[Changes of the liver blood vessels in the pulmonary trunk stenosis at compensation and decompensation].
Changes of liver blood vessel structure were studied in 23 pups with the model of compensated pulmonary trunk stenosis and in 8 animals with decompensated stenosis during 6-24 months after the establishment of stenosis. The liver of 10 age-matched dogs was used as a control. Material was studied using histological, morphometric and stereometric methods. It was found that after the establishment of pulmonary trunk stenosis and compromise to venous blood outflow from the liver, the tone of the arteries increased as well as the resistance to the blood flow. Besides the venous-arterial reaction, the bundles of oblique-longitudinal smooth muscle cells and musculo-elastic sphincters were shown to be formed in the intima of the afferent vessels, while in the efferent vessels the hypertrophy of the muscular folds took place. In decompensated stenosis, the hypoxia was combined with the relaxation of the walls of both afferent and efferent vessels, the number of arteries with the adaptational structures was decreased, while the muscular folds of hepatic veins underwent atrophy. The failure of adaptation mechanisms resulted in the development of chronic liver venous congestion.


Expression of maize gamma zein C-terminus in Escherichia coli.
Prolamins containing a highly conserved cysteine-rich C-terminal domain have been poorly expressed as soluble protein in model systems such as Escherichia coli. Possible reasons have included a combination of the reducing environment of the bacterial cytoplasm and protein secondary structure. Using a bacterial thioredoxin fusion expression system, full-length native gamma zein, native gamma zein C-terminus, and modified gamma zein C-terminus, containing 13 amino acid changes, were found to accumulate up to 58, 50, and 42% of the total cellular protein, respectively. The native gamma zein C-terminus fusion protein was six times more soluble (70%) than the full-length fusion protein (12%), four times more soluble than the N-terminus (19%), and eight times more soluble than the modified C-terminus (9%). The modified C-terminal domain contained amino acid changes that improved the lysine, isoleucine, and tryptophan content, while removing two evolutionarily conserved cysteines and one nonconserved cysteine. Expression of the native C-terminal domain without thioredoxin resulted in decreased solubility (13%) and decreased expression (8%). In contrast, coexpression with thioredoxin resulted in a sevenfold increase in solubility (86%). These results suggest that insolubility of full-length gamma zein results from structural interactions of the N-terminus and that solubility of the C-terminal domain is dependent on proper disulfide bond formation. The ability to express the C-terminal domain of gamma zein as soluble protein should allow future identification of important structural elements in gamma zein and similar proteins.


New targeted therapies in pituitary carcinoma resistant to temozolomide.
To evaluate the antitumoral efficacy of everolimus in pituitary carcinoma resistant to temozolomide, the correlation with mammalian target of rapamycin (mTOR) signaling in the tumor and to present recent advances and future treatments of pituitary carcinomas. Pituitary carcinomas are rare and largely unresponsive to current treatment options. Recent reports on the antitumoral efficacy of temozolomide in some such patients are encouraging, yet most patients appear to show resistance to its actions. As a potential alternative, the mTOR inhibitor, everolimus, has been shown to potently inhibit pituitary cell proliferation highlighting mTOR inhibition as a promising therapeutic approach for pituitary carcinomas. We described the tumoral effects of a combination therapy with everolimus (5 mg/day) and octreotide (30 mg/month) and the mTOR signalling expression in a patient with pituitary ACTH carcinoma, compared to 17 other ACTH adenomas. Clinical and biochemical evaluation were performed every month, and imaging after 3 month of treatment. mTOR signaling was assessed by microarray expression analysis of each of the 18 adenoma tissues. Combined therapy failed to control pituitary tumor growth and ACTH secretion. Slight activation of mTOR signaling was found in all ACTH tumors alongside important variations between tumors. Low antitumor efficacy shown by everolimus might be explained by the weak activation of mTOR pathway in ACTH tumors. Everolimus treatment was inefficient at controlling secretion and tumor growth of one ACTH pituitary carcinoma. More clinical cases, with mTOR signalling expression analysis of the tumor, must be published before any conclusions can be drawn.


