The nutrient density approach to healthy eating: challenges and opportunities.
The term 'nutrient density' for foods/beverages has been used loosely to promote the Dietary Guidelines for Americans. The 2010 Dietary Guidelines for Americans defined 'all vegetables, fruits, whole grains, fat-free or low-fat milk and milk products, seafood, lean meats and poultry, eggs, beans and peas (legumes), and nuts and seeds that are prepared without added solid fats, added sugars, and sodium' as nutrient dense. The 2010 Dietary Guidelines for Americans further states that nutrient-dense foods and beverages provide vitamins, minerals and other substances that may have positive health effects with relatively few (kilo)calories or kilojoules. Finally, the definition states nutrients and other beneficial substances have not been 'diluted' by the addition of energy from added solid fats, added sugars or by the solid fats naturally present in the food. However, the Dietary Guidelines Advisory Committee and other scientists have failed to clearly define 'nutrient density' or to provide criteria or indices that specify cut-offs for foods that are nutrient dense. Today, 'nutrient density' is a ubiquitous term used in the scientific literature, policy documents, marketing strategies and consumer messaging. However, the term remains ambiguous without a definitive or universal definition. Classifying or ranking foods according to their nutritional content is known as nutrient profiling. The goal of the present commentary is to address the research gaps that still exist before there can be a consensus on how best to define nutrient density, highlight the situation in the USA and relate this to wider, international efforts in nutrient profiling.


Carrierless amplitude and phase modulation in wireless visible light communication systems.
Visible light communications (VLCs) have attracted considerable interest in recent years owing to the potential to simultaneously achieve data transmission and illumination using low-cost light-emitting diodes (LEDs). However, the high-speed capability of such links is typically limited by the low bandwidth of LEDs. As a result, spectrally efficient advanced modulation formats have been considered for use in VLC links in order to mitigate this issue and enable higher data rates. Carrierless amplitude and phase (CAP) modulation is one such spectrally efficient scheme that has attracted significant interest in recent years owing to its good potential and practical implementation. In this paper, we introduce the basic features of CAP modulation and review its use in the context of indoor VLC systems. We describe some of its attributes and inherent limitations, present related advances aiming to improve its performance and potential and report on recent experimental demonstrations of LED-based VLC links employing CAP modulation. This article is part of the theme issue 'Optical wireless communication'.


Dose-response in case-control studies.
The evidence provided by a case-control study on the association between a disease and some factor is strengthened if the extent of exposure to the factor is categorised into several groups or measured on a continuous scale. Then dose-response relationships can be estimated. The methods available are illustrated by application to data on lung cancer and chrysotile asbestos exposure from Quebec in which there were three matched controls for each case. Regression-type models were fitted assuming that the relative risk of lung cancer was linearly related to an exposure measure; a covariate, smoking, was also included in the analysis. The data were first analysed ignoring the matching and secondly taking account of the matching. The methodology for the latter analysis has only recently been developed; formerly, matched studies were of necessity analysed as unmatched. Although, in this particular example, the unmatched and matched analyses gave similar results, this is not always the case and it is argued that, now that the methodology is available, matched case-control studies should be analysed taking proper account of the matching.


Presence and enzymatic activity of prostate-specific antigen in archival prostate cancer samples.
Patients with advanced prostate cancer frequently have a poor prognosis as a result of metastasis. The serum prostate-specific antigen (PSA) test is widely used for the diagnosis of prostate cancer. The enzymatic activity of PSA may be involved in the invasion of prostate cancer. We set out to determine the prevalent form of PSA in human prostate adenocarcinoma samples by ELISA and Western blot analysis and its enzymatic activity using a synthetic substrate S-2586 and fibronectin. Our results show that in serum from prostate cancer patients and in tumour homogenates, the prevalent form was PSA bound to alpha1-antichymotrypsin. All homogenates showed enzymatic activity towards a synthetic PSA substrate, whereas only five samples showed activity at 28 kDa towards fibronectin as determined by enzymography, which is most likely due to active PSA. Human prostate cancer LNCaP cells produced largely inactive PSA. In comparison, 22Rv1 cells produced 29-fold less PSA, but with high specific activity. Similarly, our results from the human prostate cancer tissue samples also show that free PSA appears to exist in diverse forms of very different specific activity. Since PSA, as a serine protease, may be involved in the invasion of prostate cancer, our results suggest that prostate cancers have potentially diverse invasive capacity due to differences in specific enzymatic activity of PSA.


Polarization sensitive surface band structure of doped BaTiO3(001).
We present a spatial and wave-vector resolved study of the electronic structure of micron sized ferroelectric domains at the surface of a BaTiO(3)(001) single crystal. The n-type doping of the BaTiO(3) is controlled by in situ vacuum and oxygen annealing, providing experimental evidence of a surface paraelectric-ferroelectric transition below a critical doping level. Real space imaging of photoemission threshold, core level and valence band spectra show contrast due to domain polarization. Reciprocal space imaging of the electronic structure using linearly polarized light provides unambiguous evidence for the presence of both in- and out-of-plane polarization with two- and fourfold symmetry, respectively. The results agree well with first principles calculations.


Clonal expansions of B lymphocytes in old mice.
The effect of age on the diversity of the murine Ig heavy chain repertoire has been studied in unimmunized C57BL/6 mice. We examined the heterogeneity of complementarity-determining region 3 (CDR3) sizes of Ig mRNA of the IgM and IgG isotypes using two VH families, VHJ558 and VHQ52, which together account for approximately 65% of the Ab repertoire. The broad and bell-shaped profiles representing the diversity of the VHJ558 family in the spleen of 2- to 6-mo-old C57BL/6 mice becomes significantly less diverse after 12 mo of age and by 18 mo of age, single CDR3 sizes that dominate the profiles can be observed in the spleens of > 85% of the mice. Readable sequences have been obtained from 40 dominant mRNA CDR3 size species indicating that they represent clonal populations of B lineage. There are no significant homologies among these sequences. Clones of B lymphocytes that express a dominant CDR3 mRNA species can also be found in the bone marrow, the mesenteric lymph nodes, and the thymus of C57BL/6 mice > 18 mo of age. Some clones of B cells can be detected in only one lymphoid compartment; others are found in two or more compartments. The splenic B cell clones in C57BL/6 mice > 18 mo of age are stable for at least 2 mo. The CDR3 mRNA species that dominate the splenic repertoire of Ig mRNA-expressing cells in vivo do not dominate the repertoire of splenic B cells activated in vitro by bacterial LPS, suggesting that they represent a modest population of B cells expressing high levels of Ig mRNA.


Three-dimensional digital planes.
Definitions of 3-D digital surface and plane are introduced. Many geometric properties of these objects are examined. In particular, it is shown that digital convexity is neither a necessary nor a sufficient condition for a digital surface element to be a convex digital plane element, but it is both necessary and sufficient for a digital surface to be a digital plane. Also algorithms are presented to determine whether or not a finite set of digital points is a (convex) digital plane element.


An extended challenge-based framework for practice design in sports coaching.
The challenge-point framework as a model for thinking about motor learning was first proposed in 2004. Although it has been well-cited, surprisingly this framework has not made its way into much of the applied sport science literature. One of the reasons for this omission is that the original framework had not been encapsulated into a paper accessible for sports practitioners. The framework had mostly a theoretical focus, providing a mechanistic summary of motor learning research. Our aims in this paper were to explain and elaborate on the challenge point framework to present an applied framework guiding practice design. We connect the framework to other theories that involve predictive coding, where information is attended when it disconfirms current predictions, providing a strong signal for learning. We also consider how two new dimensions (learners' motivation and practice specificity) need to be considered when designing practice settings. By moving around the different dimensions of functional difficulty, motivation, and specificity, coaches can optimize practice to achieve different learning goals. Specifically, we present three general "types" of practice: practice to learn, to transfer to competition, and to maintain current skills. Practical examples are given to illustrate how this framework can inform coach practice.


[Various characteristics of the psychosomatic correlations in patients with hypertension].
Data on close relationships between indicators of the somatic status (microcirculation, central hemodynamics, physical working capacity) and personal peculiarities of patients with hypertension were obtained by means of factor and regression analysis. Data on the mathematical simulation of physical working capacity in patients with hypertension with account of the somatic parameters and MMP test indices were presented.


Thyroarytenoid muscle responses to air pressure stimulation of the laryngeal mucosa in humans.
Others have observed glottic adduction in response to air puff stimuli and suggested that this is a reliable indicator of laryngeal sensation. We undertook to determine whether the same thresholds are found if one uses either thyroarytenoid (TA) muscle responses or subjects' reports of laryngeal sensation. We also studied the characteristics of TA responses to unilateral air pressure stimulation of the mucosa overlying the arytenoid cartilages. Ten normal volunteers provided button press responses to air pressure stimuli during bilateral TA electromyography. Similar thresholds were determined by reports of sensation as by electromyographic responses (p < .0005). The early TA responses occurred either around 80 ms or around 125 ms after onset of the air puff, with equal frequency on the ipsilateral and contralateral sides. The TA muscle responses to air pressure stimulation differ in physiological characteristics from the laryngeal adductor reflex that occurs in response to electrical stimulation of the superior laryngeal nerve.


Unraveling mechanisms for expert object recognition: bridging brain activity and behavior.
Behavioral sensitivity to object transformations and the response to novel objects (Greebles) in the fusiform face area (FFA) was measured several times during expertise training. Sensitivity to 3 transformations increased with expertise: (a) configural changes in which halves of objects were misaligned, (b) configural changes in which some of the object parts were moved, and (c) the substitution of an object part with a part from a different object. The authors found that holistic-configural effects can arise from object representations that are differentiated in terms of features or parts. Moreover, a holistic-inclusive effect was correlated with changes in the right FFA. Face recognition may not be unique in its reliance on holistic processing, measured in terms of both behavior and brain activation.


