Domain structure and sequence distribution in dentin phosphophoryn.
Phosphophoryn (PP) is a protein unique to the mineralized matrix of dentin. It also has a unique composition, with aspartic acid and phosphoserine comprising greater than 85% of all amino acid residues. Because of this unique composition and high content of phosphoserine, it has been difficult to apply direct peptide sequencing procedures effectively. However, to understand its function, and to prepare suitable probes for screening cDNA libraries, some sequence distribution information is required. To this end, using bovine (b) and rat incisor (ri) PPs, partial mild acid hydrolysis has been used to cleave at the aspartic acid residues and generate free amino acids and small peptides. The nature of the released amino acids and peptides has been determined. Peptides have also been generated by limited digestion with trypsin. Some of the peptides have been purified by h.p.l.c. techniques and sequenced. About 90% of the bPP and riPP were resistant to trypsin, and the large resistant fragment was sharply depleted of the non-aspartic acid and non-phosphoserine [(P)Ser] residues. All peptides isolated were acidic, but the remaining residues (other than aspartic acid and serine) appeared to be collected in regions flanking the trypsin-resistant core. These data show directly the presence of regions [Asp]n, [(P)Ser]m and [Asp-(P)Ser-Asp]k as prominent sequence features. A domain structure model is proposed.


The controversy of significance testing: misconceptions and alternatives.
The current debate about the merits of null hypothesis significance testing, even though provocative, is not particularly novel. The significance testing approach has had defenders and opponents for decades, especially within the social sciences, where reliance on the use of significance testing has historically been heavy. The primary concerns have been (1) the misuse of significance testing, (2) the misinterpretation of P values, and (3) the lack of accompanying statistics, such as effect sizes and confidence intervals, that would provide a broader picture into the researcher's data analysis and interpretation. This article presents the current thinking, both in favor and against, on significance testing, the virtually unanimous support for reporting effect sizes alongside P values, and the overall implications for practice and application.


Kinetics of carbon dioxide during cardiopulmonary resuscitation.
CO2 kinetics during CPR was investigated in 15 anesthetized piglets. BP, blood gases, and acid-base balance were monitored through catheters in the carotid artery and a central vein, as well as in cerebrospinal fluid. Cardiac arrest was induced by a transthoracic direct current shock. CPR was begun immediately by artificial ventilation and simultaneous external chest compressions. Epinephrine was administered after 8 min of CPR. One group (n = 5) of animals received no buffer treatment while another (n = 5) received an infusion of 75 mmol sodium bicarbonate and a third group (n = 5) received an equivalent amount of tris-buffer mixture. The results of these experiments, as well as previously described circulatory variables during CPR, were analyzed using a computer model describing the CO2 kinetics of the pig. Our main finding was that PaCO2 was positively correlated to cardiac output during CPR; improved cardiac output during CPR resulted in more efficient tissue CO2 elimination and was associated with increased survival rates. PaCO2 was also somewhat reduced by efficient alveolar hyperventilation. The arterial PCO2 and pH did not reflect the acid-base balance in peripheral tissues. During CPR, bicarbonate and tris-buffer mixture both quickly passed through the blood-brain barrier. When buffer treatment is indicated during CPR, a buffer which does not increase tissue PCO2 may be the drug of choice.


European guidelines on perioperative venous thromboembolism prophylaxis: Patients with preexisting coagulation disorders and after severe perioperative bleeding.
: In patients with inherited bleeding disorders undergoing surgery, we recommend assessment of individual risk for venous thromboembolism, taking into account the nature of the surgery and anaesthetic, type and severity of bleeding disorder, age, BMI, history of thrombosis, the presence of malignancy and other high-risk comorbidities. Venous thromboembolism risk should be balanced against the increased bleeding risk associated with anticoagulant use in patients with known bleeding disorders (Grade 1C). In these patients undergoing major surgery, we recommend against routine postoperative use of pharmacological thromboprophylaxis, especially for patients with haemophilia A and B (Grade 1B). Glomerular filtration rate should be assessed before initiation of each direct oral anticoagulant, and also at least once a year or more frequently as needed, such as postoperatively before the resumption of therapeutic direct oral anticoagulant administration, when it is suspected that renal function could decline or deteriorate (Grade 1C). Reduced dosages of low molecular weight heparins may be used relatively safely during transient severe (<50 × 10 l) thrombocytopaenia (Grade 2C). Monitoring of anti-Xa levels may be used to adjust the doses of low molecular weight heparin in patients with moderate or severe thrombocytopaenia (Grade 2C). The delay between major gastrointestinal bleeding and resuming warfarin should be at least 7 days (Grade 2C). For patients at a high risk of thromboembolism and with a high bleeding risk after surgery, we consider that administering a reduced dose of direct oral anticoagulant on the evening after surgery and on the following day (first postoperative day) after surgery is a good practice (Grade 2B).


Evaluation of a rapid dipstick test for identifying cholera cases during the outbreak.
Intermittent cholera outbreaks are major problem in many of the states of India. It is essential to identify cholera at the earliest for timely mobilization of public health responses and to abort the outbreaks. The present study was a part of a diarrhoeal outbreak investigation in Secunderabad, India, during May 2009 where the usefulness of Crystal VC rapid dipstick kit was assessed for detecting the aetiologic agent of the outbreak. Stool specimens were collected from 15 hospitalized patients with acute watery diarrhoea and analyzed for detection of cholera vibrios using Crystal VC rapid dipstick kit and the usefulness of the kit was determined by comparative analysis of the same set of specimens using both microbiological and real-time PCR (RT-PCR) based assays. Detection of Vibrio cholerae O1 from 10 of 15 specimens was recorded using dipstick assay. Microbiological methods detected V. cholerae O1 positivity among 11 specimens. However, RT-PCR based assay showed all 15 specimens positive for the presence of V. cholerae O1. In addition, the same assay showed that the pathogen load in the dipstick as well as RT-PCR positive specimens ranged from 10 6 colony forming units (cfu)/ml or more. Crystal VC kit had the potential to identify cholera cases in 10 min in field conditions without having good laboratory support. Therefore, dipstick kit may be considered as cholera detecting tool in diarrhoeal outbreak investigations. Specimens from clinically typical cholera cases, if negative by dipstick, should be reanalyzed by culture based methods.


Antibody-mediated drug delivery.
Passive and active targeted nanoparticulate delivery systems show promise to compensate for lacking properties of conventional therapy such as side effects, insufficient efficiency and accumulation of the drug at target site, poor pharmacokinetic properties etc. For active targeting, physically or covalently conjugated ligands, including monoclonal antibodies and their fragments, are consistently used and researched for targeting delivery systems or drugs to their target site. Currently, there are several FDA approved actively targeted antibody-drug conjugates, whereas no active targeted delivery system is in clinical use at present. However, efforts to successfully formulate actively targeted delivery systems continue. The scope of this review will be the use of monoclonal antibodies and their fragments as targeting ligands. General information about targeted delivery and antibodies will be given at the first half of the review. As for the second half, fragmentation of antibodies and conjugation approaches will be explained. Monoclonal antibodies and their fragments as targeting ligands and approaches for conjugating these ligands to nanoparticulate delivery systems and drugs will be the main focus of this review, polyclonal antibodies will not be included.


Accuracy of auto-identification of the posteroanterior cephalometric landmarks using cascade convolution neural network algorithm and cephalometric images of different quality from nationwide multiple centers.
The purpose of this study was to evaluate the accuracy of auto-identification of the posteroanterior (PA) cephalometric landmarks using the cascade convolution neural network (CNN) algorithm and PA cephalogram images of a different quality from nationwide multiple centers nationwide. Of the 2798 PA cephalograms from 9 university hospitals, 2418 images (2075 training set and 343 validation set) were used to train the CNN algorithm for auto-identification of 16 PA cephalometric landmarks. Subsequently, 99 pretreatment images from the remaining 380 test set images were used to evaluate the accuracy of auto-identification of the CNN algorithm by comparing with the identification by a human examiner (gold standard) using V-Ceph 8.0 (Ostem, Seoul, South Korea). Pretreatment images were used to eliminate the effects of orthodontic bracket, tube and wire, surgical plate, and surgical screws. Paired t test was performed to compare the x- and y-coordinates of each landmark. The point-to-point error and the successful detection rate (range, within 2.0 mm) were calculated. The number of landmarks without a significant difference between the location identified by the human examiner and by auto-identification by the CNN algorithm were 8 on the x-coordinate and 5 on the y-coordinate, respectively. The mean point-to-point error was 1.52 mm. The low point-to-point error (<1.0 mm) was observed at the left and right antegonion (0.96 mm and 0.99 mm, respectively) and the high point-to-point error (>2.0 mm) was observed at the maxillary right first molar root apex (2.18 mm). The mean successful detection rate of auto-identification was 83.3%. Cascade CNN algorithm for auto-identification of PA cephalometric landmarks showed a possibility of an effective alternative to manual identification.


Evaluation of multiple transfer of DNA using mock case scenarios.
DNA transfer and its possible role in explaining the presence of a biological sample at a crime scene is becoming more prevalent in criminal investigations and related court proceedings. To assist understanding of DNA transfer and assess the extent to which we can utilise already available information regarding transfer of DNA we compare transfer rates determined from mock multi-step transfer scenarios with transfer rates predicted by the application of currently available transfer rate data. The transfer results obtained from the scenarios tested were, in some instances, different (both lower and higher rates) from those predicted. These discrepancies are most likely the result of the impact of as yet untested variables. These may include the variations in substrate type, transfer area size and environmental factors such as temperature and humidity among others. Whilst detailed re-enactments of proposed transfer scenarios, that take into account the many possibly relevant aspects affecting transfer are desirable, to provide an accurate likelihood estimate, these are not always possible. The application of detailed transfer rate tables that include data on the many factors affecting transfer could provide a useful substitute for evaluating the likelihood of specific transfer events. The value and accuracy derived from applying such tables will improve as more research in this area is conducted and the tables expanded and refined.


