Current study evaluates echocardiographic findings in renal transplant recipients before and after kidney transplantation. In an analytic cross sectional study, 30 patients (50% male, mean age of 45.57 ± 13.32 years) with ESRD who underwent renal transplantation were studied. All patients had echocardiographic studies after the last dialysis before and 6 months after transplantation. Echocardiographic study was done by Color Doppler two dimension methods and left ventricle ejection fraction was measured by Simpson method. All echocardiograms before and after transplantation were interpreted by the same cardiologist. Mean left ventricle ejection fraction before and after renal transplantation was 53.83±10.14% and 57.33±4.49%, respectively (P = 0.09). Left ventricle hypertrophy, mitral regurgitation and tricuspid regurgitation existed in 46.7%, 76.7% and 33.3% respectively, which was improved in 30%, 50% and 33.3% after renal transplantation. According to the results of current study it is suggested that renal transplantation could improve left ventricle parameters in patients with end stage renal disease.


Polarity of volume-regulatory increase by Necturus gallbladder epithelium.
Necturus gallbladder epithelial cells respond to the presence of a hypertonic perfusate in either bathing solution by first shrinking due to osmotic water loss and then swelling back to their original volume (volume-regulatory increase). Previous investigations involving increases in the osmolality of the mucosal bath had suggested that volume-regulatory increase was due to the activation of ion exchangers in the apical cell membrane. In the present study the sidedness of the transport processes involved in volume-regulatory increase was investigated. The osmolality of the serosal bath was increased by 18% either in the absence of HCO3- or when an inhibitor of volume-regulatory increase, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), was added to the mucosal or serosal bath. Volume regulation was HCO3- dependent. DIDS was only effective in inhibiting volume regulation when it was added to mucosal bathing solution, suggesting that volume-regulatory increase depended on transport across the apical membrane. Volume-regulatory increase could also be activated by first swelling the cells in hypotonic solution and then returning the tissue to control Ringer solution. The volume-regulatory increase that occurred upon return to control Ringer was also shown to be sensitive to DIDS in the mucosal bath.


Prevalence and Predictors of Multiple Coronary Plaque Ruptures: In Vivo 3-Vessel Optical Coherence Tomography Imaging Study.
Plaque rupture may be the local expression of a widespread coronary instability. This study aimed to investigate: (1) the prevalence and characteristics of nonculprit plaque rupture; (2) the pancoronary atherosclerotic phenotype in patients with and without nonculprit plaque rupture; and (3) the prevalence and predictors of multiple plaque ruptures. Six hundred and seventy-five nonculprit plaques from 261 patients (34 acute myocardial infarction, 73 unstable angina pectoris, and 154 stable angina pectoris) were analyzed by 3-vessel optical coherence tomography. Nonculprit plaque ruptures were identified in 51 patients (20%). Patients with nonculprit plaque ruptures had higher prevalence of thin-cap fibroatheroma (51% versus 13%; P<0.001) in the 3 major epicardial coronary vessels. Multiple plaque ruptures were observed in 20% of patients (38% acute myocardial infarction versus 10% unstable angina pectoris versus 19% stable angina pectoris; P=0.042). Thin-cap fibroatheroma, intimal vasculature, and macrophages were independent morphological predictors of multiple plaque ruptures, whereas acute myocardial infarction and chronic kidney disease were independent clinical predictors. Patients with nonculprit plaque ruptures showed higher 1-year rates of nontarget lesion revascularization (11.8% versus 4.4%; P=0.039). Nonculprit plaque ruptures were observed in 20% of patients with coronary artery disease and were associated with pancoronary vulnerability and higher 1-year revascularization rate.


Release of 3H2O from 1 beta,2 beta[3H]androstenedione by equine granulosa cells.
Granulosa cells were harvested from mares at various stages of the oestrous cycle and incubated in Krebs-Ringer bicarbonate buffer with 1 beta,2 beta[3H]androstenedione as substrate. The release of 3H2O expressed as CPM/h/mg protein varied from 44000 to 768000 in follicles from 7 mares. The release of 3H2O was not significantly altered by luteinizing hormone, follicle stimulating hormone or pregnant mare's serum gonadotrophin. There was a significant negative correlation between the release of 3H2O and the concentration of progesterone in the follicular fluid. Based on the assumption that the release of 3H2O represent total aromatization, these data suggest that the equine granulosa cells have a very active aromatizing enzyme system.