[Phospholipid turnover of the liver subcellular fractions in rats receiving diets with a varying protein content].
Turnover of liver mitochondrial and microsomal phospholipids was studied in rats kept on isocaloric diets containing 4.5, 6, 9, 18% protein (controls) and 36%. Turnover rate and half-life period of mitochondrial and microsomal phospholipids were determined from degradation of membrane fractions of phospholipids labeled with 14C-palmitic acid. Increase or decrease of protein level in the diet resulted in reduced turnover rate of mitochondrial and microsomal phospholipids and their prolonged half-life period in the membranes. Changed life span of phospholipid molecules during feeding the diets imbalanced with respect to proteins may be considered as adaptation reaction to alimentary exposures on the cellular level, this reaction being aimed at preservation of the optimum structure of subcellular membranes. Earlier findings on reduced half-life period of membrane proteins during low-protein (4.5%) and high-protein (36%) diets and the present data allow a conclusion on the independent nature of the mechanisms of degradation of subcellular membrane lipid and protein components.


SARS-CoV-2 shedding dynamics across the respiratory tract, sex, and disease severity for adult and pediatric COVID-19.
Previously, we conducted a systematic review and analyzed the respiratory kinetics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Chen et al., 2021). How age, sex, and coronavirus disease 2019 (COVID-19) severity interplay to influence the shedding dynamics of SARS-CoV-2, however, remains poorly understood. We updated our systematic dataset, collected individual case characteristics, and conducted stratified analyses of SARS-CoV-2 shedding dynamics in the upper (URT) and lower respiratory tract (LRT) across COVID-19 severity, sex, and age groups (aged 0-17 years, 18-59 years, and 60 years or older). The systematic dataset included 1266 adults and 136 children with COVID-19. Our analyses indicated that high, persistent LRT shedding of SARS-CoV-2 characterized severe COVID-19 in adults. Severe cases tended to show slightly higher URT shedding post-symptom onset, but similar rates of viral clearance, when compared to nonsevere infections. After stratifying for disease severity, sex and age (including child vs. adult) were not predictive of respiratory shedding. The estimated accuracy for using LRT shedding as a prognostic indicator for COVID-19 severity was up to 81%, whereas it was up to 65% for URT shedding. Virological factors, especially in the LRT, facilitate the pathogenesis of severe COVID-19. Disease severity, rather than sex or age, predicts SARS-CoV-2 kinetics. LRT viral load may prognosticate COVID-19 severity in patients before the timing of deterioration and should do so more accurately than URT viral load. Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant, NSERC Senior Industrial Research Chair, and the Toronto COVID-19 Action Fund.


Acetabular revision with impacted morselized cancellous bone graft and a cemented cup in patients with rheumatoid arthritis: three to fourteen-year follow-up.
Acetabular revision in patients with rheumatoid arthritis is often difficult because of the poor quality and quantity of the acetabular bone stock. The purpose of this study was to evaluate the midterm clinical and radiographic outcomes of acetabular revision with use of an impaction bone-grafting technique and a cemented polyethylene cup. Thirty-five consecutive acetabular revisions were performed with impaction bone-grafting and use of a cemented cup in twenty-eight patients with rheumatoid arthritis. The average age at the revision was fifty-seven years. The minimum duration of follow-up of all reconstructions that were still functioning or that were followed until the time of death was three years (mean, 7.5 years; range, three to fourteen years). No patient was lost to follow-up, but five patients (six hips) died before the time of the review. The acetabular bone defects were classified as cavitary in twelve hips and as combined segmental-cavitary in twenty-three. The five patients (six hips) who died had been doing well at the time of their latest follow-up. Of the remaining patients, six (six hips) had a repeat revision. The average Harris hip score of the living patients with a surviving implant at the time of follow-up was 82 points, and there was no or only mild pain in twenty-one of the twenty-three hips. Radiographic analysis of all twenty-nine hips that had not been revised showed loosening in one hip and a nonprogressive radiolucent line in one zone in two others. Kaplan-Meier analysis demonstrated a prosthetic survival rate, with aseptic loosening as the end point, of 90% at eight years. Acetabular revision with impaction bone-grafting and a cemented cup in patients with rheumatoid arthritis had acceptable results at an average of 7.5 years postoperatively.


Altered synthesis of Bruch's membrane proteoglycans associated with dominant retinitis pigmentosa.
Proteoglycans, extracellular matrix molecules that have been shown to have filtration properties in some tissues, make up a significant proportion of the structural macromolecules of Bruch's membrane. Bruch's membrane may provide a selective filtration barrier between the choriocapillaris and the pigmented epithelium (PE) and outer retina. In this paper, we compare the proteoglycans extracted from metabolically-labeled normal and retinitis pigmentosa (RP) Bruch's membranes. Isolated RP Bruch's membrane proteoglycans were larger than those from normal donor eyes when chromatographed on a column of Sepharose CL-4B. In addition to the increased size, there was also a dramatic increase in the proportion of heparan sulfate proteoglycan being synthesized in RP. Considering the structural and filtration properties of proteoglycans, alterations such as these could affect the functioning of Bruch's membrane and, possibly, the PE and the outer retina.


Sleuthing the difference a nucleotide can make.
Identifying the genetic basis of natural variation in genome-wide gene expression is a daunting task, yet central to characterizing the potential evolutionary impact of gene expression polymorphism. In this issue, Brown et al. reveal the genetic variation that underlies a significant portion of the gene expression polymorphism that segregates in a natural isolate of the wine and bread yeast Saccharomyces cerevisiae. That polymorphism is shown to be associated with a single nucleotide insertion. Interestingly, the major expression polymorphism is not caused by an insertion in a cis-regulatory region or in a transcription factor, but in a homonucleotide repeat within the coding sequence of SSY1, which encodes an amino acid sensor. The expression polymorphism, perhaps unsurprisingly, is also environment-dependent and leads to differential fitness across environments. The result calls for a deeper consideration within molecular ecological genomics of the gene-by-environment interactions that lead to differential gene expression. The finding also calls for further data, clarifying the kinds of genetic variation that constitute gene expression polymorphism between individuals in natural populations.


Right pneumonectomy syndrome: a late life-threatening complication of pneumonectomy.
Right pneumonectomy syndrome, a rare complication of pneumonectomy, is secondary to a shift of the mediastinum and remaining lung toward the pneumonectomy side, leading to extrinsic airway compression and stretching. A 6-year-old boy started with initial symptoms of dyspnea on exertion, wheezing, and recurrent pneumonia 6 months after his right pneumonectomy. He received treatment with bronchodilators and antibiotics during outpatient clinic visits. Two months later, he developed increased wheezing and productive cough. A pulmonary function test showed severe reduction in expiratory volumes. He had a cardiopulmonary arrest while a surgical intervention was being planned. Chest roentgenogram showed shift of the heart and mediastinal structures into the right hemithorax with left lung hyperexpansion and no fluid in the right hemithorax. A computed tomogram of the chest revealed marked narrowing of the proximal left mainstem bronchus. He underwent thoracotomy, and a silicone prosthesis was inserted into the right hemithorax, resulting in restoration of the structures to the midline. The child presented severe neurological sequelae. Postpneumonectomy syndrome is a rare but life-threatening complication after pneumonectomy. Because it may mimic other conditions and given the consequences can be devastating, early recognition and intervention are required to ensure a favorable outcome.


Sepsis: The Involvement of Platelets and the Current Treatments.
Sepsis, a serious and life threatening complication arising from infection caused by lipopolysaccharide, is a complex inflammatory syndrome, and one of the main causes of death in intensive care units (ICU). It is characterized as an over-response of pro-coagulant agents promotes coagulopathy and thrombus formation, resulting in disseminated intravascular coagulation (DIC). Furthermore, it can cause multiple organ dysfunction and hypotension (septic shock) resulting in death. Thrombocytopenia, which is a hallmark of sepsis, is strongly correlated as a negative marker of the infection. Additionally, platelets contribute with the oxidative stress in septic patients in order to exterminate the microbial pathogen. This review summarises the important role of platelets in the pathology of sepsis, and highlights potential treatment targets to improve the outcome of sceptic patients. The search was performed in PubMed, books and retrieved journal articles for a period of three months. The figures were developed through Servier Medical Arts software. The exact treatment of sepsis is still the subject of considerable debate. Although here we presented several therapies that have shown promise for improving the outcome of patients, researching platelet function in sepsis has provided us targets to develop new medical approaches focusing specially on thrombocytopenia and DIC.


Ontogenesis of prolactin receptor gene expression in the rat olfactory system: potential roles for lactogenic hormones in olfactory development.
The PRL receptor (PRLR) is expressed at very low levels in the olfactory bulb of the adult rat but is detected in abundance in the olfactory epithelium and olfactory bulb of the fetal rat in late gestation. To explore potential roles for the lactogenic hormones in olfactory differentiation and development, we have used in situ hybridization and immunohistochemistry to examine the ontogeny of PRLR gene expression in the rat olfactory system. At midgestation (embryonic day 12.5), messenger RNAs (mRNAs) encoding the long and short isoforms of the rat PRLR were detected in the medial and lateral nasal processes, the epithelial lining of the olfactory pit, and the neuroepithelium lining the cerebral ventricles in the region of the rhinencephalon. PRLR mRNA was also expressed prominently in the frontonasal mesenchyme and in mesenchymal tissue underlying the developing brain and overlying the pontine flexure in the interpeduncular fossa. The distribution of PRLR immunoreactivity was similar to that of PRLR mRNA, indicating that the PRLR gene is translated to that of PRLR mRNA, indicating that the PRLR gene is translated to lactogenic binding protein in the rat embryo in vivo. With advancing gestation, the PRLR was expressed intensely, although discontinuously, in the olfactory epithelium and was detected in the cartilage primordia of the ethmoid, sphenoid, temporal, and mandibular bones. PRLR expression in the vomeronasal organ was confined to the luminal epithelial surface. PRLR mRNA and immunoreactive protein were first detected in the olfactory bulb on embryonic day 18. PRLR expression was most intense initially in the periventricular neuroepithelium; subsequently, robust staining of the mitral and tufted cell neurons became apparent, accompanied by intense PRLR expression in the sensory neuronal cell bodies of the olfactory epithelium. By postnatal day 5, the PRLR was expressed in abundance in mitral and tufted cells of the olfactory bulb and in neuronal cell bodies of the anterior olfactory nucleus and the piriform cortex. PRLR mRNA was also detected in the mitral cells of the olfactory bulb of the lactating rat, although at levels far lower than those in the fetal or neonatal rat. The expression of the PRLR in the olfactory system of the fetal and neonatal rat implicates novel roles for the lactogenic hormones in olfactory differentiation and development and may provide new mechanisms by which the lactogens may regulate neonatal behavior and maternal-infant interactions.