SARS-COV-2 INFECTION AND LONGITUDINAL FECAL SCREENING IN MALAYAN TIGERS (PANTHERA TIGRIS JACKSONI), AMUR TIGERS (PANTHERA TIGRIS ALTAICA ), AND AFRICAN LIONS (PANTHERA LEO KRUGERI) AT THE BRONX ZOO, NEW YORK, USA.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged as the cause of a global pandemic in 2019-2020. In March 2020, New York City became the epicenter in the United States for the pandemic. On 27 March 2020, a Malayan tiger (Panthera tigris jacksoni) at the Bronx Zoo in New York City developed a cough and wheezing with subsequent inappetence. Over the next week, an additional Malayan tiger and two Amur tigers (Panthera tigris altaica) in the same building and three lions (Panthera leo krugeri) in a separate building also became ill. The index case was anesthetized for diagnostic workup. Physical examination and bloodwork results were unremarkable. Thoracic radiography and ultrasonography revealed a bronchial pattern with peribronchial cuffing and mild lung consolidation with alveolar-interstitial syndrome, respectively. SARS-CoV-2 RNA was identified by real-time, reverse transcriptase PCR (rRT-PCR) on oropharyngeal and nasal swabs and tracheal wash fluid. Cytologic examination of tracheal wash fluid revealed necrosis, and viral RNA was detected in necrotic cells by in situ hybridization, confirming virus-associated tissue damage. SARS-CoV-2 was isolated from the tracheal wash fluid of the index case, as well as the feces from one Amur tiger and one lion. Fecal viral RNA shedding was confirmed in all seven clinical cases and an asymptomatic Amur tiger. Respiratory signs abated within 1-5 days for most animals, although they persisted intermittently for 16 days in the index case. Fecal RNA shedding persisted for as long as 35 days beyond cessation of respiratory signs. This case series describes the clinical presentation, diagnostic evaluation, and management of tigers and lions infected with SARS-CoV-2 and describes the duration of viral RNA fecal shedding in these cases. This report documents the first known natural transmission of SARS-CoV-2 from humans to nondomestic felids.


AgentDress: Realtime Clothing Synthesis for Virtual Agents using Plausible Deformations.
We present a CPU-based real-time cloth animation method for dressing virtual humans of various shapes and poses. Our approach formulates the clothing deformation as a high-dimensional function of body shape parameters and pose parameters. In order to accelerate the computation, our formulation factorizes the clothing deformation into two independent components: the deformation introduced by body pose variation (Clothing Pose Model) and the deformation from body shape variation (Clothing Shape Model). Furthermore, we sample and cluster the poses spanning the entire pose space and use those clusters to efficiently calculate the anchoring points. We also introduce a sensitivity-based distance measurement to both find nearby anchoring points and evaluate their contributions to the final animation. Given a query shape and pose of the virtual agent, we synthesize the resulting clothing deformation by blending the Taylor expansion results of nearby anchoring points. Compared to previous methods, our approach is general and able to add the shape dimension to any clothing pose model. Furthermore, we can animate clothing represented with tens of thousands of vertices at 50+ FPS on a CPU. We also conduct a user evaluation and show that our method can improve a user's perception of dressed virtual agents in an immersive virtual environment (IVE) compared to a realtime linear blend skinning method.


Hypoglycaemia and hyperglycaemia in neonatal encephalopathy: a systematic review and meta-analysis.
Although hypoglycaemia and hyperglycaemia represent the most common metabolic problem in neonates, there is still uncertainty regarding the effects of glucose homoeostasis on the neurological outcomes of infants with neonatal encephalopathy (NE). To systematically investigate the association between neonatal hypoglycaemia and hyperglycaemia with adverse outcome in children who suffered from NE. We searched Pubmed, Embase and Web of Science databases to identify studies which reported prespecified outcomes and compared infants with NE who had been exposed to neonatal hypoglycaemia or hyperglycaemia with infants not exposed. We assessed the risk of bias (ROBINS-I), quality of evidence (Grading of Recommendations, Assessment, Development and Evaluation (GRADE)) for each of the studies. RevMan was used for meta-analysis (inverse variance, fixed effects). Death or neurodevelopmental outcomes at 18 months of age or later. 82 studies were screened, 28 reviewed in full and 12 included. Children who were exposed to neonatal hypoglycaemia had higher odds of neurodevelopmental impairment or death (6 studies, 685 infants; 40.6% vs 25.4%; OR=2.17, 95% CI 1.46 to 3.25; p=0.0001). Neonatal exposure to hyperglycaemia was associated with death or neurodisability at 18 months or later (7 studies, 807 infants; 46.1% vs 28.0%; OR=3.07, 95% CI 2.17 to 4.35; p<0.00001). These findings were confirmed in the subgroup analysis, which included only the infants who underwent therapeutic hypothermia. These data suggest that neonatal hypoglycaemia and hyperglycaemia may be associated with the neurodevelopmental outcome later on in infants with NE. Further studies with long-term follow-up are needed to optimise the metabolic management of these high-risk infants. CRD42022368870.


Molecular and physiological characterization of arabidopsis GAI alleles obtained in targeted Ds-tagging experiments.
Bioactive gibberellin (GA) is an essential regulator of vascular plant development. The GAI gene of Arabidopsis thaliana (L.) Heynh. encodes a product (GAI) that is involved in GA signalling. The dominant mutant gai allele encodes an altered product (gai) that confers reduced GA responses, dwarfism, and elevated endogenous GA levels. Recessive, presumed loss-of-function alleles of GAI confer normal height and resistance to the GA biosynthesis inhibitor paclobutrazol. One explanation for these observations is that GAI is a growth repressor whose activity is opposed by GA, whilst gai retains a constitutive repressor activity that is less affected by GA. Previously, we described gai-t6, a mutant allele which contains an insertion of a maize Ds transposable element into gai. Here we describe the molecular and physiological characterization of two further alleles (gai-t5, gai-t7) identified during the Ds mutagenesis experiment. These alleles confer paclobutrazol resistance and normal endogenous GA levels. Thus the phenotype conferred by gai-t5, gai-t6 and gai-t7 is not due to elevated GA levels, but is due to loss of gai, a constitutively active plant growth repressor.


Dynamic facial reanimation with orthodromic temporalis tendon transfer in children.
To our knowledge, orthodromic temporalis tendon transfer (OTTT) for dynamic facial reanimation has not been described for use in children. Three pediatric patients with permanent facial paralysis underwent OTTT using our modified technique between August 30, 2010, and January 23, 2012. Outcomes were assessed by the surgeons, patients, and patient families, with the longest follow-up period being 13 months after surgery. Two patients were 4 years old at the time of surgery, and the third patient was 17 years old. All underwent upper eyelid gold weight placement and OTTT. The hospital length of stay was 1 to 2 nights. By the first postoperative visit, all patients exhibited improved symmetry at rest, creation of a melolabial crease, and voluntary movement of the oral commissure and smile production without physical therapy. The OTTT for dynamic facial reanimation in children seems to be safe and effective. To our knowledge, this is the first report of the use of this procedure in pediatric patients. This procedure has an advantage over free muscle transfer procedures in achieving immediate dynamic reanimation in a single-stage surgical procedure, without significant additional donor site morbidity. This is an important procedure in our armamentarium for treating pediatric facial paralysis.


Cryo-electron microscopic structure of SecA protein bound to the 70S ribosome.
SecA is an ATP-dependent molecular motor pumping secretory and outer membrane proteins across the cytoplasmic membrane in bacteria. SecA associates with the protein-conducting channel, the heterotrimeric SecYEG complex, in a so-called posttranslational manner. A recent study further showed binding of a monomeric state of SecA to the ribosome. However, the true oligomeric state of SecA remains controversial because SecA can also form functional dimers, and high-resolution crystal structures exist for both the monomer and the dimer. Here we present the cryo-electron microscopy structures of Escherichia coli SecA bound to the ribosome. We show that not only a monomeric SecA binds to the ribosome but also that two copies of SecA can be observed that form an elongated dimer. Two copies of SecA completely surround the tunnel exit, providing a unique environment to the nascent polypeptides emerging from the ribosome. We identified the N-terminal helix of SecA required for a stable association with the ribosome. The structures indicate a possible function of the dimeric form of SecA at the ribosome.


Factors associated with spousal physical violence in Albania: cross sectional study.
To describe the prevalence of intimate partner violence and associated factors among married women in Albania. Cross sectional study. Tirana, the capital city of Albania. A representative sample of 1039 married women aged 25-65 living in Tirana and recorded in the 2001 census. Questionnaire on intimate partner violence and social and demographic characteristics of the women and their husbands. Women's experience within the past year of being hit, slapped, kicked, or otherwise physically hurt by the husband. More than a third (37%, 384/1039) of women had experienced violence. Risk was greatest among women aged 25-34 (odds ratio 1.47, 95% CI 1.04 to 2.09), women with tertiary education (3.70, 2.04 to 6.67), women in white collar jobs (4.0, 1.59 to 10.0), women with least educated husbands (5.01, 2.91 to 8.64), and women married to men raised in rural areas (3.31, 2.29 to 4.80). Women were at higher risk if they were more educated than their husbands (4.76, 2.56 to 9.09). In transitional Albania, the risk of spousal violence is high, and more empowered women are at greater risk.


Calcium signaling during the plant-plant interaction of parasitic Cuscuta reflexa with its hosts.
The plant parasite Cuscuta reflexa induces various responses in compatible and incompatible host plants. The visual reactions of both types of host plants including obvious morphological changes require the recognition of Cuscuta ssp. A consequently initiated signaling cascade is triggered which leads to a tolerance of the infection or, in the case of some incompatible host plants, to resistance. Calcium (Ca(2+)) release is the major second messenger during signal transduction. Therefore, we have studied Ca(2+) spiking in tomato and tobacco during infection with C. reflexa. In our recently published study Ca(2+) signals were monitored as bioluminescence in aequorin-expressing tomato plants after the onset of C. reflexa infestation. Signals at the attachment sites were observed from 30 to 48 h after infection. In an assay with leaf disks of aequorin-expressing tomato which were treated with different C. reflexa plant extracts it turned out that the substance that induced Ca(2+) release in the host plant was closely linked to the parasite's haustoria.


ECT, blood pressure changes and neuropsychological deficit.
Twenty psychiatric in-patients were studied before and after five bilateral electroconvulsive treatments for major depression. There were significant memory and neuropsychological changes after treatment, and significant reductions in depression rating scores, but they did not correlate with various measures of blood pressure elevation during treatment. The importance of ECT-related amnesia is discussed.