Genetic analysis of suppressors of the veA1 mutation in Aspergillus nidulans.
Light-dependent conidiation in the filamentous ascomycete, Aspergillus nidulans, is contingent on the allelic state of the velvet (veA) gene. Light dependence is abolished by a mutation in this gene (veA1), which allows conidiation to occur in the absence of light. We have isolated and characterized six extragenic suppressors of veA1 that restore the light-dependent conidiation phenotype. Alleles of four genes, defined by complementation tests, were subjected to extensive genetic and phenotypic analysis. The results of light-dark shifting experiments and the phenotypes of double mutant combinations are consistent with the possibility that the expression of the light-dependent phenotype is regulated by specific interactions of the suppressor gene products with the velvet gene product and with each other.


Phase I trial of intravesical Bacillus Calmette-Guérin combined with intravenous pembrolizumab in recurrent or persistent high-grade non-muscle-invasive bladder cancer after previous Bacillus Calmette-Guérin treatment.
We conducted the first phase I dose-escalation trial (NCT02324582) of intravesical Bacillus Calmette-Guérin (BCG) in combination with systemic pembrolizumab in patients with high-grade non-muscle-invasive bladder cancer (HGNMIBC) who had persistent or recurrent disease after prior intravesical therapy with BCG. The primary endpoint was the safety of this combination. The secondary endpoint was clinical activity at three months following BCG treatment. Eighteen patients were consented for the study, five of which were screen failures. Six doses of pembrolizumab were administered every 3 weeks over 16 weeks concurrently with six weekly doses of BCG beginning at week 7. Patient safety was evaluated from the time of consent through 30 days following pembrolizumab treatment. Clinical activity was determined using cystoscopy and biopsy of suspicious lesions. Treatment-related adverse events included one grade 4 adverse event (AEs) (adrenal insufficiency). There were nine grade 3 AEs (chest discomfort, pulmonary embolism, arthritis, wrist edema, injection site reaction, bilateral wrist pain, cardiomyopathy, hypokalemia, urinary tract infection). There were 49 grade 1 and 30 grade 2 AEs (88% of AEs). Eleven patients finished the treatment, and two patients died during the study. Of 13 patients treated, nine patients (69%) had no evidence of disease at 3 months following BCG treatment. We report for the first time that combining BCG and pembrolizumab in treating HGNMIBC is safe allowing complete treatment of most patients. A phase III trial has opened to test the efficacy of this combination in HGNMIBC (KEYNOTE-676).


Arthroscopic all-inside ligament repair has similar or superior clinical outcomes compared to open repair for chronic ankle instability without concomitant intra-articular pathology at 5 years follow-up.
Open ligament repair is widely considered the gold standard treatment for chronic ankle instability. Nevertheless, arthroscopic treatment of ankle instability has gained popularity becoming the preferred technique for many surgeons. This study aimed to compare the clinical outcomes of all-inside arthroscopic versus open lateral ligament repair for chronic ankle instability at 5 years follow-up. Ninety consecutive patients were surgically treated for chronic ankle instability without concomitant intra-articular pathology observed on MRI: 41 patients [median age 28 (range 15-54) years] underwent an open lateral ligament repair (OLR); 49 patients [median age 30 (range 19-47) years] underwent an all-inside arthroscopic ligament repair (ALR). Functional outcomes using the Foot Functional Index (FFI), the American Orthopaedic Foot and Ankle Society (AOFAS) Hindfoot Score, and the Foot and Ankle Ability Measure-Sports Subscale (FAAM-SS) were assessed preoperatively and at the latest follow-up. At the latest follow-up, the satisfaction rate and complications were also recorded. The mean follow-up was 58 ± 17.6 (range 47-81) months. In both groups FFI, AOFAS and FAAM-SS score significantly improved compared to preoperative values (p < 0.001). There was no statistically significant difference in postoperative outcomes between groups in the AOFAS (n.s) and FAAM-SS (n.s), but the FFI results were significantly better in the ALR group (p < 0.05). No major complications were reported in either group. Open and arthroscopic ligament repair to treat chronic ankle instability without concomitant intra-articular pathology produced excellent comparable clinical outcomes at 5 years follow-up. The complications were minimal in both study groups with no significant differences in AOFAS and FAAM-SS scores. However, arthroscopic repair showed significantly better results on the FFI. Therefore, when treating chronic lateral ankle instability, surgeons should consider arthroscopic ligament repair. III.