Highly unsaturated (n-3) fatty acids, but not alpha-linolenic, conjugated linoleic or gamma-linolenic acids, reduce tumorigenesis in Apc(Min/+) mice.
We showed previously that dietary eicosapentaenoic acid [EPA, 20:5(n-3)] is antitumorigenic in the APC:(Min/+) mouse, a genetic model of intestinal tumorigenesis. Only a few studies have evaluated the effects of dietary fatty acids, including EPA and docosahexaenoic acid [DHA, 22:6(n-3)], in this animal model and none have evaluated the previously touted antitumorigenicity of alpha-linolenic acid [ALA, 18:3(n-3)], conjugated linoleic acid [CLA, 77% 18:2(n-7)], or gamma-linolenic acid [GLA, 18:3(n-6)]. Stearidonic acid [SDA, 18:4(n-3)], the Delta6-desaturase product of ALA, which is readily metabolized to EPA, has not been evaluated previously for antitumorigenic efficacy. This study was undertaken to evaluate the antitumorigenicity of these dietary fatty acids (ALA, SDA, EPA, DHA, CLA and GLA) compared with oleic acid [OA, 18:1(n-9)] at a level of 3 g/100 g in the diets of APC:(Min/+) mice and to determine whether any alterations in tumorigenesis correspond to alterations in prostaglandin biosynthesis. Tumor multiplicity was significantly lower by approximately 50% in mice fed SDA or EPA compared with controls, whereas less pronounced effects were observed in mice fed DHA (P: = 0.15). ALA, CLA and GLA were ineffective at the dose tested. Although lower tumor numbers coincided with significantly lower prostaglandin levels in SDA- and EPA-fed mice, ALA and DHA supplementation resulted in equally low prostaglandin levels, despite proving less efficacious with regard to tumor number. Prostaglandin levels did not differ significantly in the CLA and GLA groups compared with controls. These results suggest that SDA and EPA attenuate tumorigenesis in this model and that this effect may be related in part to alterations in prostaglandin biosynthesis.


Hypotensive resuscitation strategy reduces transfusion requirements and severe postoperative coagulopathy in trauma patients with hemorrhagic shock: preliminary results of a randomized controlled trial.
Trauma is a leading cause of death worldwide and is thus a major public health concern. Previous studies have shown that limiting the amount of fluids given by following a strategy of permissive hypotension during the initial resuscitation period may improve trauma outcomes. This study examines the clinical outcomes from the first 90 patients enrolled in a prospective, randomized controlled trial of hypotensive resuscitation, with the primary aim of assessing the effects of a limited transfusion and intravenous (IV) fluid strategy on 30-day morbidity and mortality. Patients in hemorrhagic shock who required emergent surgery were randomized to one of the two arms of the study for intraoperative resuscitation. Those in the experimental (low mean arterial pressure [LMAP]) arm were managed with a hypotensive resuscitation strategy in which the target mean arterial pressure (MAP) was 50 mm Hg. Those in the control (high MAP [HMAP]) arm were managed with standard fluid resuscitation to a target MAP of 65 mm Hg. Patients were followed up for 30 days. Intraoperative fluid requirements, mortality, postoperative complications, and other clinical data were prospectively gathered and analyzed. Patients in the LMAP group received a significantly less blood products and total i.v. fluids during intraoperative resuscitation than those in the HMAP group. They had significantly lower mortality in the early postoperative period and a nonsignificant trend for lower mortality at 30 days. Patients in the LMAP group were significantly less likely to develop immediate postoperative coagulopathy and less likely to die from postoperatively bleeding associated with coagulopathy. Among those who developed coagulopathy in both groups, patients in the LMAP group had significantly lower international normalized ratio than those in the HMAP group, indicating a less severe coagulopathy. Hypotensive resuscitation is a safe strategy for use in the trauma population and results in a significant reduction in blood product transfusions and overall IV fluid administration. Specifically, resuscitating patients with the intent of maintaining a target minimum MAP of 50 mm Hg, rather than 65 mm Hg, significantly decreases postoperative coagulopathy and lowers the risk of early postoperative death and coagulopathy. These preliminary results provide convincing evidence that support the continued investigation and use of hypotensive resuscitation in the trauma setting.


Risk factors for occult nodal metastasis in clinical T1N0 lung cancer: a negative impact on survival.
The application of CT imaging has increased the identification of patients with clinical T1N0 (cT1N0) lung cancer. The optimal management strategy for these early stage lung cancers remains unclear. We analyzed the impact of occult nodal metastasis on cT1N0 lung cancer patients. We studied patients with cT1N0 lung cancer enrolled in our database from January 1995 to December 2002. Preoperative staging was confirmed by review of CT and PET scan studies. Pathology specimens were reviewed. Multivariate analysis was performed to determine the risk of occult nodal involvement. Kaplan-Meier method was applied to analyze survival. Two hundred and ninety-seven patients with cT1N0 disease were identified. Fifty-eight percent of patients were pathological T1N0. Overall, 15% of patients had occult nodal metastasis. Logistic regression analysis demonstrated a three-fold increase in the risk of having pathologic stage II or stage III disease with every 1.0 cm increase in tumor size (odds ratio 3.2; 95% CI: 2.3-4.6). Multivariate analysis demonstrated tumor size to be a significant predictor of nodal metastasis (adjusted odds ratio 3.5; 95% CI: 2.4-5.1). Median survival was different between pathological stage I (96.3 months), stage II (41.4 months), and stage III (36.1 months) disease (p=0.002). Clinical T1N0 tumors are often understaged. The risk of occult nodal disease increases with tumor size, and this occult disease negatively impacts survival. Because of the limitations of clinical staging, we believe that lobectomy and lymph node analysis should be offered to cT1N0 lung cancer patients to provide accurate staging and to optimize multimodality adjuvant treatment of lung cancer.


Chinese handwriting performance in preterm children in grade 2.
First graders born prematurely perform poorly on handwriting speed and legibility. However, whether there are specific legibility factors in which preterm children demonstrate difficulty remains unknown. In addition, handwriting performance beyond the first grade and the influence of sex on handwriting performance in preterm children are still unclear. We aimed to investigate the influence of prematurity and sex on multiple dimensions of handwriting in grade two and to identify the contributors to performance. Sixty-three preterm (34 boys and 29 girls) and 67 full-term (27 boys and 40 girls) peers in grade two were included. Class teachers were asked to complete the Chinese Handwriting Evaluation Form. A subgroup of 39 preterm children received assessments on intelligence, visual perception, tactile and kinesthetic sensation, and fine motor skills. Their inattention behavior was rated using a maternal self-report with a behavioral scale. Boys born prematurely exhibited poorer performance in the speed dimension than full-term boys (p = 0.008), whereas there was comparable performance in the two groups of girls (p = 0.221). In the dimensions related to legibility, preterm boys (32.4%) had a higher percentage of children with difficulty in the construction dimension than the other groups (preterm girls: 6.9%, full-term boys: 7.4%, full-term girls: 5.0%). However, no group difference was found in the dimensions of accuracy and directionality. Of the sensory-perceptual-motor factors, attention was the most significant predictor of accuracy in performance (p = 0.046) and speed dimensions (p = 0.001) in preterm children. Boys appear to be vulnerable to the adverse impacts of preterm birth in terms of performance in the dimensions of speed and construction in grade two. Based on the significant contribution of attention to handwriting performance in preterm children, assessment and intervention in the area of attention is strongly suggested for preterm children with handwriting problems.


Personal indium exposure concentration in respirable dusts and serum indium level.
The aim of this study was to assess the relationship between indium exposure concentration in the respirable dust fraction (In-E) and indium in serum (In-S) in workers. A total of 39 workers were studied. The study subjects were categorized into 3 groups, namely, smelting workers (n=7), ITO workers (n=6) in an ITO grinding plant, and other workers (n=26). In-E and In-S ranged from 0.004-24.0 μg/m3 and 0.1-8.50 μg/L, respectively. The simple regression equation was log(In-S)=0.322×log(In-E)-0.443. The simple correlation coefficients for the smelting workers, ITO workers and other workers were 0.489, 0.812 and 0.163, respectively. The differences in the relationships among the three groups suggest that In-S may vary with the chemical form to which the workers were exposed. In-E and In-S seem to be positively correlated. The correlation coefficient was higher for both smelting and ITO workers than for other workers.


[Fat composition of several "fast food"].
The percentage of fat of a variety of foods served in fast food establishments has been determined. This percentage is very variable, with mean contents of total fat of 35.83 +/- 10.68% in beef hamburgers, 35.84 +/- 8.66% in chips, 23.02 +/- 5.07% in chicken hamburgers and 34.02 +/- 13.49% in "hot dogs". The lipidic composition is mainly formed by saturated fatty acids (28-52% of total fat) and monounsaturated (46-48%), whereas the proportion of polyunsaturated fatty acids showed more variable values, ranging from 6.9% in beef hamburgers to 25.1% in chips. Statistical treatment of the results of relative percentage of fatty acids by multivariate methods revealed clusters of samples grouped as a function of the type of food and in some instances of its source, which can be interesting in case of healthy problems. Percentages of trans fatty acids slightly higher than the maximum recommended values have been detected in some cases. These results show the urgent need of modifying the laws to force fast food establishments to specify the type and amounts of fat used in the processing of these foods, as well as a greater control from the local administrations.


A subset of SR proteins activates splicing of the cardiac troponin T alternative exon by direct interactions with an exonic enhancer.
The cardiac troponin T pre-mRNA contains an exonic splicing enhancer that is required for inclusion of the alternative exon 5. Here we show that enhancer activity is exquisitely sensitive to changes in the sequence of a 9-nucleotide motif (GAGGAAGAA) even when its purine content is preserved. A series of mutations that increased or decreased the level of exon inclusion in vivo were used to correlate enhancer strength with RNA-protein interactions in vitro. Analyses involving UV cross-linking and immunoprecipitation indicated that only four (SRp30a, SRp40, SRp55, and SRp75) of six essential splicing factors known as SR proteins bind to the active enhancer RNA. Moreover, purified SRp40 and SRp55 activate splicing of exon 5 when added to a splicing-deficient S100 extract. Purified SRp30b did not stimulate splicing in S100 extracts, which is consistent with its failure to bind the enhancer RNA. In vitro competition of SR protein splicing activity and UV cross-linking demonstrated that the sequence determinants for SR protein binding were precisely coincident with the sequence determinants of enhancer strength. Thus, a subset of SR proteins interacts directly with the exonic enhancer to promote inclusion of a poorly defined alternative exon. Independent regulation of the levels of SR proteins may, therefore, contribute to the developmental regulation of exon inclusion.