Challenges confronting female surgical leaders: overcoming the barriers.
The number of women reaching top ranks in academic surgery is remarkably low. The purpose of this study was to identify: 1) barriers to becoming a female surgical leader; 2) key attributes that enable advancement and success; and 3) current leadership challenges faced as senior leaders. Semi-structured interviews of ten female surgical leaders queried the following dimensions: attributes for success, lessons learned, mistakes, key career steps, the role of mentoring, gender advantages/disadvantages, and challenges. Perseverance (60%) and drive (50%) were identified as critical success factors, as were good communication skills, a passion for scholarship, a stable home life and a positive outlook. Eighty percent identified discrimination or gender prejudice as a major obstacle in their careers. While 90% percent had mentors, 50% acknowledged that they had not been effectively mentored. Career advice included: develop broad career goals (50%); select a conducive environment (30%); find a mentor (60%); take personal responsibility (40%); organize time and achieve balance (40%); network (30%); create a niche (30%); pursue research (30%); publish (50%); speak in public (30%); and enjoy the process (30%). Being in a minority, being highly visible and being collaborative were identified as advantages. Obtaining buy-in and achieving consensus was the greatest leadership challenge reported. Female academic surgeons face challenges to career advancement. While these barriers are real, they can be overcome by resolve, commitment, and developing strong communication skills. These elements should be taken into consideration in designing career development programs for junior female surgical faculty.


Liebig's alkaloid analyses: the uncertain route from content to molecular formulae.
Liebig's 1831 paper that describes a new apparatus for the analysis of organic compounds and the results of several analyses using the apparatus is a justly famous contribution to the evolution of modern chemistry. In this paper, I look at the three separate components of Liebig's combustion apparatus that collect the water, carbon dioxide and nitrogen released by the combustion of six alkaloids. Gravimetric data included in the paper reveal that very accurate results could be obtained for water by absorption in a calcium chloride tube, and even better results for carbon dioxide resulted from use of the Kaliapparat. Volumetric measurement of nitrogen gave very poor results despite Liebig's efforts to improve it. Inaccuracies in nitrogen measurement made consistent construction of accurate molecular formulae for nitrogenous substances impossible, and only fortuitous decisions intended to bring molecular formulae into agreement with measured combining weights gave formulae in agreement with modern ones, as in the case for quinine.


Disruption of microtubules as an early sign of irreversible ischemic injury. Immunohistochemical study of in situ canine hearts.
Structural disruption of the cytoskeleton may be involved in irreversible ischemic injury. In the present study, ischemic changes in microtubules during various periods of myocardial ischemia were studied with an immunohistochemical technique in open-chest dogs. In intact myocardium, microtubules were stained as a filamentous network throughout cytoplasm and a circular network around the nucleus, which disappeared with colchicine treatment. In brief ischemia of less than 15 minutes, microtubule patterns were unaltered. After 20 minutes, however, characteristic microtubule stains were partly lost in patchy lesions. As an increase in ischemic period, lesions of loss of microtubule stains were increased in number and size. After 120 minutes of reperfusion following 60 minutes of ischemia, the lesions with intact actin filaments but with disrupted microtubules were replaced by the severely injured cells in which the regular myofibrillar registrations were distinctly disrupted. After 24 hours of reperfusion following 40 minutes of occlusion of the left circumflex artery, the percent area of disrupted microtubules at 40 minutes of ischemia was replaced by that of irreversibly injured lesions in the posterior papillary muscle. These results indicate that disruption of microtubules during ischemia heralds irreversible ischemic injury. However, in in vitro study, the myocardium incubated in hypoxic solution for 60-120 minutes demonstrated earlier disruption of the microtubules than the vinculin. Electron microscopic study also showed minimal irreversible changes in the lesions with disrupted microtubules. Thus, taken together, we conclude that microtubules that support the structural integration of myofibrils and other organelles are disrupted in severe myocardial ischemia before the irreversible injury, promoting the irreversible change after reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)


Reduced cerebral infection of Neospora caninum-infected mice after vaccination with recombinant microneme protein NcMIC3 and ribi adjuvant.
C57BL/6 mice were vaccinated with a bacterially expressed and purified polyhistidine-tagged full-length version of the microneme protein NcMIC3 (recNcMIC3) emulsified in Ribi Adjuvant System (RAS). Subsequently, they were challenged by intraperitoneal inoculation of 2 x 10(6) live Neospora caninum tachyzoites. As controls, groups of mice received phosphate-buffered saline (PBS)-RAS alone (adjuvant control) or were treated with PBS before infection (infection control). The protective effect of vaccination was assessed by Neospora-specific polymerase chain reaction (PCR), immunohistochemical investigation of brain tissue, and serological means (enzyme-linked immunosorbent assay). Assessment by PCR performed on DNA from different organs revealed that in all treatment groups parasite DNA could only be detected in brain tissue. According to the PCR results. the recNcMIC3 vaccine conferred protection to 75% of mice (n = 16 in 2 independent experiments), whereas application of PBS-RAS and of PBS alone resulted in protection of 12.5% and 0% of mice, respectively (n = 16 as above). Mice in the PBS-treated infection control group were affected by evident clinical signs of neosporosis starting on day 6 postinfection (p.i.). Conversely, none of the animals treated with either PBS-RAS or recNcMIC3 exhibited any symptoms until day 21 p.i. Immunohistochemical staining of paraffin-embedded brain tissue sections confirmed the protective effect of recNcMIC3 vaccination. Quantitative Neospora-specific real-time PCR revealed that infection intensities were lower in the brain tissues of recNcMIC3-vaccinated mice compared with PBS-RAS-treated adjuvant control mice. Serological analysis showed that the protective effect observed in recNcMIC3-vaccinated mice was associated with a Th2-type IgG1 antibody response directed against native NcMIC3 and a mixed IgG1-IgG2a antibody response directed against the recombinant antigen itself. Taken together, these results demonstrated that recombinant NcMIC3 vaccine confers a significant protectivity against experimentally induced cerebral neosporosis in mice.


TCF4 and CDX2, major transcription factors for intestinal function, converge on the same cis-regulatory regions.
Surprisingly few pathways signal between cells, raising questions about mechanisms for tissue-specific responses. In particular, Wnt ligands signal in many mammalian tissues, including the intestinal epithelium, where constitutive signaling causes cancer. Genome-wide analysis of DNA cis-regulatory regions bound by the intestine-restricted transcription factor CDX2 in colonic cells uncovered highly significant overrepresentation of sequences that bind TCF4, a transcriptional effector of intestinal Wnt signaling. Chromatin immunoprecipitation confirmed TCF4 occupancy at most such sites and co-occupancy of CDX2 and TCF4 across short distances. A region spanning the single nucleotide polymorphism rs6983267, which lies within a MYC enhancer and confers colorectal cancer risk in humans, represented one of many co-occupied sites. Co-occupancy correlated with intestine-specific gene expression and CDX2 loss reduced TCF4 binding. These results implicate CDX2 in directing TCF4 binding in intestinal cells. Co-occupancy of regulatory regions by signal-effector and tissue-restricted transcription factors may represent a general mechanism for ubiquitous signaling pathways to achieve tissue-specific outcomes.


[Os trigonum syndrome].
The os trigonum is one of the most frequent accessory bones of the foot. It is located dorsal of the talus. Os trigonum syndrome means a typical pain syndrome localized in the back-foot caused by this ossicle. This syndrome occurs mostly in man with sports activities accompanied with intensive stress to different parts of the foot. It can be caused particularly by standing on the toe in the "en-pointe-position" in ballet dancers when the flexor hallucis tendon is under maximal tension or by activities accompanied with maximal plan-tarflexion in soccer players for instance. Typical complaints, findings and different therapeutic procedures are demonstrated in two cases. Therapy includes different non-operative methods. Resistance to non-operative procedures is indication for operative therapy. Excision of this ossicle is surgical therapy of first choice.


Identification of Hub Genes and Pathways in Zika Virus Infection Using RNA-Seq Data: A Network-Based Computational Approach.
Zika virus (ZIKV), a single-strand RNA flavivirus, is transmitted primarily through Aedes aegypti. The recent outbreaks in America and unexpected association between ZIKV infection and birth defects have triggered the global attention. This vouches to understand the molecular mechanisms of ZIKV infection to develop effective drug therapy. A systems-level understanding of biological process affected by ZIKV infection in fetal brain sample led us to identify the candidate genes for pharmaceutical intervention and potential biomarkers for diagnosis. To identify the key genes, transcriptomics data (RNA-Seq) with GSE93385 of ZIKV (Strain: MR766) infected human fetal neural stem cell are analyzed. In total, 1,084 differentially expressed genes (DEGs) are identified, that is, 471 upregulated and 613 downregulated genes. Further analysis such as the gene ontology term suggested that the downregulated genes are mostly enriched in defense response to virus, receptor binding, laminin binding, extracellular matrix, endoplasmic reticulum, and for upregulated DEGs: translation initiation, RNA binding, cytosol, and nucleosome are enriched. And through pathway analysis, systemic lupus erythematosus (SLE) is found to be the most enriched pathway. Protein-protein interaction (PPI) network is constructed to find the hub genes using STRING database. The seven key genes namely cyclin-dependent kinase 1 (CDK1), cyclin B1 (CCNB1), histone cluster 1 H2B family member K, (HIST1H2BK) histone cluster 1 H2B family member O (HIST1H2BO), and histone cluster 1 H2B family member B (HIST1H2BB), polo-like kinase 1 (PLK1), and cell division cycle 20 (CDC20) with highest degree are found to be hub genes using Centiscape, a Cytoscape plugin. The modules of PPI network using Molecular Complex Detection plugin are found significant in structural constituent of ribosome, defense response to virus, nucleosome, SLE, extracellular region, and regulation of gene silencing. Thus, identified key hub genes and pathways shed light on molecular mechanism that may contribute to the discovery of novel therapeutic targets and development of new strategies for the intervention of ZIKV disease.