Analysis of Live Single Cells by Confocal Microscopy and High-Resolution Mass Spectrometry to Study Drug Uptake, Metabolism, and Drug-Induced Phospholipidosis.
The analysis of large numbers of cells from a population results in information that does not reflect differences in cell phenotypes. Individual variations in cellular drug uptake, metabolism, and response to drug treatment may have profound effects on cellular survival and lead to the development of certain disease states, drug persistence, and resistance. Herein, we present a method that combines live cell confocal microscopy imaging with high-resolution mass spectrometry to achieve absolute cell quantification of the drug amiodarone (AMIO) and its major metabolite, N-desethylamiodarone (NDEA), in single liver cells (HepG2 and HepaRG cells). The method uses a prototype system that integrates a confocal microscope with an XYZ stage robot to image and automatically sample selected cells from a sample compartment, which is kept under growth conditions, with nanospray tips. Besides obtaining the distributions of AMIO and NDEA cell concentrations across a population of individual cells, as well as variabilities in drug metabolism, the effect of these on phospholipidosis and cell morphology was studied. The method was suited to identify subpopulations of cells that metabolized less drug and to correlate cell drug concentrations with cell phospholipid content, cell volume, sphericity, and other cell phenotypic features. Using principal component analysis (PCA), the treated cells could be clearly distinguished from vehicle control cells (0 μM AMIO) and HepaRG cells from HepG2 cells. The potential of using multidimensional and multimodal information collected from single cells to build predictive models for cell classification is demonstrated.


[Analysis of dietary intake in preschool children from Cheboksary].
The purpose of the study was to analyze the diets of preschool children going to infant schools (IS) in Cheboksary and to evaluate their provision with calcium and phosphorus. For this, the authors developed the serum content of calcium and phosphorus, the indices of children's physical development, the levels of macro- and micronutrients, and calorie content by the calculation method and chemical analytical method and quantities of calcium and phosphorus in the IS food allowances. Our studies using the calculation and chemical analytical methods revealed differences in the content of macroelements. In the children being examined, the serum levels of calcium complied with the normal values; 59% of the children were found to have mild hypophospathemia attributable to inadequate phosphorus amount in the diet. The study showed it necessary to correct the quantities of calcium and phosphorus in the children's diets.


The Need for a Dynamic Approach to Health System-Centered Innovations Comment on "What Health System Challenges Should Responsible Innovation in Health Address? Insights From an International Scoping Review".
Lehoux and colleagues plea for a health systems perspective to evaluate innovations. Since many innovations and their scale-up strategies emerge from processes that are not (centrally) steered, we plea for any assessment with a dynamic, instead of a sequential, approach. We provide further guidance on how to adopt such dynamic approach, in order to better un-derstand and steer innovations for better health systems. A systems-level challenge is constituted by interactions and feedback loops between different actors and components of the health system. It is therefore essential to explore both the entry-point of innovation and the interactions with other components. If innovation is regarded as an injection of resources and opportunities into a health system, this system needs to have the capacity to transform these into desired outputs, the 'absorption capacity.' The highly organic diffusion of innovation in complex adapative systems cannot be easily controlled, but the system behaviours can be analysed, with occurance of phenomena such as path dependence, feedback loops, scale-free networks, emergent behaviour and phase transitions. This helps to anticipate unintended consequences, and to engage key actors in ongoing problem-solving and adaptation. By adopting a prospective approach, responsible innovation could set in motion prospective policy evaluations, which on the basis of iterative learning would allow decisionmakers to continuously adapt their policies and programmes. Priority-setting for innovation is an essentially political process that is geared towards consensus-building and grounded in values.