[Determination of restrictase activity in toluene lysates of bacterial cells].
A rapid method for determination of restrictase Bam H1 activity in bacterial cells has been devised. It is based on cell treatment with toluene followed by incubation of toluene lysates with DNA substrate. The method is unsophisticated, well reproducible and requires insignificant amount of biomass necessary for testing the restrictase activity, which makes it compare very favourably with the known methods. The treatment of microbial cells with toluene can serve the first stage in purification of restriction endonucleases.


Multiobjective evolutionary optimization of the size, shape, and position parameters of radial basis function networks for function approximation.
This paper presents a multiobjective evolutionary algorithm to optimize radial basis function neural networks (RBFNNs) in order to approach target functions from a set of input-output pairs. The procedure allows the application of heuristics to improve the solution of the problem at hand by including some new genetic operators in the evolutionary process. These new operators are based on two well-known matrix transformations: singular value decomposition (SVD) and orthogonal least squares (OLS), which have been used to define new mutation operators that produce local or global modifications in the radial basis functions (RBFs) of the networks (the individuals in the population in the evolutionary procedure). After analyzing the efficiency of the different operators, we have shown that the global mutation operators yield an improved procedure to adjust the parameters of the RBFNNs.


Electronic structure engineering on Co-based metal-organic frameworks for concurrent electrocatalytic hydrogen generation and formate electrosynthesis.
A facile one-step solvothermal method was developed to synthesize Ir-doped Co-based metal-organic framework (CoIr-MOF) nanoarrays as a bifunctional electrocatalyst for water-glucose co-electrolysis. It was demonstrated that in situ incorporation of a low-content of Ir cations could modulate the electronic structure of Co active centers and thus boost the electrocatalytic performance towards both the hydrogen evolution reaction and glucose-to-formate oxidation reaction.


Quantitative understanding of the optical properties of a single, complex-shaped gold nanoparticle from experiment and theory.
We report on a combined study of Rayleigh and Raman scattering spectroscopy, 3D electron tomography, and discrete dipole approximation (DDA) calculations of a single, complex-shaped gold nanoparticle (NP). Using the exact reconstructed 3D morphology of the NP as input for the DDA calculations, the experimental results can be reproduced with unprecedented precision and detail. We find that not only the exact NP morphology but also the surroundings including the points of contact with the substrate are of crucial importance for a correct prediction of the NP optical properties. The achieved accuracy of the calculations allows determining how many of the adsorbed molecules have a major contribution to the Raman signal, a fact that has important implications for analyzing experiments and designing sensing applications.


Review: neutrophil gelatinase-associated lipocalin: a troponin-like biomarker for human acute kidney injury.
Acute kidney injury (AKI) is a common and serious condition, the diagnosis of which currently depends on functional markers such as serum creatinine measurements. Unfortunately, creatinine is a delayed and unreliable indicator of AKI. The lack of early biomarkers of structural kidney injury (akin to troponin in acute myocardial injury) has hampered our ability to translate promising experimental therapies to human AKI. Fortunately, understanding the early stress response of the kidney to acute injuries has revealed a number of potential biomarkers. The discovery, translation and validation of neutrophil gelatinase-associated lipocalin (NGAL), possibly the most promising novel AKI biomarker, is reviewed. NGAL is emerging as an excellent stand-alone troponin-like structural biomarker in the plasma and urine for the early diagnosis of AKI, and for the prediction of clinical outcomes such as dialysis requirement and mortality in several common clinical scenarios. The approach of using NGAL as a trigger to initiate and monitor therapies for AKI, and as a safety biomarker when using potentially nephrotoxic agents, is also promising. In addition, it is hoped that the use of sensitive and specific biomarkers such as NGAL as endpoints in clinical trials will result in a reduction in required sample sizes, and hence the cost incurred. Furthermore, predictive biomarkers like NGAL may play a critical role in expediting the drug development process. However, given the complexity of AKI, additional biomarkers (perhaps a panel of plasma and urinary biomarkers) may eventually need to be developed and validated for optimal progress to occur.


Thrombin stimulation of guanosine 3',5'-monophosphate formation in murine neuroblastoma cells (clone N1E-115).
Thrombin, the central regulatory enzyme in coagulation, when incubated in nanomolar concentrations with murine neuroblastoma cells produced a rapid and marked increase in tritiated guanosine 3',5'-monophosphate (cyclic GMP) formation that was blocked by hirudin and competitively antagonized by dansylarginine N-(3-ethyl-1,5-pentanediyl)amide. Diisopropylphosphofluoridate-inactivated thrombin as well as the serine protease trypsin were markedly less potent and less effective than alpha-thrombin in producing this effect. Thrombin-stimulated cyclic GMP formation was inhibited by mepacrine and nordihydroguaiaretic acid but unaffected by indomethacin, suggesting that lipoxygenase metabolites of arachidonic acid are involved in the response. These results suggest that a thrombin-like protease in the brain may be involved with the function of neurons or that thrombin interactions with nerve cells, such as those following cerebral hemorrhage or other trauma of the central nervous system, may be important in the subsequent neuropathology.


Discrepancy in glucose and fructose utilisation during fermentation by Saccharomyces cerevisiae wine yeast strains.
While unfermented grape must contains approximately equal amounts of the two hexoses glucose and fructose, wine producers worldwide often have to contend with high residual fructose levels (>2 gl(-1)) that may account for undesirable sweetness in finished dry wine. Here, we investigate the fermentation kinetics of glucose and fructose and the influence of certain environmental parameters on hexose utilisation by wine yeast. Seventeen Saccharomyces cerevisiae strains, including commercial wine yeast strains, were evaluated in laboratory-scale wine fermentations using natural Colombard grape must that contained similar amounts of glucose and fructose (approximately 110 gl(-1) each). All strains showed preference for glucose, but to varying degrees. The discrepancy between glucose and fructose utilisation increased during the course of fermentation in a strain-dependent manner. We ranked the S. cerevisiae strains according to their rate of increase in GF discrepancy and we showed that this rate of increase is not correlated with the fermentation capacity of the strains. We also investigated the effect of ethanol and nitrogen addition on hexose utilisation during wine fermentation in both natural and synthetic grape must. Addition of ethanol had a stronger inhibitory effect on fructose than on glucose utilisation. Supplementation of must with assimilable nitrogen stimulated fructose utilisation more than glucose utilisation. These results show that the discrepancy between glucose and fructose utilisation during fermentation is not a fixed parameter but is dependent on the inherent properties of the yeast strain and on the external conditions.


Schizandrin A exerts anti-tumor effects on A375 cells by down-regulating H19.
Malignant melanoma (MM) is one of the malignant tumors with highly metastatic and aggressive biological actions. Schizandrin A (SchA) is a bioactive lignin compound with strong anti-oxidant and anti-aging properties, which is stable at room temperature and is often stored in a cool dry place. Hence, we investigated the effects of SchA on MM cell line A375 and its underlying mechanism. A375 cells were used to construct an in vitro MM cell model. Cell viability, proliferation, apoptosis, and migration were detected by Cell Counting Kit-8, BrdU assay, flow cytometry, and transwell two-chamber assay, respectively. The cell cycle-related protein cyclin D1 and cell apoptotic proteins (Bcl-2, Bax, cleaved-caspase-3, and cleaved-caspase-9) were analyzed by western blot. Alteration of H19 expression was achieved by transfecting with pEX-H19. PI3K/AKT pathway was measured by detecting phosphorylation of PI3K and AKT. SchA significantly decreased cell viability in a dose-dependent manner. Furthermore, SchA inhibited cell proliferation and cyclin D1 expression. SchA increased cell apoptosis along with the up-regulation of pro-apoptotic proteins (cleaved-caspase-3, cleaved-caspase-9, and Bax) and the down-regulation of anti-apoptotic protein (Bcl-2). Besides, SchA decreased migration and down-regulated matrix metalloproteinases (MMP)-2 and MMP-9. SchA down-regulated lncRNA H19. Overexpression of H19 blockaded the inhibitory effects of SchA on A375 cells. SchA decreased the phosphorylation of PI3K and AKT while H19 overexpression promoted the phosphorylation of PI3K and AKT. SchA inhibited A375 cell growth, migration, and the PI3K/AKT pathway through down-regulating H19.


[Effect of combined application of the synthetic luteinizing hormone-releasing hormone agonist and nonsteroidal antiandrogen on the reproductive system of male rats].
The influence of combined use of different doses of LGRH agonist (Surfagon) and non-steroidal antiandrogen Flutamide (Niftolid) on the structure and functional state of accessory sexual glands and hypophyseal-gonadal system of rate males had been studied. Optimal ratio of the drug doses for achieving the best antiprostatic effect has been determined. It was shown that combined use of above mentioned drugs resulted in the potentiation of antiprostatic effects. A maximal effect was observed after 30 days of Surfagon administration in a dose of 50 mg/kg b.w. together with flutamid in a dose of 10 mg/kg. b.w. Such a combination of drugs is recommended for clinical approbation as therapy for prostate cancer.