Embodied airflow sensing for improved in-gust flight of flapping wing MAVs.
Flapping wing micro aerial vehicles (FWMAVs) are known for their flight agility and maneuverability. These bio-inspired and lightweight flying robots still present limitations in their ability to fly in direct wind and gusts, as their stability is severely compromised in contrast with their biological counterparts. To this end, this work aims at making in-gust flight of flapping wing drones possible using an embodied airflow sensing approach combined with an adaptive control framework at the velocity and position control loops. At first, an extensive experimental campaign is conducted on a real FWMAV to generate a reliable and accurate model of the in-gust flight dynamics, which informs the design of the adaptive position and velocity controllers. With an extended experimental validation, this embodied airflow-sensing approach integrated with the adaptive controller reduces the root-mean-square errors along the wind direction by 25.15% when the drone is subject to frontal wind gusts of alternating speeds up to 2.4 m/s, compared to the case with a standard cascaded PID controller. The proposed sensing and control framework improve flight performance reliably and serve as the basis of future progress in the field of in-gust flight of lightweight FWMAVs.


Intracellular pH in the isolated perfused rabbit proximal straight tubule.
For the purpose of measuring the intracellular pH (pHi) of the mammalian renal proximal tubule, a liquid membrane pH microelectrode was made using a neutral hydrogen ion-selective carrier. The pHi of the rabbit proximal straight tubule perfused in vitro with a solution containing 25 mM HCO3- was 7.22 +/- 0.03. We noted a value significantly lower than the bath pH of 7.44 +/- 0.02 but significantly higher than the pHi of 6.62 +/- 0.03 predicted for passive H+ distribution. Replacement of luminal Na+ with choline quickly (within 1 min) decreased pHi from 7.25 +/- 0.05 to 7.10 +/- 0.05 (P less than 0.001). This change was reversible when Na+ was added again in the luminal solution. A reduction of luminal Na+ from 20 mM to 0 also reduced pHi from 7.15 +/- 0.06 to 7.04 +/- 0.08, and this pHi reduction was blocked by luminal addition of 1 mM amiloride. However, pHi reduction induced by luminal Na+ removal was not affected by luminal addition of 1 mM SITS. Replacement of bath Na+ with choline also reversibly reduced pHi from 7.27 +/- 0.02 to 7.15 +/- 0.02 (P less than 0.001), but this change was totally blocked by the presence of 1 mM SITS. Accordingly, these data suggest that a Na+-H+ exchanger exists in the luminal membrane of the intact rabbit proximal straight tubule.


Lymphocyte blastogenesis, complement fixation, and fecal culture as diagnostic tests for paratuberculosis in North American wild ruminants and domestic sheep.
The efficacy of the lymphocyte blastogenesis and complement-fixation tests and fecal culture for detection of Mycobacterium paratuberculosis infection was assessed in bighorn sheep (Ovis canadensis), elk (Cervus elaphus nelsoni), mule deer (Odocoileus hemionus), white-tailed deer (O virginianus), bighorn X mouflon (O musimon) hybrid sheep, and domestic sheep. Spontaneously infected bighorns were tested at the time of capture; experimentally infected animals were tested monthly for 12 months or periodically for 36 months. Lymphocyte blastogenesis tests were conducted with peripheral blood mononuclear cells and protein antigens of M avium, M bovis, and M paratuberculosis. Best diagnostic results were obtained when M avium purified-protein derivative was used as antigen and 20% bovine fetal serum was incorporated in the culture medium; a positive test was defined as a stimulation index greater than or equal to 3.5. Test sensitivity and specificity, respectively, were 82% and 94% in hybrid sheep and were 72% and 100% in domestic sheep. Sensitivity and specificity, respectively, were 39% and 94% in elk and 53% and 92% in deer. When infection was determined in spontaneously infected bighorns by culture of M paratuberculosis and/or the presence of acid-fast bacilli in characteristic microscopic lesions, sensitivity was 75% and specificity was 87%. Fecal cultures and the complement-fixation tests seldom correctly identified infected animals.


Technology Implementation and Associated Pharmacy Interruptions.
This study focuses on interruptions in an inpatient pharmacy setting and the impact of CPOE implementation on the types, frequency, and duration of interruptions. A cross-sectional observation study of pharmacy employees in an inpatient pharmacy was conducted. The independent variables included day of week, time of day, job position of the person interrupted, and description of each interruption. A total of 552 interruptions were observed with a mean frequency of 10.6 interruptions per hour lasting a mean (SD) duration of 1.34 (1.43) minutes. Incoming calls were the most frequent interruption type across all phases. Pharmacy employees spend almost a quarter of their time on interruptions, and pharmacists have longer interruptions than technicians. Immediately after CPOE implementation, durations tend to be one-and-a-half times longer than before. CPOE implementation did not affect the frequency of interruptions. Recommendations included redesign of work processes and job responsibilities.


Identification of the Resveratrol Potential Targets in the Treatment of Osteoarthritis.
Osteoarthritis (OA) is a chronic joint degenerative disease and has become an important health problem for the elderly. However, there is still a lack of effective drugs for the treatment of OA. Our research combines bioinformatics and experimental strategies to determine the target of resveratrol for OA treatment. First, the differentially expressed genes (DEGs) of OA joint tissues were obtained from the related microarray gene expression data. Second, resveratrol, a natural polyphenol compound, was used to screen the drug treatment target genes. Third, the drug-disease network was established, and the resveratrol target genes for OA treatment were obtained and verified through experimental verification. A total of 300 differentially expressed genes with 246 upregulated and 54 downregulated were found in OA joint tissues, and 310 resveratrol potential target genes were obtained. Finally, six genes, namely, CXCL1, HIF1A, IL-6, MMP3, NOX4, and PTGS2, were selected to validate the treatment effects of the resveratrol. The results showed that all six genes in human OA chondrocytes were significantly increased. In addition, in these chondrocytes, CXCL1, HIF1A, IL-6, MMP3, NOX4, and PTGS2 were reduced considerably, but HIF1A was significantly increased after resveratrol treatment. Our data indicates that CXCL1, HIF1A, IL-6, MMP3, NOX4, and PTGS2 are all targets of resveratrol therapy. Our findings may provide valuable information for the mechanism and therapeutic of OA.


[Measurement of local blood flow in the nasal mucosa by the method of hydrogen clearance].
The hydrogen clearance method was used to measure local blood flow in the inferior concha nasalis of 22 patients, aged 18 to 48 years. According to the method, the nasal mucosa was saturated with hydrogen and the rate of hydrogen washout was recorded in the form of hydrogen clearance curves. The response was tested by applying 0.1% epinephrine solution and the volume blood flow velocity was calculated. In response to epinephrine, blood flow velocity in the nasal mucosa diminished significantly. The hydrogen clearance method allowed an accurate quantitative evaluation of the volume blood flow velocity in a limited area of concha nasalis. The epinephrine test demonstrated a high sensitivity of the method that gave an adequate idea of mucosal microcirculation. This method, together with other procedures, can be used to examine the nasal mucosa.


Laparoscopy in the management of lumboperitoneal shunt catheter in obese patients with pseudotumor cerebri.
Lumboperitoneal shunts are widely used for the treatment of patients diagnosed with pseudotumor cerebri (PTC). Obesity is a risk factor for PTC. In particular, catheter migration out of the abdominal cavity is more commonly observed in morbidly obese patients. The aim of this study was to discuss the underlying mechanisms of catheter migration and treatment modalities in morbidly obese patients with PTC. The present study included four morbidly obese patients. All cases had undergone the previous laparotomy for insertion of a distal catheter into the abdominal cavity. In three cases, migration of the distal catheter out of the abdominal cavity was observed. Migration of the proximal tip of the catheter out of the spinal canal was observed in the fourth case. In all cases, laparoscopic revision surgeries were performed. During revision surgery, a catheter tunnel was prepared immediately over the external oblique fascia to obtain the shortest and deepest tunnel, and a distal catheter was inserted by laparoscopic guidance posterolaterally, i.e., through the postaxillary line. None of the patients developed any complications during the follow-up period of 4 years. We recommend laparoscopic insertion of distal catheters through the postaxillary line into the abdominal cavity using as short a catheter route as possible. Thus, tension and traction on the catheter due to abdominal movements can be decreased in morbidly obese patients to prevent catheter migration.


Bowenoid papulosis. Demonstration of human papillomavirus (HPV) with anti-HPV immune serum.
Two cases of bowenoid papulosis (BP) occurred. The presence of human papillomavirus was demonstrated in one patient. In the other patient, condyloma acuminatum developed after initial spontaneous improvement in his lesions. The discovery of a possible oncogenic virus in BP and the epidemiologic behavior of carcinoma in situ and multicentric carcinomas suggest the need for a very careful follow-up evaluation of such lesions. Bowenoid papulosis may be a chronic dysplasia with a variable long-term prognosis linked to a cocarcinogenic factor.


Purinergic receptor antagonists inhibit odorant-mediated CREB phosphorylation in sustentacular cells of mouse olfactory epithelium.
Extracellular nucleotides have long been known to play neuromodulatory roles and to be involved in intercellular signalling. In the olfactory system, ATP is released by olfactory neurons, and exogenous ATP can evoke an increase in intracellular calcium concentration in sustentacular cells, the nonneuronal supporting cells of the olfactory epithelium. Here we investigate the hypothesis that olfactory neurons communicate with sustentacular cells via extracellular ATP and purinergic receptor activation. Here we show that exposure of mice to a mixture of odorants induced a significant increase in the levels of the transcription factor CREB phosphorylated at Ser-133 in the nuclei of both olfactory sensory neurons and sustentacular cells. This activation was dependent on adenylyl cyclase III-mediated olfactory signaling and on activation of P2Y purinergic receptors on sustentacular cells. Purinergic receptor antagonists inhibited odorant-dependent CREB phosphorylation specifically in the nuclei of the sustentacular cells. Our results point to a possible role for extracellular nucleotides in mediating intercellular communication between the neurons and sustentacular cells of the olfactory epithelium in response to odorant exposure. Maintenance of extracellular ionic gradients and metabolism of noxious chemicals by sustentacular cells may therefore be regulated in an odorant-dependent manner by olfactory sensory neurons.


Dermatophytes: host-pathogen interaction and antifungal resistance.
Cutaneous mycoses are among the most common infections in humans and have become an important public health issue because they cause invasive infections in immunocompromised patients. During the infectious process, dermatophyte-host interactions trigger specific metabolic adaptations that allow the pathogen to adhere to and penetrate the host tissue, scavenge nutrients, and overcome the host defense mechanisms. This metabolic shift and the interplay between metabolism, morphogenesis and stress response are important factors that have been extensively studied in several pathogens. Host cells also respond to the pathogen stimuli by activating intracellular signaling pathways that trigger the immune response against the infectious agent. The comprehension of the molecular aspects of these responses may help to establish new therapeutical strategies. In this review, different aspects of the biology of dermatophytes are addressed, with emphasis on the dermatophyte-host interaction and the mechanisms of antifungal resistance.