Deep Learning for Classifying Physical Activities from Accelerometer Data.
Physical inactivity increases the risk of many adverse health conditions, including the world's major non-communicable diseases, such as coronary heart disease, type 2 diabetes, and breast and colon cancers, shortening life expectancy. There are minimal medical care and personal trainers' methods to monitor a patient's actual physical activity types. To improve activity monitoring, we propose an artificial-intelligence-based approach to classify physical movement activity patterns. In more detail, we employ two deep learning (DL) methods, namely a deep feed-forward neural network (DNN) and a deep recurrent neural network (RNN) for this purpose. We evaluate the two models on two physical movement datasets collected from several volunteers who carried tri-axial accelerometer sensors. The first dataset is from the UCI machine learning repository, which contains 14 different activities-of-daily-life (ADL) and is collected from 16 volunteers who carried a single wrist-worn tri-axial accelerometer. The second dataset includes ten other ADLs and is gathered from eight volunteers who placed the sensors on their hips. Our experiment results show that the RNN model provides accurate performance compared to the state-of-the-art methods in classifying the fundamental movement patterns with an overall accuracy of 84.89% and an overall F1-score of 82.56%. The results indicate that our method provides the medical doctors and trainers a promising way to track and understand a patient's physical activities precisely for better treatment.


Cardiac cell-based therapy: cell types and mechanisms of actions.
Over the past decade, the concept that the heart could undergo cardiac regeneration has rapidly evolved. Studies have indicated that numerous sites in the body harbor stem or progenitor cells, prompting clinical trials of these potential therapeutic cell-based approaches. Most notable are the series of trials utilizing either skeletal myoblasts or autologous whole bone marrow. More recently the quest has focused on specific bone marrow constituents, most notably the mesenchymal stem cell, which has several unique advantages including immunoprivilege, immunosuppression, and the ability to home to areas of tissue injury. Most recently, cells have been identified within the heart itself that are capable of self-replication and differentiation. The discovery of cardiac stem cells offers not only a potential therapeutic approach but also provides a plausible target for endogenous activation as a therapeutic strategy. Together the new insights obtained from studies of cell-based cardiac therapy have ushered in new biological paradigms and enormous potential for novel therapeutic strategies for cardiac disease.


Optical biopsy in human gastrointestinal tissue using optical coherence tomography.
Optical coherence tomography (OCT) is a new technique for performing high-resolution, cross-sectional tomographic imaging in human tissue. OCT is somewhat analogous to ultrasound B mode imaging except that it uses light rather than acoustical waves. OCT has over 10 times the resolution of currently available clinical high-resolution imaging technologies. In this work, we investigate the capability of OCT to differentiate the architectural morphology of gastrointestinal tissue with the long-term objective of extending OCT to endoscopic based diagnostics. Normal and diseased gastrointestinal tissues were taken postmortem and imaged using OCT. Images were compared with corresponding histology to confirm tissue identity and suggest the mechanisms that produce tissue contrast. Microstructure was delineated in different tissues, including the esophagus and colon, at 16 +/- 1 microns resolution, higher than any clinically available cross-sectional imaging technology. Differentiation of tissue layers, such as the mucosa, submucosa, and muscularis were achieved because of their different optical properties. The ability of OCT to provide high-resolution in situ imaging of gastrointestinal microstructure, without the need for excisional biopsy, suggests the feasibility of using OCT as a powerful diagnostic imaging technology, which can be integrated with conventional endoscopy.


Respiratory tract illness in meat wrappers.
A questionnaire survey was done in 152 Houston supermarkets to assess the prevalence of respiratory tract symptoms in meat wrappers exposed to the thermal decomposition fumes of polyvinyl chloride (PVC) film wrap and in two supermarket control groups (checkers and meat cutters). Meat wrappers had increased respiratory tract symptoms; 12% of meat wrappers who smoked (vs 6% and 2% of controls) and 5% of meat wrappers who did not smoke (vs 0% and 0% of controls) had multiple respiratory tract symptoms. It is probable that a large number of meat wrappers have mild symptoms with some progressing to more severe respiratory impairment or clinical asthma.