Conformational Intermediate That Controls KPC-2 Catalysis and Beta-Lactam Drug Resistance.
The KPC-2 carbapenemase enzyme is responsible for drug resistance in the majority of carbapenem-resistant gram-negative bacterial infections in the United States. A better understanding of what permits KPC-2 to hydrolyze carbapenem antibiotics and how this might be inhibited is thus of fundamental interest and great practical importance to development of better anti-infectives. By correlating molecular dynamics simulations with experimental enzyme kinetics, we have identified conformational changes that control KPC-2's ability to hydrolyze carbapenem antibiotics. Related beta-lactamase enzymes can interconvert between catalytically permissive and catalytically nonpermissive forms of an acylenzyme intermediate critical to drug hydrolysis. Using molecular dynamics simulations, we identify a similar equilibrium in KPC-2 and analyze the determinants of this conformational change. Because the conformational dynamics of KPC-2 are complex and sensitive to allosteric changes, we develop an information-theoretic approach to identify key determinants of this change. We measure unbiased estimators of the reaction coordinate between catalytically permissive and nonpermissive states, perform information-theoretic feature selection and, using restrained molecular dynamics simulations, validate the protein conformational changes predicted to control catalytically permissive geometry. We identify two binding-pocket residues that control the conformational transitions between catalytically active and inactive forms of KPC-2. Mutations to one of these residues, Trp105, lower the stability of the catalytically permissive state in simulations and have reduced experimental k cat values that show a strong linear correlation with the simulated catalytically permissive state lifetimes. This understanding can be leveraged to predict the drug resistance of further KPC-2 mutants and help design inhibitors to combat extreme drug resistance.


A novel approach to structure proof of glyceryl ether-containing glycerophospholipids. Base-catalyzed methanolysis of platelet-activating factor (AGEPC) at 60 degrees C.
A novel reaction was explored in which synthetic platelet-activating factor, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (AGEPC), upon treatment with 1 N NaOH in methanol at 60 degrees C for 20 min, sequentially released the acetyl group, then the choline moiety with concomitant formation of the monomethyl ester of 1-O-alkyl-glycero-phosphoric acid. A mechanism is proposed in which a transient cyclic phosphate intermediate is formed and then attacked by a CH3O moiety to yield a mixture of the sn-2 and sn-3 methyl esters. Proof of structure of the monomethyl ester derivative was achieved through the use of thin-layer chromatography, aluminum oxide chromatography, and examination of the trimethylsilyl derivative of the monomethyl ester by gas-liquid chromatography-mass spectrometry. Replacement of the acyl group on the 2 position with an ethyl or methyl residue completely prevented any attack by 1 N NaOH in methanol at 60 degrees C. Sphingomyelin was not attacked and only acetate removal was noted with 1-O-alkyl-2-acetyl-sn-glycero-3-phosphoethanolamine under similar conditions. The significance of these findings as they relate to the influence of substituents on the chemical and biological reactivity of AGEPC is discussed.


ECF σ factors with regulatory extensions: the one-component systems of the σ universe.
The σ subunit of the bacterial RNA polymerase determines promoter specificity. The extracytoplasmic function σ factors (ECFs) represent the most abundant and diverse group of alternative σ factors and are present in the vast majority of bacterial genomes. Typically, ECFs are regulated by anti-σ factors that sequester their cognate ECFs, thereby preventing their interaction with the RNA polymerase. Beyond these ECF paradigms, a number of distinct modes of regulation have been proposed and experimentally investigated. Regulatory extensions represent one such alternative mechanism of ECF regulation that can be found in 18 phylogenetically distinct ECF groups. Here, the σ factors contain additional domains that are fused to the ECF core domains and are involved in stimulus perception and modulation of σ factor activity. We will summarize the current state of knowledge on regulating ECF activity by C-terminal extensions. We will also discuss newly identified ECF groups containing either N- or C-terminal extensions and propose possible mechanisms by which these extensions have been generated and affect ECF σ factor activity. Based on their modular architecture and the resulting physical connection between stimulus perception and transcriptional output, these ECFs are analogous to one-component systems, the primary mechanism of bacterial signal transduction.


Dialogues between the Astana Declaration, the Right to Health and Family and Community Medicine training in Rio de Janeiro, Brazil.
This paper discusses and fosters concerns in light of the repercussions of both the 40th anniversary of the Alma-Ata Declaration and the Astana Declaration, discussing the possible influence on Family and Community Medicine training, as per the lenses of two Residency Programs of three public institutions, namely, State University of Rio de Janeiro, Federal University of Rio de Janeiro, and the Oswaldo Cruz Foundation. These are inserted in a historical and social context, between the world of work, public policies, international organizations, the population and subjects involved in the construction, maintenance, and consolidation of the Brazilian PHC. Thus, in a brief historical revival, we contextualized which Primary Care was a practice setting and where we might be headed. We concluded that the willingness to ensure the Right to Health would be threatened by the concept of Universal Coverage, advocated by the Astana Declaration, which leads to essential discussions: ensuring state-provided services, advocating for equity and integrality of actions, reaffirming the risk of generating inequality by creating multiple service offerings for different segments of the population, reiterating the relevance of access to health, and valuation of territorialization.


Quality of chronic disease care for older people in care homes and the community in a primary care pay for performance system: retrospective study.
To describe the quality of care for chronic diseases among older people in care homes (nursing and residential) compared with the community in a pay for performance system. Retrospective analysis of The Health Improvement Network (THIN), a large primary care database. 326 English and Welsh general practices, 2008-9. 10,387 residents of care homes and 403,259 residents in the community aged 65 to 104 and registered for 90 or more days with their general practitioner. 16 process quality indicators for chronic disease management appropriate for vulnerable older people for conditions included in the UK Quality and Outcomes Framework. After adjustment for age, sex, dementia, and length of registration, attainment of quality indicators was significantly lower for residents of care homes than for those in the community for 14 of 16 indicators. The largest differences were for prescribing in heart disease (β blockers in coronary heart disease, relative risk 0.70, 95% confidence interval 0.65 to 0.75) and monitoring of diabetes (retinal screening, 0.75, 0.71 to 0.80). Monitoring hypothyroidism (0.93, 0.90 to 0.95), blood pressure in people with stroke (0.92, 0.90 to 0.95), and electrolytes for those receiving loop diuretics (0.89, 0.87 to 0.92) showed smaller differences. Attainment was lower in nursing homes than in residential homes. Residents of care homes were more likely to be identified by their doctor as unsuitable or non-consenting for all Quality and Outcomes Framework indicators for a condition allowing their exclusion from targets; 33.7% for stroke and 34.5% for diabetes. There is scope for improving the management of chronic diseases in care homes, but high attainment of some indicators shows that pay for performance systems do not invariably disadvantage residents of care homes compared with those living in the community. High use of exception reporting may compromise care for vulnerable patient groups. The Quality and Outcomes Framework, and other pay for performance systems, should monitor attainment and exception reporting in vulnerable populations such as residents of care homes and consider measures that deal with the specific needs of older people.


Impact of physicochemical parameters of Aedes aegypti breeding habitats on mosquito productivity and the size of emerged adult mosquitoes in Ouagadougou City, Burkina Faso.
Outbreaks of dengue fever caused by viruses transmitted by Aedes aegypti mosquitoes are repeated occurrences in West Africa. In recent years, Burkina Faso has experienced major dengue outbreaks, most notably in 2016 and 2017 when 80% of cases were recorded in Ouagadougou City (Central Health Region). In order to better understand the ecology of this vector and to provide information for use in developing control measures, a study on the characteristics of Aedes container breeding sites and the productivity of such sites, as measured by the abundance of immature stages and resultant adult body size, was undertaken in three health districts (Baskuy, Bogodogo and Nongremassom) of Ouagadougou. Adult mosquitoes were collected indoors and outdoors in 643 households during the rainy season from August to October 2018. The presence of water containers was systematically recorded and the containers examined for the presence or absence of larvae. Characteristics of the container breeding sites, including size of the container and temperature, pH and conductivity of the water contained within, were recorded as well as the volume of water. Traditional Stegomyia indices were calculated as quantitative indicators of the risk of dengue outbreaks; generalised mixed models were fitted to larval and pupal densities, and the contribution of each covariate to the model was evaluated by the Z-value and associated P-value. A total of 1061 container breeding sites were inspected, of which 760 contained immature stages of Ae. aegypti ('positive' containers). The most frequent container breeding sites found in each health district were tyres and both medium (buckets/cans/pots) and large (bins/barrels/drums) containers; these containers were also the most productive larval habitats and the types that most frequently tested positive. Of the Stegomyia indices, the Breteau, House and Container indices exceeded WHO dengue risk thresholds. Generalised linear mixed models showed that larval and pupal abundances were associated with container type, physicochemical characteristics of the water and collection month, but there were significant differences among container types and among health districts. Aedes aegypti body size was positively associated with type and diameter of the container, as well as with electrical conductivity of the water, and negatively associated with pH and temperature of the water and with the level of exposure of the container to sunlight. This study provides data on putative determinants of the productivity of habitats regarding Ae. aegypti immature stages. These data are useful to better understand Ae. aegypti proliferation. The results suggest that identifying and targeting the most productive container breeding sites could contribute to dengue vector control strategies in Burkina Faso.


Genetic determinants of teratogen-induced abnormal development in mouse and rat embryos in vitro.
The response of an embryo to a teratogenic treatment is often critically dependent on its genetic makeup. However, in conventional in vivo studies of gene-teratogen interactions it may be difficult to distinguish between the effects of genes that are carried by the embryo and those that are carried by the mother. It is likewise not easy to determine whether an observed interaction is between a particular gene and the parent compound administered, or whether it is with a metabolite that has been generated by the maternal system. The use of whole rodent embryo culture offers certain advantages in the study of gene-teratogen interactions. Not only can the effects of metabolism and the maternal genotype be more carefully controlled, but the stage of development at which embryos of different genotypes are exposed can be matched. Rodent whole embryo culture has been used to a limited extent to study interactions between single gene mutations and teratogenic treatments, variations in responses of different strains to teratogens, as well as species differences in response to teratogens. These studies point to the need to precisely control the stage of development at the time of treatment in order to be able to make valid comparisons. But, even more important, they highlight the versatility of the whole embryo culture technique, and underscore the need for its wider use in evaluating the relative contribution of genes and environment to abnormal embryonic development.


Activators of adenylate cyclase and cyclic AMP prolong calcium-dependent action potentials of mouse sensory neurons in culture by reducing a voltage-dependent potassium conductance.
The effects of compounds that activate adenylate cyclase and of cAMP on calcium-dependent action potentials recorded from mouse dorsal root ganglion neurons were assessed. Application of compounds that stimulate the adenylate cyclase system (forskolin, cholera toxin, and prostaglandin E1) increased action potential duration with an associated decrease in afterhyperpolarization. An adenylate cyclase inhibitor, 2',5'-dideoxyadenosine, partially inhibited the responses to forskolin and cholera toxin. cAMP analogs mimicked the effect of forskolin, and the phosphodiesterase inhibitor theophylline enhanced the response to forskolin. Following intracellular injection of the potassium channel blocker cesium, the forskolin response was reduced. Forskolin did not significantly alter resting membrane potential or conductance. The action potential responses to forskolin were voltage dependent, being reduced when the membrane was held at less negative (less than -50 mV) potentials. The data suggest that activators of adenylate cyclase and cAMP prolong calcium-dependent action potentials by blocking a voltage-dependent potassium conductance that is responsible, in part, for action potential repolarization and that inactivates at membrane potentials less negative than -50 mV.