Prediction of mild cognitive impairment that evolves into Alzheimer's disease dementia within two years using a gene expression signature in blood: a pilot study.
The focus on Alzheimer's disease (AD) is shifting from dementia to the prodromal stage of the disorder, to a large extent due to increasing efforts in trying to develop disease modifying treatment for the disorder. For development of disease-modifying drugs, a reliable and accurate test for identification of mild cognitive impairment (MCI) due to AD is essential. In the present study, MCI progressing to AD will be predicted using blood-based gene expression. Gene expression analysis using qPCR was performed on blood RNA from a cohort of patients with amnestic MCI (aMCI; n = 66). Within the aMCI cohort, patients progressing to AD within 1 to 2 years were grouped as MCI converters (n = 34) and the patients remaining at the MCI stage after 2 years were grouped as stable MCI (n = 32). AD and control populations were also included in the study. Multivariate statistical method partial least square regression was used to develop predictive models which later were tested using leave-one-out cross validation. Gene expression signatures that identified aMCI subjects that progressed to AD within 2 years with a prediction accuracy of 74%-77% were identified for the complete dataset and subsets thereof. The present pilot study demonstrates for the first time that MCI that evolves into AD dementia within 2 years may be predicted by analyzing gene expression in blood. Further studies will be needed to validate this gene signature as a potential test for AD in the predementia stage.


Deep Learning augmented osteoarthritis grading standardization.
Manual grading of cartilage histology images for investigating the extent and severity of osteoarthritis (OA) involves critical examination of the cell characteristics, which makes this task tiresome, tedious and error-prone. This results in wide inter-observer variation, causing ambiguities in OA grade prediction. Such drawbacks of manual assessment can be overcome by implementing artificial intelligence (AI) based automated image classification techniques such as deep learning (DL). Hence in this manuscript, we present the feasibility of training a deep neural network with cartilage histology images, which can grade the extent and severity of knee OA based on modified Mankin scoring system. The grading system used here for automating OA grading was simplified and modified based on the microscopic observations from the histology images, where three parameters (Safranin-O staining intensity, chondrocyte distribution & arrangement, and morphology) were considered for evaluating the OA progression. The histology images were tiled, labelled, and grouped together based on the developed grading system (Grade 0-3). Four different DL architectures were tried for image classification and the best performing model was selected by five-fold validation method. With a validation accuracy of about 84%, 0.632 Cohen's kappa score, and an excellent ROC-AUC ranging between 0.89-0.99, DenseNet121 was selected among the four models as the best performing model, and was used for inferencing on new data. Final grades obtained from the models were in accordance with the grades provided by the medical experts. We hereby demonstrate that a DL architecture can be taught to interpret the degree of cartilage degradation, with excellent discriminatory ability across all four classes of OA severity. Unlike other works where radiographic images have been considered for grading of OA, we have considered histology images which is a fundamental approach for grading OA extent and severity. This would bring a paradigm shift in histology-based assessment of OA, making this automated approach to be explored as an option for OA grading standardization.


Movement of genotypes of Ceratocystis fimbriata within and among Eucalyptus plantations in Brazil.
Ceratocystis wilt on eucalyptus, caused by Ceratocystis fimbriata, was first recognized in 1997 in the state of Bahia, Brazil, but is now known in five other states and in four other countries. C. fimbriata is a native, soilborne pathogen in some parts of Brazil but we hypothesized that genotypes of the pathogen have been moved among plantations in rooted cuttings collected from diseased trees and within plantations on cutting tools. We used six microsatellite markers to identify 78 genotypes of C. fimbriata among 177 isolates from individual trees in 20 eucalyptus plantations. The highest gene and genotypic diversity values were found in plantations on formerly wild Cerrado forest in Minas Gerais, suggesting that the fungus was in the soil prior to planting eucalyptus. In contrast, one or only a few genotypes were found in plantations on previous pastureland (with no woody hosts) in Bahia and São Paulo, and most of these genotypes were found in a Bahian nursery or in one of two Bahian plantations that were sources for rooted cuttings. Sources of cuttings tended to be dominated by one or a few genotypes that may have been spread within the plantation on cutting tools.


In vitro perfusion of the isolated dog glomerulus.
Recent technological advances allowing direct in vivo measurements of the determinants of glomerular ultrafiltration have greatly expanded our understanding of that process. In addition, these in vivo studies have clarified the dynamics of glomerular ultrafiltration in a number of physiologic and pathophysiologic conditions. Despite this progress, important issues remain unresolved and beyond the scrutiny of in vivo techniques. We have therefore devised a technique for in vitro glomerular perfusion of the isolated dog glomerulus. In eight glomeruli perfused at physiologic rates, the glomerular filtration rate averaged 39 nl/min and the filtration fraction was 0.19. Filtration pressure disequilibrium was observed in all studies and thus allowed calculation of a unique value for the ultrafiltration coefficient. That parameter averaged 2.34 nl/(min X mmHg). Morphologic studies employing transmission electron microscopy indicate that isolated perfused glomeruli remain ultrastructurally intact. The method for glomerular isolation and in vitro perfusion is presented in detail, the results obtained are compared with published in vivo results, and the advantages offered by the technique are discussed.


Women's responses to intimate partner violence in Rwanda: Rethinking agency in constrained social contexts.
This paper explores instances of agency in women's responses to intimate partner violence (IPV) in Rwanda. The literature on women's responses to IPV conceptualises agency primarily as an individual's capacity to take action by reporting violence or leaving a relationship, obscuring other ways women may respond to violence in contexts where reporting or leaving are unlikely. We aim to replace this narrow conceptualisation of agency with a social constructivist focus on the meanings women attribute to possible IPV responses. We draw on data from a study of IPV in Rwanda, which includes semi-structured interviews with women experiencing violence and four focus group discussions with women community members (n = 39). Our findings highlight sociocultural, economic, political-legal and historical constraints that shape women's actions in this context. In relation to these constraints, women describe four possible responses to IPV: reporting the violence; seeking emotional support; 'fighting back' against violence; or remaining silent. While reporting and leaving violent relationships are identified, women also discuss the social constraints that make these actions extremely difficult. In designing effective strategies, we conclude that public health strategies need to consider women's understandings of their own actions, particularly in social contexts where certain actions may be constrained.


Metabolic syndrome, endocrine disruptors and prostate cancer associations: biochemical and pathophysiological evidences.
This review summarizes the main pathophysiological basis of the relationship between metabolic syndrome, endocrine disruptor exposure and prostate cancer that is the most common cancer among men in industrialized countries. Metabolic syndrome is a cluster of metabolic and hormonal factors having a central role in the initiation and recurrence of many western chronic diseases including hormonal-related cancers and it is considered as the world's leading health problem in the coming years. Many biological factors correlate metabolic syndrome to prostate cancer and this review is aimed to focus, principally, on growth factors, cytokines, adipokines, central obesity, endocrine abnormalities and exposure to specific endocrine disruptors, a cluster of chemicals, to which we are daily exposed, with a hormone-like structure influencing oncogenes, tumor suppressors and proteins with a key role in metabolism, cell survival and chemo-resistance of prostate cancer cells. Finally, this review will analyze, from a molecular point of view, how specific foods could reduce the relative risk of incidence and recurrence of prostate cancer or inhibit the biological effects of endocrine disruptors on prostate cancer cells. On the basis of these considerations, prostate cancer remains a great health problem in terms of incidence and prevalence and interventional studies based on the treatment of metabolic syndrome in cancer patients, minimizing exposure to endocrine disruptors, could be a key point in the overall management of this disease.


Childhood adversities in UK treatment-seeking military veterans.
The long-term consequences of adverse childhood experiences (ACEs) on adult physical and mental health are well documented in the literature. The current study sought to examine this relationship in a sample of UK treatment-seeking military veterans. The data were collected through a cross-sectional self-report survey from military veterans who have sought help for mental health difficulties from a veteran-specific UK-based charity. The response rate was 67.2% (n=403) and the effective sample for this study consisted of 386 male veterans. Participants' history of ACEs and current mental/physical health difficulties were assessed. A latent class analysis was conducted to categorise participants into subgroups based on their ACEs and the relationship of these to the mental and physical health outcomes was examined. Five classes of veterans with different combinations of ACEs were identified. A total of 97% reported at least one ACE. There were minimal differences between the classes on mental and physical health outcomes, but the total number of ACEs was related to aggression, common mental health problems and post-traumatic stress disorder (PTSD). No combination of ACEs was specifically predictive of adverse mental/physical health difficulties in our sample. Instead, those with a higher number of ACEs may be more prone to developing problems with aggression, common mental health problems and PTSD. Assessing the history of childhood adversities in military veterans is therefore important when veterans are seeking help for mental health difficulties, as some of these may be related to childhood adversities and may need to be addressed in treatment.


RMTLysPTM: recognizing multiple types of lysine PTM sites by deep analysis on sequences.
Post-translational modification (PTM) occurs after a protein is translated from ribonucleic acid. It is an important living creature life phenomenon because it is implicated in almost all cellular processes. Identification of PTM sites from a given protein sequence is a hot topic in bioinformatics. Lots of computational methods have been proposed, and they provide good performance. However, most previous methods can only tackle one PTM type. Few methods consider multiple PTM types. In this study, a multi-label classification model, named RMTLysPTM, was developed to recognize four types of lysine (K) PTM sites, including acetylation, crotonylation, methylation and succinylation. The surrounding sites of a lysine site were selected to constitute a peptide segment, representing the lysine at the center. Deep analysis was conducted to count the distribution of 2-residues with fixed location across the four types of lysine PTM sites. By aggregating the distribution information of 2-residues in one peptide segment, the peptide segment was encoded by informative features. Furthermore, a prediction engine that can precisely capture the traits of the above representations was designed to recognize the types of lysine PTM sites. The cross-validation results on two datasets (Qiu and CPLM training datasets) suggested that the model had extremely high performance and RMTLysPTM had strong generalization ability by testing it on protein Q16778 and CPLM testing datasets. The model was found to be generally superior to all previous models and those using popular methods and features. A web server was set up for RMTLysPTM, and it can be accessed at http://22.214.171.124/.