Recent Advances in the Diagnosis of Classical Swine Fever and Future Perspectives.
Classical swine fever (CSF) is a highly contagious viral disease of pigs, including wild boar. It is regarded as one of the major problems in the pig industry as it is still endemic in many regions of the world and has the potential to cause devastating epidemics, particularly in countries free of the disease. Rapid and reliable diagnosis is of utmost importance in the control of CSF. Since clinical presentations of CSF are highly variable and may be confused with other viral diseases in pigs, laboratory diagnosis is indispensable for an unambiguous diagnosis. On an international level, well-established diagnostic tests of CSF such as virus isolation, fluorescent antibody test (FAT), antigen capture antibody enzyme-linked immunosorbent assay (ELISA), reverse-transcription polymerase chain reaction (RT-PCR), virus neutralization test (VNT), and antibody ELISA have been described in detail in the OIE Terrestrial Manual. However, improved CSF diagnostic methods or alternatives based on modern technologies have been developed in recent years. This review thus presents recent advances in the diagnosis of CSF and future perspectives.


Identification of genes involved in biosynthesis of Actinobacillus pleuropneumoniae serotype 1 O-antigen and biological properties of rough mutants.
Actinobacillus pleuropneumoniae is an important pathogen of swine. Lipopolysaccharide (LPS) has been identified as the major adhesin of A. pleuropneumoniae and it is involved in adherence to porcine respiratory tract cells. We previously generated seven rough LPS mutants of A. pleuropneumoniae serotype 1 by using a mini-Tn10 transposon mutagenesis system [Rioux S, Galarneau C, Harel J et al. Isolation and characterization of mini-Tn10 lipopolysaccharide mutants of Actinobacillus pleuropneumoniae serotype 1. Can J Microbiol 1999; 45: 1017-1026]. The purpose of the present study was to characterize these mutants in order to learn more about LPS O-antigen biosynthesis genes and their organization in A. pleuropneumoniae, and to determine the surface properties and virulence in pigs of these isogenic mutants. By mini-Tn10 insertions in rough mutants, four putative genes (ORF12, ORF16, ORF17, and ORF18) involved in O-antigen biosynthesis in A. pleuropneumoniae serotype 1 were found within a region of 18 ORFs. This region is homologous to the gene cluster of serotype-specific O-polysaccharide biosynthesis from A. actinomycetemcomitans strain Y4 (serotype b). Two mutants showed homology to a protein with identity to glycosyltransferases (ORF12); two others had the mini-Tn10 insertion localized in genes encoding for two distinct proteins with identity to rhamnosyltransferases (ORF16 and ORF17) and three showed homology to a protein which is known to initiate polysaccharide synthesis (ORF18). These four ORFs were also present in A. pleuropneumoniae serotypes 9 and 11 that express an O-antigen that serologically cross-reacts with serotype 1. Evaluation of some biological properties of rough mutants seems to indicate that the absence of O-chains does not appear to have an influence on the virulence of the bacteria in pigs and on the overall surface hydrophobicity, charge and hemoglobin-binding activity, or on LAL activation. An acapsular mutant was included in the present study in order to compare the influence of O-chains and capsule polysaccharides on different cell surface properties. Our data suggest that capsular polysaccharides and not O-chains polysaccharides have a major influence on surface properties of A. pleuropneumoniae serotype 1 and its virulence in pigs.


Neural saccadic response estimation during natural viewing.
Studying neural activity during natural viewing conditions is not often attempted. Isolating the neural response of a single saccade is necessary to study neural activity during natural viewing; however, the close temporal spacing of saccades that occurs during natural viewing makes it difficult to determine the response to a single saccade. Herein, a general linear model (GLM) approach is applied to estimate the EEG neural saccadic response for different segments of the saccadic main sequence separately. It is determined that, in visual search conditions, neural responses estimated by conventional event-related averaging are significantly and systematically distorted relative to GLM estimates due to the close temporal spacing of saccades during visual search. Before the GLM is applied, analyses are applied that demonstrate that saccades during visual search with intersaccadic spacings as low as 100-150 ms do not exhibit significant refractory effects. Therefore, saccades displaying different intersaccadic spacings during visual search can be modeled using the same regressor in a GLM. With the use of the GLM approach, neural responses were separately estimated for five different ranges of saccade amplitudes during visual search. Occipital responses time locked to the onsets of saccades during visual search were found to account for, on average, 79 percent of the variance of EEG activity in a window 90-200 ms after the onsets of saccades for all five saccade amplitude ranges that spanned a range of 0.2-6.0 degrees. A GLM approach was also used to examine the lateralized ocular artifacts associated with saccades. Possible extensions of the methods presented here to account for the superposition of microsaccades in event-related EEG studies conducted in nominal fixation conditions are discussed.