Distinguishing chinese star anise from Japanese star anise using thermal desorption-gas chromatography-mass spectrometry.
The volatile compounds from the pericarps of Illicium anisatum L., Illicium brevistylum A.C.Sm., Illicium griffithii Hook.f. & Thomson, Illicium henryi Diels, Illicium lanceolatum A.C.Sm., Illicium majus Hook.f. & Thomson, Illicium micranthum Dunn, and Illicium verum Hook.f. were examined by thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS). The volatiles desorbed from the pericarps of I. verum (Chinese star anise), the species traded for culinary purposes, were generally characterized by a high proportion of (E)-anethole (57.6-77.1%) and the presence of foeniculin; the latter was otherwise only detected in the pericarps of I. lanceolatum. In the pericarps of all other species analyzed, the percentage composition of (E)-anethole was comparatively lower (<or=16.0%). The volatiles desorbed from the pericarps of the toxic I. anisatum (Japanese star anise) were characterized by the presence of asaricin, methoxyeugenol, and two other eugenol derivatives, none of which were detected in any of the other species examined. TD-GC-MS enables the direct analysis of the volatile components from the pericarps of Illicium and can assist with differentiating the fruits of I. verum from other species of Illicium, particularly the more toxic I. anisatum.


Docetaxel in castration-resistant prostate cancer: a single-centre experience.
We present a single-institution experience reporting the efficacy and safety of docetaxel, administered as first-line chemotherapy, in castration-resistant prostate cancer (CRPC), focusing on patients and treatment parameters. From November 2004 to January 2012, 51 patients received chemotherapy with docetaxel. With a mean follow-up time (from the beginning of CHT) of 1.6 years (range 0.1-5.1 years), 35 patients (68.6%) died for prostate cancer and 48 patients (94.1%) showed progression of the disease. Five factors influenced overall survival: nodal status at diagnosis, neoadjuvant hormonal therapy, number of cycles of docetaxel administered, schedule of docetaxel and ECOG performance status before starting chemotherapy.


Does anti-TNF therapy cause any change in platelet activation in ankylosing spondylitis patients? A comparative study.
Recently, it has been reported that ankylosing spondylitis (AS) was characterised by endothelial dysfunction and the development of atherosclerotic complications. In this study, we evaluated platelet and endothelial activation parameters in AS patients. Fiftynine AS patients and 22 healthy controls were included. The clinical features and acute phase parameters were evaluated. In all patients and healthy controls, platelet-monocyte complexes (PMC), platelet-neutrophil complexes, basal and ADP-stimulated P-selectin (CD62P) expression were determined by flow cytometry; soluble E-selectin (sE-selectin) and soluble CD40L (sCD40L) were determined by ELISA. AS patients were divided into two groups as active and inactive by using BASDAI. In 15 AS patients, the evaluated parameters were assessed before and after 12 weeks of anti-TNF therapy. PMC and sCD40L levels in AS patients were significantly higher than in the control group (P values 0.013 and 0.016). The evaluated variables were similar in active and inactive AS groups (P > 0.05). There were no significant changes in platelet and endothelial activation parameters in AS patients after anti-TNF therapy (P > 0.05). Platelet activation which is reflected by high levels of PMC and sCD40L might be responsible for the increased frequency of atherosclerosis in AS. The platelet activation in our AS patients was not associated with disease activity and did not improve after anti-TNF therapy.


Quality of care issues for dysphagia: modifications involving oral fluids.
This study examined practices of health care providers who thicken oral fluids for patients with impaired swallowing (dysphagia). It contrasts viscosity (thickness) of nectar-like and honey-thick consistencies prepared and measured in a laboratory setting to actual practices in health care settings and to guidelines of the National Dysphagia Diet. The care plans for many patients include changes to fluid thickness to maintain safe intake of oral fluids. Serving patients improperly prepared beverages may contribute to medical complications such as dehydration if patients consume less fluid, or aspiration of overly thin or thickened liquids, which may increase the risk of pneumonia. Descriptive analysis of group trends for viscosity measurements of liquids prepared by health care providers in four care settings to laboratory measurements and the National Dysphagia Diet. Forty-two health care providers participated. Each prepared thickened samples in their natural work environment using typical procedures. Viscosity measurements of modified liquids prepared by health care providers did not compare favourably to published findings of laboratory viscosity measures or to the ranges of the National Dysphagia Diet. Participants who prepared overly thick or overly thin nectar-like liquids followed a similar pattern with honey-like samples. Many participants failed to use product label information in sample preparation. Results suggest that many patients are served modified liquids that are too thick or too thin in relation to their target level of thickness, possibly increasing risk of further medical complications for those who consume them. Product directions that are too vague or general also may contribute to inaccurate results. The patient's nursing staff typically oversees nutritional care plans that may include modifications to oral fluids to enable their patients to safely drink by mouth. Additional consideration should be given to training procedures and possible noncompliance with preparation guidelines.


[Laparoscopic curative surgery for early gastric cancer].
We have successfully treated 40 patients with early gastric cancer by using two different laparoscopic procedures since March 1992, which are laparoscopic wedge resection of the stomach using a lesion-lifting method (n = 25) and laparoscopic intragastric mucosal resection (n = 15). The indication is as follows; 1) mucosal cancer, 2) < 25 mm, if the lesion is protruded type, 3) < 15 mm and Ul(-), if the lesion is depressive type. All patients were discharged within 4-8 days uneventfully. The resected specimens were 66 +/- 16 mm and 48 +/- 8 mm in diameter respectively, and had a sufficient surgical margin horizontally (16 +/- 5 mm, 8 +/- 4 mm) and vertically. Histology revealed they were all curative surgeries except one case in whom an additional gastrectomy with lymph node dissection by lapalotomy was required one month after surgery because lymphatic invasion had been revealed by pathology. In conclusion, these laparoscopic procedures are curative and minimally invasive treatment for early gastric cancer.


Functional consequences of a novel middle ear adaptation in the central African frog Petropedetes parkeri (Ranidae).
During the breeding season, each tympanic membrane of males of the Old World treefrog Petropedetes parkeri is decorated with a single, prominent, fleshy tympanic papilla. The tympanic papilla, located dorsally on the tympanic membrane, is covered by an epidermal surface and is composed of non-ossified, spongiform tissue containing a number of globular, fluid-filled vesicles found at highest density near the papillar tip. These vesicles appear to have exit pores and are probably simple alveolar exocrine glands. Injecting sound into the pressurized vocal cavity of the male and measuring the vibration velocity response of the tympanic membrane revealed that from 0.3 to 2.0 kHz the tympanic papilla velocity amplitude is on average 20 dB lower than that of a point diametrically opposite on the ventral half of the tympanic membrane. The close agreement between the dominant frequency of the call and the frequency of the maximum spectral peak of the Fast Fourier Transform of the impulse response of the eardrum is consistent with the use of the eardrum in this species both as a call receiver and as a call radiator, similar to the function suggested for the eardrum of the male bullfrog Rana catesbeiana. Unexpectedly, surgically removing the tympanic papilla lowered the frequency of the peak vibrational amplitude, testifying to the importance of membrane tension as a dominant factor in the vibratory behavior of the eardrum. During normal positive-pressure breathing, the tympanic papillae move conspicuously, suggesting a possible rôle as a visual signal.


Biosynthesis of thyroglobulin. Incorporation of [1-14C] galactose, [1-14C] manose and [4,5-3H2] leucine into soluble proteins by rat thyroids in vitro.
1. Rat thyroid lobes were incubated for various periods of time in Krebs-Ringer bicarbonate containing [(3)H]leucine and either [1-(14)C]galactose or [1-(14)C]mannose. Radioactivity in soluble proteins was determined after their separation by sucrose-gradient centrifugation. 2. The time-course of incorporation of label from [(14)C]-mannose into soluble thyroid proteins was parallel to that observed for [(3)H]leucine. There was a lag of at least 30min. before either label appeared in non-iodinated thyroglobulin (protein 17-18s). During this time both labels were detected in two fractions known to contain subunit precursors of thyroglobulin (fractions 12s and 3-8s). Radioactivity from double-labelled fractions 12s and 3-8s was transferred to protein 17-18s during subsequent incubation in an unlabelled medium. 3. In contrast, most of the [(14)C]galactose was immediately incorporated into protein 17-18s. 4. During the first hour of incubation, puromycin almost completely inhibited the incorporation of label from [(3)H]leucine and [(14)C]mannose into all protein fractions, but had little effect on the incorporation of [(14)C]galactose into protein 17-18s. 5. These results indicate that mannose is incorporated into the carbohydrate groups of protein 17-18s at an earlier stage in its formation than galactose. It is suggested that the synthesis of the carbohydrate groups of ghyroglobulin begins soon after formation of the polypeptide components, more than 30min. before these are aggregated to protein 17-18s; carbohydrate synthesis then proceeds in a stepwise manner, galactose being incorporated at about the time of aggregation of subunits to protein 17-18s. Most, if not all, the carbohydrate is added to thyroglobulin before it is iodinated.


Meta-Analysis of the Association between Asbestos Exposure and Esophageal Cancer.
We conducted a meta-analysis to quantitatively assess the association between asbestos exposure and esophageal cancer. We systematically collected articles from three electronic databases and calculated the pooled standardized mortality rate (SMR) from the meta-analysis. Subgroup analysis according to the type of asbestos exposure, follow-up years, sample size, industry classification, sex, and high-dose exposure was conducted. From 242 studies, 34 cohort studies were included in our meta-analysis. Pooled SMR was positively associated with asbestos exposure and esophageal cancer (pooled SMR = 1.28; 95% confidence interval (CI) 1.19-1.38, p < 0.00001). In the subgroup analysis, (1) chrysolite, (2) four groups with follow-up over ten years, (3) the textile industry and shipyard, (4) both male and female, and (5) eight studies on highest asbestos exposure, all the subgroups showed significantly increased pooled SMRs. Asbestos exposure was significantly and positively associated with esophageal cancer, especially chrysolite. Considering the long latency period, we suggest that patients should be followed up for cancer, including esophageal cancer, for over ten years.