[Early results of esophagectomy and total or proximal gastrectomy without perioperative administration of total parenteral nutrition].
The aim of the study was to analyse complications after radical oesophagectomy or gastrectomy in cancer patients without administration of total parental nutrition (TPN). 45 consecutive patients underwent oesophagectomy (8 patients), proximal subtotal gastrectomy (10 patients) and total gastrectomy (27 patients). Stapler sutures were used to create anastomoses between oesophagus and stomach or oesophagus and jejunum. None patient received TPN. In all patients antropometrical and biochemical characteristics were assessed. Preoperative risk factors and type of complications were estimated. Patients with surgical complications were compared with patients without surgical complications using anthropometric and biochemical values. Surgical complications occurred in 10(22%) patients. The most common complication was postoperative wound infection (6 patients). Anastomotic dehiscence occurred in 4 patients and resulted in 2 deaths. Complications and deaths were observed more frequently in severely malnourished patients (BMI < 18). There is no justification for routine perioperative use of TPN in patients without severe malnutrition undergoing oesophageal or gastric surgery for cancer.


Stem cells marked by the R-spondin receptor LGR5.
Since the discovery of LGR5 as a marker of intestinal stem cells, the field has developed explosively and led to many new avenues of research. The inner workings of the intestinal crypt stem cell niche are now well understood. The study of stem cell-enriched genes has uncovered some previously unknown aspects of the Wnt signaling pathway, the major driver of crypt dynamics. LGR5(+) stem cells can now be cultured over long periods in vitro as epithelial organoids or "mini-guts." This technology opens new possibilities of using cultured adult stem cells for drug development, disease modeling, gene therapy, and regenerative medicine. This review describes the rediscovery of crypt base columnar cells as LGR5(+) adult stem cells and summarizes subsequent progress, promises, unresolved issues, and challenges of the field.


The dangers of stopping a trial too early.
To ensure that participants in randomized controlled trials are protected from harm, interim analyses and review of results by an independent data monitoring committee have become standard practice. If an analysis of accumulating data partway through a trial reveals an unanticipated degree of benefit or toxicity, or differences in outcomes between the intervention and control groups are so unimpressive that any prospect of a positive result with the planned sample size is extremely unlikely, investigators may stop the trial earlier than originally scheduled. The practice of stopping randomized controlled trials early is, however, problematic, especially if the trial is stopped for apparent benefit. Concerns in trials stopped early for apparent benefit include appropriate interpretation of results and ethical problems concerning trial participants, clinicians, and society as a whole. In this article, we review the epidemiology of trials stopped early and illustrate some of the problems and controversies associated with stopping randomized controlled trials early for apparent benefit. Finally, we offer guidance for clinicians, those running clinical trials, and authors of systematic reviews.


Tuning the magnetic properties of Co-ferrite nanoparticles through the 1,2-hexadecanediol concentration in the reaction mixture.
This work reports on the effect of the 1,2-hexadecanediol content on the structural and magnetic properties of CoFe2O4 nanoparticles synthesized by thermal decomposition of metal-organic precursors in 1-octadecene. Although pseudo-spherical particles having an average size of about 8 nm and similar stoichiometry have been observed in all studied samples, a high level of variability in the crystal quality and, in turn, in the magnetic properties has been found as a function of the amount of 1,2-hexadecanediol added to the reaction mixture. The magnetic study reveals that samples progress from glassy magnetic behavior to bulk-like, ferrimagnetic order as the crystal quality improves. The analysis of the reaction mixtures by Fourier transform infrared spectroscopy at various stages of the reaction shows the key role of the 1,2-hexadecanediol in favoring the decomposition of the metal-organic precursor, formation of an intermediate Co(2+)Fe(3+)-oleate complex and, finally, the nucleation of nanoparticles at lower temperatures.


Cell surface expression of glycosylated, nonglycosylated, and truncated forms of a cytoplasmic protein pyruvate kinase.
The soluble cytoplasmic protein pyruvate kinase (PK) has been expressed at the cell surface in a membrane-anchored form (APK). The hybrid protein contains the NH2-terminal signal/anchor domain of a class II integral membrane protein (hemagglutinin/neuraminidase, of the paramyxovirus SV5) fused to the PK NH2 terminus. APK contains a cryptic site that is used for N-linked glycosylation but elimination of this site by site-specific mutagenesis does not prevent cell surface localization. Truncated forms of the APK molecule, with up to 80% of the PK region of APK removed, can also be expressed at the cell surface. These data suggest that neither the complete PK molecule nor its glycosylation are necessary for intracellular transport of PK to the cell surface, and it is possible that specific signals may not be needed in the ectodomain of this hybrid protein to specify cell surface localization.


The effectiveness of aromatherapy massage using lavender oil as a treatment for infantile colic.
The aim of this paper was to investigate the effect of aromatherapy massage using lavender oil as a possible treatment for this condition. This research was carried out on a group of 40 infants between 2 and 6 weeks of age with a gestational age of 38-42 weeks and normal development and growth. All the infants weighed between 2500 and 4000 g at birth and all exhibited the signs of colic. Infants in the treatment group received abdominal massage by their mothers using lavender oil, while those in the control group were not subject to an intervention. The infants in both control and treatment groups were monitored once a week by the researchers, in total five times. The effect of the massage was measured in terms of changes in the length of time the infants cried per week. The use of aromatherapy massage using lavender oil was found to be effective in reducing the symptoms of colic.


Simulated car crashes at intersections in drivers with Alzheimer disease.
Current evidence suggests that car crashes in cognitively impaired older drivers often occur because of failure to notice other drivers at intersections. We tested whether licensed drivers with mild to moderate cognitive impairment due to Alzheimer disease (AD) are at greater risk for intersection crashes. In this experiment, 30 participants drove on a virtual highway in a simulator scenario where the approach to within 3.6 seconds of an intersection triggered an illegal incursion by another vehicle. To avoid collision with the incurring vehicle, the driver had to perceive, attend to, and interpret the roadway situation; formulate an evasive plan; and then exert appropriate action on the accelerator, brake, or steering controls, all under pressure of time. The results showed that 6 of 18 drivers with AD (33%) experienced crashes versus none of 12 nondemented drivers of similar age. Use of a visual tool that plots control over steering wheel position, brake and accelerator pedals, vehicle speed, and vehicle position during the 5 seconds preceding a crash event showed inattention and control responses that were either inappropriate or too slow. The findings were combined with those in another recent study of collision avoidance in drivers with AD that focused on potential rear end collisions. Predictors of crashes in the combined studies included visuospatial impairment, disordered attention, reduced processing of visual motion cues, and overall cognitive decline. The results help to specify the linkage between decline in certain cognitive domains and increased crash risk in AD and also support the use of high-fidelity simulation and neuropsychologic assessment in an effort to standardize the assessment of fitness to drive in persons with medical impairments.


Search for Borrelia burgdorferi in kidneys of dogs with suspected "Lyme nephritis".
"Lyme nephritis" is a poorly characterized condition associated with proteinuria and often fatal renal failure in dogs with serological evidence of infection with Borrelia burgdorferi. The aim of this study was to determine if intact B. burgdorferi organisms were present in the kidneys of serologically Lyme-positive dogs with histopathologic features of Lyme nephritis. Twenty-six affected and 10 control dogs were identified over an 8-year period (1996-2004) in databases at Cornell University's College of Veterinary Medicine. Case inclusion required serologic evidence of natural exposure to B. burgdorferi and availability of renal tissue (frozen or paraffin embedded) exhibiting pathology consistent with Lyme nephritis. Renal tissue samples were assessed using modified Steiner (silver) (MS) staining, immunohistochemistry (IHC), polymerase chain reaction (PCR) using 4 primer sets (eubacterial, B. burgdorferi, Bartonella, and canine genomic DNA), and fluorescence in situ hybridization (FISH) using a 5'-cy3-eubacterial probe for 16S rRNA. MS stain was positive in 1 case; IHC was negative in all cases. None of the B. burgdorferi or Bartonella PCR reactions was positive. Two of the B. burgdorferi FISH analyses were positive. Minimal evidence of the presence of intact B. burgdorferi or any other bacterial organism was found in the renal tissue of dogs with suspected Lyme nephritis. Direct renal invasion by B. burgdorferi organisms does not appear to be responsible for this syndrome.


Dialyzer membrane permeability and survival in hemodialysis patients.
We previously showed that nutritional protein concentrations were predictive of outcome, whereas variables reflecting body composition and dialysis dose were not, in a 30-month prospective follow-up of 1,610 hemodialysis patients. Information on dialysis membrane and erythropoietin use had to be evaluated in an additional follow-up. A subset of 650 patients from the initial cohort of 1,610 was analyzed for survival in a 2-year extension of follow-up. Detailed data were collected: demographics; cause of renal failure; time on dialysis therapy; type of membrane; erythropoietin treatment; body mass index (BMI); predialysis albumin, prealbumin, and bicarbonate levels; and outcome. Normalized protein catabolic rate (nPCR), dialysis adequacy, and lean body mass were computed from predialysis and postdialysis urea and creatinine values. Patient characteristics were age of 61 +/- 16 years, 58% men, BMI of 22.7 +/- 4.4 kg/m2 , time on dialysis therapy of 102 +/- 73 months, and 8.8% had diabetes. Dialysis parameters were duration of 247 +/- 31 minutes, Kt/V of 1.4 +/- 0.3, and nPCR of 1.2 +/- 0.3 g/kg/d. Albumin level was 3.73 +/- 0.53 g/dL (37.3 +/- 5.3 g/L), and prealbumin level was 31 +/- 8 mg/dL. The survival rate was 78.7% after 2 years. Survival was influenced by age, presence of diabetes, use of high-flux membrane, and serum albumin level, but not other variables, including Kt/V and prealbumin level. Two-year variations in values for urea, creatinine, and weight were predictive of survival in univariate, but not multivariate, analyses. In patients on dialysis therapy for a long period, better survival was observed when high-flux dialysis membranes were used.


Preparation and adsorption performance of MnO2/PAC composite towards aqueous glyphosate.
Glyphosate (N-phosphonomethylglycine (PMG)) is the organophosphate herbicide most widely used in the world, and industrial production of PMG generates large quantities of wastewater. A manganese dioxide-coated powdered activated carbon (MnO2/PAC) composite was synthesized and investigated for the adsorption of PMG from wastewater. The results of scanning electron microscopy (SEM) combined with energy-dispersive X-ray spectrometry (EDAX) revealed that MnO2 was formed on the surface of the carbon during the modification process. Batch adsorption results showed that the optimal pH for glyphosate adsorption on MnO2/PAC was 3.0. In the range 0.01(-1) molL(-1), glyphosate removal by MnO2/PAC decreased with an increase in ionic strength. Among the coexistent anions, only phosphate showed significant inhibition of PMG removal due to competitive complexation. Batch studies revealed that MnO2/PAC could reach a maximum PMG adsorption capacity of 283 mg g(-1). The Langmuir equilibrium model was found to be suitable for describing PMG sorption, and kinetic studies revealed that adsorption followed second-order rate kinetics. It was also proved that the adsorbed PMG could be effectively desorbed from MnO2/PAC in 1.0 molL(-1) NaOH. All of these results implied that the MnO2/PAC composite may be used as an effective adsorbent for recycling PMG from wastewater.


Apiaceous vegetable consumption decreases PhIP-induced DNA adducts and increases methylated PhIP metabolites in the urine metabolome in rats.
Heterocyclic aromatic amines, such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), are carcinogenic compounds produced during heating of protein-containing foods. Apiaceous vegetables inhibit PhIP-activating enzymes, whereas cruciferous vegetables induce both PhIP-activating and -detoxifying enzymes. We investigated the effects of these vegetables, either alone or combined, on PhIP metabolism and colonic DNA adduct formation in rats. Male Wistar rats were fed cruciferous vegetables (21%, wt:wt), apiaceous vegetables (21%, wt:wt), or a combination of both vegetables (10.5% wt:wt of each). Negative and positive control groups were fed an AIN-93G diet. After 6 d, all groups received an intraperitoneal injection of PhIP (10 mg · kg body weight(-1)) except for the negative control group, which received only vehicle. Urine was collected for 24 h after the injection for LC-tandem mass spectrometry metabolomic analyses. On day 7, rats were killed and tissues processed. Compared with the positive control, cruciferous vegetables increased the activity of hepatic PhIP-activating enzymes [39.5% and 45.1% for cytochrome P450 (CYP) 1A1 (P = 0.0006) and CYP1A2 (P < 0.0001), respectively] and of uridine 5'-diphospho-glucuronosyltransferase 1A (PhIP-detoxifying) by 24.5% (P = 0.0267). Apiaceous vegetables did not inhibit PhIP-activating enzymes, yet reduced colonic PhIP-DNA adducts by 20.4% (P = 0.0496). Metabolomic analyses indicated that apiaceous vegetables increased the relative abundance of urinary methylated PhIP metabolites. The sum of these methylated metabolites inversely correlated with colonic PhIP-DNA adducts (r = -0.43, P = 0.01). We detected a novel methylated urinary PhIP metabolite and demonstrated that methylated metabolites are produced in the human liver S9 fraction. Apiaceous vegetables did not inhibit the activity of PhIP-activating enzymes in rats, suggesting that the reduction in PhIP-DNA adducts may involve other pathways. Further investigation of the importance of PhIP methylation in carcinogen metabolism is warranted, given the inverse correlation of methylated PhIP metabolites with a biomarker of carcinogenesis and the detection of a novel methylated PhIP metabolite.


Phenotypic clusters within sepsis-associated multiple organ dysfunction syndrome.
Sepsis is a devastating condition that is generally treated as a single disease. Identification of meaningfully distinct clusters may improve research, treatment and prognostication among septic patients. We therefore sought to identify clusters among patients with severe sepsis or septic shock. We retrospectively studied all patients with severe sepsis or septic shock admitted directly from the emergency department to the intensive care units (ICUs) of three hospitals, 2006-2013. Using age and Sequential Organ Failure Assessment (SOFA) subscores, we defined clusters utilizing self-organizing maps, a method for representing multidimensional data in intuitive two-dimensional grids to facilitate cluster identification. We identified 2533 patients with severe sepsis or septic shock. Overall mortality was 17 %, with a mean APACHE II score of 24, mean SOFA score of 8 and a mean ICU stay of 5.4 days. Four distinct clusters were identified; (1) shock with elevated creatinine, (2) minimal multi-organ dysfunction syndrome (MODS), (3) shock with hypoxemia and altered mental status, and (4) hepatic disease. Mortality (95 % confidence intervals) for these clusters was 11 (8-14), 12 (11-14), 28 (25-32), and 21 (16-26) %, respectively (p < 0.0001). Regression modeling demonstrated that the clusters differed in the association between clinical outcomes and predictors, including APACHE II score. We identified four distinct clusters of MODS among patients with severe sepsis or septic shock. These clusters may reflect underlying pathophysiological differences and could potentially facilitate tailored treatments or directed research.


Hand-assisted partial nephrectomy with early arterial clamp removal: Impact of the learning curve.
The aims of this study were to present the results of hand-assisted laparoscopic partial nephrectomy according to the margin, ischaemia and complications system; to assess the role of the learning curve; and to compare this approach with other approaches. Data from 60 consecutive patients were obtained from a prospectively maintained database. The patients were divided into three cohorts (1, 2 and 3), with 20 patients each, according to their surgery dates. The overall margin, ischaemia and complications rate was 90%. The warm ischaemia time was 9.5 min in cohort 1, decreasing to 5 min in cohort 3 (p < 0.0001). The Padua score (p = 0.0287) and tumour size (p = 0.0003) were significantly increased in cohort 3, but loss of kidney function decreased significantly to 3.5% in this cohort. Loss of kidney function of less than 5% was reported for eight (40%), nine (45%) and 14 (70%) patients in cohorts 1, 2 and 3, respectively (p = 0.0185). Hand-assisted laparoscopic partial nephrectomy with early removal of arterial clamps is safe and easy to learn. An expert laparoscopic surgeon can perform hand-assisted laparoscopic partial nephrectomy for complex tumours with a relatively high success rate according to the margin, ischaemia and complications system. Warm ischaemia time could be obtained within 5 min after 40 procedures.


[Correlation between genetic and environmental factors in the display of predatory reactions in the rat].
Manifestation of the hunting and mice-killing reactions by non-linear rats-observers did not depend on the presence of rats killing mice. The absence of such dependence was observed in conditions of free access to food, of food deprivation stimulating predatory aggressiveness, and also of learning in the early postnatal period. Acquisition of the habit of eating killed mice by the rats-observers was facilitated in the presence of rats executing this reaction. It is suggested that in manifestation of the aggressive component of predatory behaviour of rats, a greater role is played by inborn mechanisms while environmental factors are more significant for organization of the alimentary mechanism.


Simple Skeletal Muscle Mass Estimation Formulas: What We Can Learn From Them.
One century ago Harris and Benedict published a short report critically examining the relations between body size, body shape, age, and basal metabolic rate. At the time, basal metabolic rate was a vital measurement in diagnosing diseases such as hypothyroidism. Their conclusions and basal metabolic rate prediction formulas still resonate today. Using the Harris-Benedict approach as a template, we systematically examined the relations between body size, body shape, age, and skeletal muscle mass (SM), the main anatomic feature of sarcopenia. The sample consisted of 12,330 non-Hispanic (NH) white and NH black participants in the US National Health and Nutrition Survey who had complete weight, height, waist circumference, age, and dual-energy X-ray (DXA) absorptiometry data. A conversion formula was used to derive SM from DXA-measured appendicular lean soft tissue mass. Weight, height, waist circumference, and age alone and in combination were significantly correlated with SM (all, p < 0.001). Advancing analyses through the aforementioned sequence of predictor variables allowed us to establish how at the anatomic level these body size, body shape, and age measures relate to SM much in the same way the Harris-Benedict equations provide insights into the structural origins of basal heat production. Our composite series of SM prediction equations should prove useful in modeling efforts and in generating hypotheses aimed at understanding how SM relates to body size and shape across the adult lifespan.


Overactivated neddylation pathway as a therapeutic target in lung cancer.
A number of oncoproteins and tumor suppressors are known to be neddylated, but whether the neddylation pathway is entirely activated in human cancer remains unexplored. NEDD8-activating enzyme (NAE) (E1) and NEDD8-conjugating enzyme (E2) expression and global-protein neddylation were examined by immunohistochemistry, immunoblotting, and real-time polymerase chain reaction analysis. Cell proliferation, clonogenic survival, migration, and motility in vitro, as well as tumor formation and metastasis in vivo, were determined upon neddylation inhibition by MLN4924, an investigational NEDD8-activating enzyme inhibitor. Survival was analyzed with Kaplan-Meier methods and compared by the log-rank test. All statistical tests were two-sided. The entire neddylation pathway, including NEDD8-activating enzyme E1, NEDD8-conjugating enzyme E2, and global-protein neddylation, is overactivated in both lung adenocarcinoma and squamous-cell carcinoma. Compared with lung adenocarcinoma patients with low expression, those with high expression had worse overall survival (NEDD8-activating enzyme E1 subunit 1 [NAE1]: hazard ratio [HR] = 2.07, 95% confidence interval [CI] = 0.95 to 4.52, P = .07; ubiquitin-conjugating enzyme E2M (UBC12): HR = 13.26, 95% CI = 1.77 to 99.35, P = .01; global protein neddylation: HR = 3.74, 95% CI = 1.65 to 8.47, P = .002). Moreover, inhibition of neddylation by the NAE inhibitor MLN4924 statistically significantly suppressed proliferation, survival, migration, and motility of lung cancer cells in vitro and tumor formation and metastasis in vivo. At the molecular level, MLN4924 inactivated Cullin-RING E3 ligases, led to accumulation of tumor-suppressive Cullin-RING E3 ligase substrates and induced phorbol-12-myristate-13-acetate-induced protein 1 (NOXA)-dependent apoptosis or cellular senescence. Our study highlights the overactivated neddylation pathway in lung cancer development and as a promising therapeutic target.