Inequality in measles vaccination coverage in the "big six" countries of the WHO South-East Asia region.
The "big six" countries (Bangladesh, India, Indonesia, Myanmar, Nepal, and Thailand) in the World Health Organization South-East Asia Region (WHO SEAR) are currently facing severe challenges in measles elimination and consequent childhood mortality reduction, with inadequacies and inequalities in the coverage of the measles-containing-vaccine first-dose (MCV1) being major obstacles. However, these issues of inequality in MCV1 coverage have not yet been systematically examined. We used data from the latest Demographic and Health Surveys and Multiple Indicator Cluster Surveys. To provide a comprehensive picture of existing MCV1 coverage gaps, data were disaggregated by geographic location, as well as by socioeconomic and nutritional dimensions. National MCV1 coverage ranged from 77% in Myanmar to 92% in Thailand. Only nine of the 104 sub-national districts had achieved the 95% MCV1 coverage goal as set by the WHO. Geographic inequalities were more pronounced in countries with lower coverage levels. Areas in clusters with poor MCV1 coverage performances as well as disadvantaged socioeconomic profiles require increased attention. Inequalities were evident in all countries, except Thailand, and were more pronounced in the sectors of wealth, education, antenatal care (ANC) status, and vitamin A supplementation (VAS) when compared against the areas of gender and urban/rural residence. Wealth-related inequality in Bangladesh, education-related inequality in Indonesia, ANC-related inequalities in Myanmar and Nepal, and VAS-related inequalities in Indonesia and Myanmar were all noteworthy. Equity-oriented changes in policies focusing on health promotion and integrated interventions among disadvantaged populations need to be implemented in order to increase MCV1 coverage and reduce childhood mortality.


Cost effectiveness of radioembolization compared with conventional transarterial chemoembolization for treatment of hepatocellular carcinoma.
To assess cost effectiveness of radioembolization versus conventional transarterial chemoembolization. The cost of radioembolization versus conventional transarterial chemoembolization was determined based on Medicare reimbursements. Three patient subgroups were defined based on the Barcelona Clinic Liver Cancer (BCLC) classification system (A, B, or C). Efficacy and safety outcomes after each procedure were obtained from the literature. A Monte Carlo case-based simulation was designed for 60 months in 250 patients in each subgroup. Survival was calculated based on average survival from the literature and the Monte Carlo model. The primary outcome was the cost effectiveness of radioembolization over transarterial chemoembolization by considering calculated survival. The costs approached $17,000 for transarterial chemoembolization versus $31,000 or $48,000 for unilobar or bilobar radioembolization, respectively. Based on the simulation, median estimated survival was greater with transarterial chemoembolization than radioembolization in BCLC-A and BCLC-B subgroups (40 months vs 30 months and 23 months vs 16 months, respectively, P = .001). However, in the BCLC-C subgroup, survival was greater with radioembolization than transarterial chemoembolization (13 months vs 17 months, P = .001). The incremental cost-effectiveness ratio of radioembolization over transarterial chemoembolization in the BCLC-C subgroup was $360 per month. The results were dependent on bilobar versus unilobar radioembolization and the total number of radioembolization procedures. The model suggests radioembolization costs may be justified for patients with BCLC-C disease, whereas radioembolization may not be cost effective in patients with BCLC-A disease; however, many patients with BCLC-C disease have extensive disease precluding locoregional therapies. Secondary considerations may determine treatment choice in more borderline patients (BCLC-B disease) because there is no persistent survival benefit with radioembolization.


MicroRNA-381 facilitates autophagy and apoptosis in prostate cancer cells via inhibiting the RELN-mediated PI3K/AKT/mTOR signaling pathway.
MicroRNAs (miRNAs) function as oncogenes or tumor suppressors in an extensive variety of human cancers, including prostate cancer (PCa). Herein, the aim of this study is to investigate the effect of miR-381 on autophagy and apoptosis of PCa cells through the reelin (RELN)-mediated the PI3K/AKT/mTOR signaling pathway. PCa-related differentially expressed genes and regulatory miRNA were retrieved according to microarray-based analysis and online mRNA-miRNA interaction analysis. The regulatory relationship between miR-381 and RELN was verified by bioinformatics prediction and dual-luciferase reporter gene assay. Gain- and loss-of-function experiments were applied to analyze the effects of miR-381 and RELN on the abilities of proliferation, apoptosis as well as autophagy of PCa cells. Furthermore, xenograft tumor was developed in nude mice to examine the tumorigenic ability of PCa. RELN, which was found to be up-regulated in PCa, was identified as a target of miR-381. Overexpressed miR-381 suppressed PCa cell proliferation while promoted autophagy and apoptosis of PCa cells. In addition, miR-381 inhibited the activation of the PI3K/AKT/mTOR signaling pathway by targeting RELN. In vivo experiments also confirmed that overexpression of miR-381 could inhibit the tumorigenic ability of PCa. Up-regulation of miR-381 inhibits the expression of RELN, which in turn inhibits the activation of the PI3K/AKT/mTOR signaling pathway, thereby inhibiting PCa cell proliferation, and promoting PCa cell apoptosis and autophagy.


Influence of genetics on disease susceptibility and progression.
For many chronic diseases, the influence of genetics is complex and phenotypes do not conform to simple Mendelian patterns of inheritance. Discussed here are two types of genetic influences on healthy aging. The first involves variation in the gene sequence itself and how this may influence disease susceptibility, progression, and severity, interacting with other recognized risk factors. The second involves epigenetic regulatory mechanisms that may potentially provide insight into how environmental influences affect the expressed genome, thus improving our understanding of the genetic mechanisms underlying multifactorial diseases. The interleukin-1 family of cytokines can be used to illustrate how genetic sequence variation may affect such diseases. This cytokine family plays a key role in mediating inflammation, which is now understood to be a central component of a growing number of chronic diseases. Recent work has revealed many sequence variations in the regulatory DNA of genes encoding important members of the interleukin-1 family, and these variations are associated with differential effects on the inflammatory response. The interactions of environmental factors with both DNA sequence variations and epigenetic modifications are likely to determine the phenotypes of multifactorial diseases of aging as well as the phenotype of healthy aging.


Direct composites in anteriors: a matter of substrate.
When planning a restoration, the color of the substrate should also be taken into account in order to achieve a satisfactory esthetic outcome. In some clinical situations, clinicians are asked to hide the substrate with the restoration; in other situations, clinicians can take advantage of an unaltered color substrate and therefore select less opaque materials that exploit the color of the underlying tissue.


Effects of abomasal infusion of conjugated linoleic acids, Sterculia foetida oil, and fish oil on production performance and the extent of fatty acid Δ⁹-desaturation in dairy cows.
The purpose of this study was to determine the effects of conjugated linoleic acid (CLA), Sterculia foetida oil (STO), and fish oil (FO) on milk yield and composition, milk FA profile, Δ(9)-desaturation activity, and mammary expression of 2 isoforms of stearoyl-coenzyme A desaturase (SCD-1 and SCD-5) in lactating dairy cows. Eight multiparous Holstein cows (69 ± 13 d postpartum) were used in a double 4 × 4 Latin square design with 28-d periods. For the first 14 d of each period, cows received an abomasal infusion of (1) 406 g of a saturated fatty acid (SFA) supplement (112 g of 16:0 + 230 g of 18:0) used as a control (CTL), (2) 36 g of a CLA supplement (13.9 g of trans-10,cis-12 18:2) + 370 g of SFA, (3) 7 g of STO (3.1g of 19:1 cyclo) + 399 g of SFA, or (4) 406 g of FO (55.2 g of cis-5,-8,-11,-14,-17 20:5 + 59.3 g of cis-4,-7,-10,-13,-16,-19 22:6). Infusions were followed by a 14-d washout interval. Compared with CTL, STO decreased milk yield from 38.0 to 33.0 kg/d, and increased milk fat concentration from 3.79 to 4.45%. Milk fat concentration was also decreased by CLA (2.23%) and FO (3.34%). Milk fat yield was not affected by STO (1,475 g/d) compared with CTL (1,431 g/d), but was decreased by CLA (774 g/d) and FO (1,186 g/d). Desaturase indices for 10:0, 12:0, and 20:0 were decreased, whereas the extent of desaturation of 14:0, 16:0, 17:0, and 18:0 was not affected by CLA treatment compared with CTL. Infusion of STO significantly decreased all calculated desaturase indices compared with CTL; the 14:0 index was reduced by 80.7%. Infusion of FO decreased the desaturase indices for 10:0, 14:0, 20:0, trans-11 18:1, and 18:0. The effect of FO on the 14:0 index indicates a decrease in apparent Δ(9)-desaturase activity of 30.2%. Compared with CTL, mammary mRNA abundance of SCD-1 was increased by STO (+30%) and decreased by CLA (-24%), whereas FO had no effect. No effect was observed on mRNA abundance of SCD-5. In conclusion, abomasal infusion of CLA, STO, and FO were shown to exhibit varying and distinct effects on desaturase indices, an indicator of apparent SCD activity, and mammary mRNA abundance of SCD-1.


From Molecular Insights to Clinical Perspectives in Drug-Associated Bullous Pemphigoid.
Bullous pemphigoid (BP), the most common autoimmune blistering disease, is characterized by the presence of autoantibodies targeting BP180 and BP230 in the basement membrane zone. This leads to the activation of complement-dependent and independent pathways, resulting in proteolytic cleavage at the dermoepidermal junction and an eosinophilic inflammatory response. While numerous drugs have been associated with BP in the literature, causality and pathogenic mechanisms remain elusive in most cases. Dipeptidyl peptidase 4 inhibitors (DPP4i), in particular, are the most frequently reported drugs related to BP and, therefore, have been extensively investigated. They can potentially trigger BP through the impaired proteolytic degradation of BP180, combined with immune dysregulation. DPP4i-associated BP can be categorized into true drug-induced BP and drug-triggered BP, with the latter resembling classic BP. Antineoplastic immunotherapy is increasingly associated with BP, with both B and T cells involved. Other drugs, including biologics, diuretics and cardiovascular and neuropsychiatric agents, present weaker evidence and poorly understood pathogenic mechanisms. Further research is needed due to the growing incidence of BP and the increasing identification of new potential triggers.