Technical advance: single pollen typing combined with laser-mediated manipulation.
We combined single pollen typing with laser-mediated manipulation. After drilling a hole in the wall of a pollen grain from a dioecious plant (Silene latifolia) with a UV-laser microbeam, the single pollen grain was recovered directly in the cap of a PCR tube, using a non-contact method called laser pressure catapulting. The entire genome of the single pollen grain was then amplified with improved primer-extension-preamplification PCR (I-PEP PCR). Nested PCR with sequence tagged site (STS)-specific primers was used to analyze several loci in the haploid genome. The single copy gene MROS1 was detected in most of the single pollen grains analyzed. Bgl10, which is localized on the Y chromosome, was detected in approximately half of the pollen grains. MROS3 is reported to be localized on the X chromosome. Using inverse PCR, we isolated two genomic clones of MROS3: MROS3A and MROS3B. The single pollen analysis using nested PCR showed that MROS3A and MROS3B are derived from different loci that are not located on the X chromosome. Single pollen typing not only reveals sex chromosome-linkage within the haploid genome, but can also discriminate between alleles and different loci. This method should also be useful for measuring recombination frequencies without genetic crossover analysis.


[Economy of generic drugs in Latin America].
In terms of economics, implementing generic drug policy is nothing other than consolidating (or even, creating) drug markets that set competitive prices, the result of which favors public access to essential drugs. This article approaches the topic of generic drugs from the economic perspective by examining various regulatory models in order to evaluate and leverage generic drug policy implementation options as a mechanism for battling some of the markets' specific weaknesses. The conclusion is that there is no single unequivocal method for promoting the use of generic drugs, and that the most favorable way to integrate markets may be through a broad combination of alternatives. These alternatives are grouped and analyzed according to the market issues or challenges that must be overcome. Several options are then identified based on the degree of market consolidation to be obtained.


IPEM Topical Report: an evidence and risk assessment based analysis of the efficacy of quality assurance tests on fluoroscopy units-part I; dosimetry and safety.
This work aims to assess the efficacy of x-ray quality assurance tests undertaken on fluoroscopy units in the UK. Information was gathered on the results of dosimetry and safety tests recommended by the reports of the Institute of Physics and Engineering in Medicine, and those additionally undertaken by medical physics departments. The assessment of efficacy considers the frequency with which a test result breaches the remedial level or other relevant threshold where applicable. The third quartile of those results exceeding the remedial level or threshold is used to estimate the severity of such a breach in terms of potential impact on patient dose and image quality. A risk assessment approach is then used to recommend to what degree, if any, the test should be included in an on-going test regimen. Data was analysed from 468 testing sessions to 336 unique fluoroscopy units throughout the UK. Across all tests, the rate with which the remedial level was exceeded varied from 0%-29.5%, with severity ranging from little or none to major degradation to image quality or significant increase on population dose. Where possible, the data has also been used to produce representative ranges for the results of dosimetric tests. These could be useful as an up to date comparator for those sites considering the purchase of or commissioning new equipment. Overall the results indicate a wide range for the efficacy of those tests undertaken at present; this can be used to review local test protocols and to inform future changes to national guidance in the UK. The results also highlight some tests where measurement technique varies significantly throughout the UK, making any valid comparison difficult. This may indicate a need for further guidance on how best to undertake these tests.


The effects of age and estrogen on stress responsivity in older women.
The current study examined whether age after menopause impacted the effect of estradiol (E2) on mood after a psychosocial stress manipulation. Previous studies have shown that E2 improves mood in women around the menopause transition but does not improve mood for older postmenopausal women. We have previously shown that E2 treatment in nondepressed women resulted in increased negative mood after psychosocial stress. Participants were 22 postmenopausal women placed on either oral placebo or 17β-estradiol (1 mg/day for 1 month, then 2 mg/day for 2 months). At the end of the 3-month treatment phase, the participants performed the Trier Social Stress Test followed by mood ratings. To examine the effects of age on the estrogen-stress interaction, we performed a median split on age and created four groups of participants: younger-placebo (mean age: 55.5 years), younger-E2 (mean age: 55.5 years), older-placebo (mean age: 73.0 years), and older-E2 (mean age: 76.8 years). : The results showed that both older and younger E2-treated participants exhibited a significant and similar increase in negative mood after psychosocial stress compared with placebo-treated women. These results suggest that E2 may play a significant role in modulating emotional reactivity to stressful events and that this effect persists in older women. Furthermore, responsivity to E2 effects on emotional processing appears to be intact even years after menopause in contrast with other cognitive and behavioral effects of E2, which may be limited to the early postmenopausal years.


Assessment of toxicity of nanoparticles using insects as biological models.
Nanomaterials have become increasingly important in medicine, manufacturing, and consumer products. The fundamental understanding in effects of nanoparticles (NPs) on and their interactions with biomolecules and organismal systems have yet to be achieved. In this chapter, we firstly provide a brief review of the interactions between nanoparticles and biological systems. We will then provide an example by describing a novel method to assess the effects of NPs on biological systems, using insects as a model. Nanoparticles were injected into the central nervous system of the discoid cockroach (Blaberus discoidalis). It was found that insects became hyperactive compared to negative control (water injections). Our method could provide a generic method of assessing nanoparticles toxicity.


Disease burden for patients with primary immunodeficiency diseases identified at reference hospitals in Guanajuato, Mexico.
In addition to the deleterious effect on health, there is considerable economic and psychosocial morbidity associated with primary immunodeficiency diseases (PID). Also, the cost of a late diagnosis frequently results in a heavy disease burden on the patient. The objective of this study was to collect and analyze data on patients with PID in the state of Guanajuato in Mexico, to indirectly estimate the burden of the disease. An observational, longitudinal, and comparative study was conducted. A total of 44 patients were included and grouped according to the updated classification of PID. The median time elapsed from the onset of symptoms to the reference and diagnosis by a tertiary hospital was of 2.17 (IQR = 6.44) years. Before diagnosis, the number of hospitalizations/year per patient was 0.86 (IQR = 2.28), the number of visit to emergency room/year per patient was 0.92 (IQR = 1.77), the number of doctor's visits/year per patient was 15 (IQR = 11.25), whereas the school/work absence days per patient were reported in 52.72 (IQR = 56.35) days per year. After diagnosis, 20 patients (45.45%) received IVIG replacement therapy, and all of them presented a significant improvement (p <0.05) in all the mentioned variables. Characteristically, even when patients with PID received IVIG, there was still an important disease burden when comparing them against healthy controls. Complications secondary to PID were detected in 19 patients (43.18%). The reported overall mortality rate was 6.82% (n = 3). We were able to indirectly estimate an important disease burden in patients with PID; which is considered to be preventable, at least in part, with effective interventions like health planning, research, collaboration with primary care providers, and generation of policies and practices, in order to improve the quality of life and care of families with PID.


Medically mediated reproduction: posthumous conception and the best interests of the child.
Advances in medical technology have provided the means for posthumous reproduction to become a foreseen and intended event. This "medically mediated", "non coital" form of reproduction raises a number of esoteric legal and ethical issues, and has much to teach us about broader issues of personal autonomy, parenthood, gender relations, family structure and the best interests of the child. In this article the author, drawing on recent Australian jurisprudence, argues that the best interests of the potential child should be the primary consideration in any case involving posthumous conception. Drawing heavily on the normative foundations provided by international law, the author attempts to identify and clarify the interests of the child relevant in the context of posthumous conception. The author concludes that a denial of access to treatment, on the basis that treatment is contrary to the best interests of the child, has no sound basis. The current treatment of the interests of the deceased and surviving partner and the interests of the child as conflicting dichotomies fails to recognise the inherent logic in converging these interests. It is only in stripping away this discriminatory façade that one comes to recognise that the promotion of the rights of the deceased and surviving partner is likely, in many cases, to enhance the best interests of the child.


Usability of a Disease Management Mobile Application as Perceived by Patients With Diabetes.
The use of mobile applications in chronic disease management has grown significantly over the past decade. When properly designed, these apps provide a convenient, safe, high-quality service to patients. In this study, a health management app was developed, and its usability among patients with diabetes mellitus was examined. A convenience sample of 136 patients, referred to two academic centers from December 2016 to July 2017, was enrolled. Upon completion of informed consent, the participants were asked to install the app on their smartphone. Two weeks later, they were required to complete a postapplication usability questionnaire, comprising 21 questions classified into six domains. The response rate was 89%. The highest scores were given for "ease of use and learnability"; the lowest-scored domains were "interaction quality" and "reliability." Urban residents, participants with lower educational qualifications, and retirees were significantly more satisfied with the app. Overall, patients with diabetes mellitus perceived the app as useful for disease management. However, the overall usability of health apps is expected to improve when a multidisciplinary team (health professionals, computer engineers, art designers) is involved in the development process.


Li-Yorke chaos of linear differential equations in a finite-dimensional space with a weak topology.
Li-Yorke chaos of linear differential equations in a finite-dimensional space with a weak topology is introduced. Based on this topology on the Euclidean space, a flow generated from a linear differential equation is proved to be Li-Yorke chaotic under certain conditions, which is in sharp contract to the well-known fact that linear differential equations cannot be chaotic in a finite-dimensional space with a strong topology.


Impaired visceral sensitivity to acid reflux in patients with Barrett's esophagus. The role of esophageal motility*.
Patients with Barrett's esophagus have been reported to have impaired visceral sensitivity to acid perfusion and distension compared with non-Barrett's refluxers, but the mechanism is poorly understood. Esophageal motility and clearance mechanisms may be important, and this study explored the relationship of motility with symptoms. Seventy-four patients with Barrett's esophagus were compared with 216 patients with gastro-esophageal reflux disease (GERD) with abnormal acid reflux scores, and 50 symptomatic patients who had normal acid exposure. All patients had esophageal manometry and 24-h pH monitoring. Thirty-six Barrett's patients also had 24-h bile reflux monitoring. Symptoms were assessed by Symptom Index (SI) during 24-h pH monitoring. Barrett's patients with normal motility had a significantly lower SI than GERD patients for similar acid exposure (P < 0.001). Barrett's patients with abnormal motility had higher acid exposure than those with normal motility (P < 0.05), but the SI values for this group was not significantly different from the GERD patients. SI and Bile reflux in Barrett's esophagus was not significantly different in patients with normal or abnormal motility. Barrett's patients had less sensitivity than GERD patients for similar acid exposure. Normal motility in Barrett's esophagus is associated with the poorest sensitivity and the presence of increased acid exposure is required in order to achieve sensitivity levels comparable with GERD patients.