A critical epithelial survival axis regulated by MCL-1 maintains thymic function in mice.
T-cell differentiation is governed by interactions with thymic epithelial cells (TECs) and defects in this process undermine immune function and tolerance. To uncover new strategies to restore thymic function and adaptive immunity in immunodeficiency, we sought to determine the molecular mechanisms that control life and death decisions in TECs. Guided by gene expression profiling, we created mouse models that specifically deleted prosurvival genes in TECs. We found that although BCL-2 and BCL-XL were dispensable for TEC homeostasis, MCL-1 deficiency impacted on TECs as early as embryonic day 15.5, resulting in early thymic atrophy and T-cell lymphopenia, with near complete loss of thymic tissue by 2 months of age. MCL-1 was not necessary for TEC differentiation but was continually required for the survival of mature cortical and medullary TECs and the maintenance of thymic architecture. A screen of TEC trophic factors in organ cultures showed that epidermal growth factor upregulated MCL-1 via MAPK/ERK kinase activity, providing a molecular mechanism for the support of TEC survival. This signaling axis governing TEC survival and thymic function represents a new target for strategies for thymic protection and regeneration.


The draft genome of Mycobacterium aurum, a potential model organism for investigating drugs against Mycobacterium tuberculosis and Mycobacterium leprae.
Mycobacterium aurum (M. aurum) is an environmental mycobacteria that has previously been used in studies of anti-mycobacterial drugs due to its fast growth rate and low pathogenicity. The M. aurum genome has been sequenced and assembled into 46 contigs, with a total length of 6.02Mb containing 5684 annotated protein-coding genes. A phylogenetic analysis using whole genome alignments positioned M. aurum close to Mycobacterium vaccae and Mycobacterium vanbaalenii, within a clade related to fast-growing mycobacteria. Large-scale genomic rearrangements were identified by comparing the M. aurum genome to those of Mycobacterium tuberculosis and Mycobacterium leprae. M. aurum orthologous genes implicated in resistance to anti-tuberculosis drugs in M. tuberculosis were observed. The sequence identity at the DNA level varied from 68.6% for pncA (pyrazinamide drug-related) to 96.2% for rrs (streptomycin, capreomycin). We observed two homologous genes encoding the catalase-peroxidase enzyme (katG) that is associated with resistance to isoniazid. Similarly, two embB homologues were identified in the M. aurum genome. In addition to describing for the first time the genome of M. aurum, this work provides a resource to aid the use of M. aurum in studies to develop improved drugs for the pathogenic mycobacteria M. tuberculosis and M. leprae.


Insights From a Text Messaging-Based Sexual and Reproductive Health Information Program in Tanzania (m4RH): Retrospective Analysis.
Many mobile health (mHealth) interventions have the potential to generate and store vast amounts of system-generated participant interaction data that could provide insight into user engagement, programmatic strengths, and areas that need improvement to maximize efficacy. However, despite the popularity of mHealth interventions, there is little documentation on how to use these data to monitor and improve programming or to evaluate impact. This study aimed to better understand how users of the Mobile for Reproductive Health (m4RH) mHealth intervention engaged with the program in Tanzania from September 2013 to August 2016. We conducted secondary data analysis of longitudinal data captured by system logs of participant interactions with the m4RH program from 127 districts in Tanzania from September 2013 to August 2016. Data cleaning and analysis was conducted using Stata 13. The data were examined for completeness and "correctness." No missing data was imputed; respondents with missing or incorrect values were dropped from the analyses. The total population for analysis included 3,673,702 queries among 409,768 unique visitors. New users represented roughly 11.15% (409,768/3,673,702) of all queries. Among all system queries for new users, 46.10% (188,904/409,768) users accessed the m4RH main menu. Among these users, 89.58% (169,218/188,904) accessed specific m4RH content on family planning, contraceptive methods, adolescent-specific and youth-specific information, and clinic locations after first accessing the m4RH main menu. The majority of these users (216,422/409,768, 52.82%) requested information on contraceptive methods; fewer users (23,236/409,768, 5.67%) requested information on clinic location. The conversion rate was highest during the first and second years of the program when nearly all users (11,246/11,470, 98.05%, and 33,551/34,830, 96.33%, respectively) who accessed m4RH continued on to query more specific content from the system. The rate of users that accessed m4RH and became active users declined slightly from 98.05% (11,246/11,470) in 2013 to 87.54% (56,696/64,765) in 2016. Overall, slightly more than one-third of all new users accessing m4RH sent queries at least once per month for 2 or more months, and 67.86% (278,088/409,768) of new and returning users requested information multiple times per month. Promotional periods were present for 15 of 36 months during the study period. The analysis of the rich data captured provides a useful framework with which to measure the degree and nature of user engagement utilizing routine system-generated data. It also contributes to knowledge of how users engage with text messaging (short message service)-based health promotion interventions and demonstrates how data generated on user interactions could inform improvements to the design and delivery of a service, thereby enhancing its effectiveness.


Umbelliferone and scopoletin target tyrosine kinases on fibroblast-like synoviocytes to block NF-κB signaling to combat rheumatoid arthritis.
Rheumatoid arthritis (RA) is a complex autoimmune condition primarily affecting synovial joints, which targeted synthetic drugs have damaging safety issues. Saussurea laniceps, a reputed anti-rheumatic medicinal herb, is an excellent place to start looking for natural products as safe, effective, targeted therapeutics for RA. Via biomimetic ultrafiltration, umbelliferone and scopoletin were screened as two anti-rheumatic candidates with the highest specific affinities towards the membrane proteomes of rheumatic fibroblast-like synoviocytes (FLS), the pivotal effector cells in RA. In vitro assays confirmed that the two compounds, to varying extents, inhibited RA-FLS proliferation, migration, invasion, and NF-κB signaling. Network pharmacology analysis and molecular docking analysis jointly revealed that umbelliferone and scopoletin act on multiple targets, mostly tyrosine kinases, in combating RA. Taken together, our present study identified umbelliferone and scopoletin as two major anti-rheumatic components from SL that may bind and inhibit tyrosine kinases and subsequently inactivate NF-κB in RA-FLSs. Our integrated drug discovery strategy could be valuable in finding other multi-target bioactive compounds from complex matrices for treating multifactorial diseases.


THE EFFECT OF ILEOCECAL VALVE REMOVAL IN A MODEL OF SHORT BOWEL SYNDROME.
Short bowel syndrome is a harmful condition that needs experimental research. To assess the impact of the ileocecal valve removal in a model of short bowel syndrome, in order to investigate the evolution of the colon under this circumstance. Fifteen Wistar rats were equitable divided into: Control (Sham), Group I (70% enterectomy preserving ileocecal valve) and Group II (70% enterectomy excluding ileocecal valve). After enterectomy was performed jejunoileal or jejunocecal anastomosis and sacrificed the animals on 30th postoperative day for histomorphometric study of the colon. During this period, was observed the clinical evolution of the animals weekly including body weight measurement. Group I and II presented progressive loss of weight. In Group I was observed diarrhea, perineal hyperemia and purple color of the colon during autopsy. Histomorphometry assay showed hypertrophy and hyperplasia of colon mucosa in Group I. In Group II the colon wall was thicker due to hypertrophy and muscular hyperplasia, and in mucosa vascular proliferation and inflammatory infiltrate were intense. This short bowel syndrome model is relevant and achieve 100% of survival. Animal's weight loss was not altered by the presence or exclusion of the ileocecal valve. Animals with 70% of small bowel removal and presence of the ileocecal valve attained a better clinical evolution and histological colon adaptation than those without ileocecal valve.


Matching Biomedical Ontologies: Construction of Matching Clues and Systematic Evaluation of Different Combinations of Matchers.
Ontology matching seeks to find semantic correspondences between ontologies. With an increasing number of biomedical ontologies being developed independently, matching these ontologies to solve the interoperability problem has become a critical task in biomedical applications. However, some challenges remain. First, extracting and constructing matching clues from biomedical ontologies is a nontrivial problem. Second, it is unknown whether there are dominant matchers while matching biomedical ontologies. Finally, ontology matching also suffers from computational complexity owing to the large-scale sizes of biomedical ontologies. To investigate the effectiveness of matching clues and composite match approaches, this paper presents a spectrum of matchers with different combination strategies and empirically studies their influence on matching biomedical ontologies. Besides, extended reduction anchors are introduced to effectively decrease the time complexity while matching large biomedical ontologies. In this paper, atomic and composite matching clues are first constructed in 4 dimensions: terminology, structure, external knowledge, and representation learning. Then, a spectrum of matchers based on a flexible combination of atomic clues are designed and utilized to comprehensively study the effectiveness. Besides, we carry out a systematic comparative evaluation of different combinations of matchers. Finally, extended reduction anchor is proposed to significantly alleviate the time complexity for matching large-scale biomedical ontologies. Experimental results show that considering distinguishable matching clues in biomedical ontologies leads to a substantial improvement in all available information. Besides, incorporating different types of matchers with reliability results in a marked improvement, which is comparative to the state-of-the-art methods. The dominant matchers achieve F1 measures of 0.9271, 0.8218, and 0.5 on Anatomy, FMA-NCI (Foundation Model of Anatomy-National Cancer Institute), and FMA-SNOMED data sets, respectively. Extended reduction anchor is able to solve the scalability problem of matching large biomedical ontologies. It achieves a significant reduction in time complexity with little loss of F1 measure at the same time, with a 0.21% decrease on the Anatomy data set and 0.84% decrease on the FMA-NCI data set, but with a 2.65% increase on the FMA-SNOMED data set. This paper systematically analyzes and compares the effectiveness of different matching clues, matchers, and combination strategies. Multiple empirical studies demonstrate that distinguishing clues have significant implications for matching biomedical ontologies. In contrast to the matchers with single clue, those combining multiple clues exhibit more stable and accurate performance. In addition, our results provide evidence that the approach based on extended reduction anchors performs well for large ontology matching tasks, demonstrating an effective solution for the problem.