Resilience to Plasma and Cerebrospinal Fluid Amyloid-β in Cognitively Normal Individuals: Findings From Two Cohort Studies.
Objective: To define resilience metrics for cognitive decline based on plasma and cerebrospinal fluid (CSF) amyloid-β (Aβ) and examine the demographic, genetic, and neuroimaging factors associated with interindividual differences among metrics of resilience and to demonstrate the ability of such metrics to predict the diagnostic conversion to mild cognitive impairment (MCI). Methods: In this study, cognitively normal (CN) participants with Aβ-positive were included from the Sino Longitudinal Study on Cognitive Decline (SILCODE, n = 100) and Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 144). Using a latent variable model of data, metrics of resilience [brain resilience (BR), cognitive resilience (CR), and global resilience (GR)] were defined based on the plasma Aβ and CSF Aβ. Linear regression analyses were applied to investigate the association between characteristics of individuals (age, sex, educational level, genetic, and neuroimaging factors) and their resilience. The plausibility of these metrics was tested using linear mixed-effects models and Cox regression models in longitudinal analyses. We also compared the effectiveness of these metrics with conventional metrics in predicting the clinical progression. Results: Although individuals in the ADNI cohort were older (74.68 [5.65] vs. 65.38 [4.66], p < 0.001) and had higher educational levels (16.3 [2.6] vs. 12.6 [2.8], p < 0.001) than those in the SILCODE cohort, similar loadings between resilience and its indicators were found within both models. BR and GR were mainly associated with age, women, and brain volume in both cohorts. Prediction models showed that higher CR and GR were related to better cognitive performance, and specifically, all types of resilience to CSF Aβ could predict longitudinal cognitive decline. Conclusion: Different phenotypes of resilience depending on cognition and brain volumes were associated with different factors. Such comprehensive resilience provided insight into the mechanisms of susceptibility for Alzheimer's disease (AD) at the individual level, and interindividual differences in resilience had the potential to predict the disease progression in CN people.


Characterization of tetracycline resistance plasmids from Campylobacter jejuni and Campylobacter coli.
Tetracycline resistance in strains of Campylobacter jejuni and Campylobacter coli was mediated by plasmids. Intra- and interspecies transfer was demonstrated within the genus Campylobacter. Buoyant densities of plasmid DNAs ranged from 1.691 to 1.694 g/cm3 (31 to 33% guanine plus cytosine). Restriction enzymes AccI, BclI, BglII, and PstI were found to be most useful for comparing the plasmids. The molecular weight of C. jejuni plasmid pMAK175 was 44.7 kilobases (29 X 10(6), and the other plasmids had similar sizes. Two plasmids from Belgian isolates of C. coli of human origin had very similar restriction enzyme profiles and are probably identical. Plasmids from human isolates of C. jejuni originating in Canada and the animal isolate of C. coli showed greater diversity. DNA homology among the campylobacter plasmids was assessed by probing the digests with a nick-translated campylobacter plasmid, pMAK175. All restriction fragments showed significant homology with pMAK175 probe DNA. No homology was noted between campylobacter plasmid DNA and plasmids specifying the four classes of tetracycline resistance determinants found in Enterobacteriaceae.


Reflux symptoms in 100 normal infants: diagnostic validity of the infant gastroesophageal reflux questionnaire.
To identify the prevalence of reflux symptoms in normal infants, to characterize the diagnostic validity of a previously described 138-item Infant Gastroesophageal Reflux Questionnaire (I-GERQ) for separating normal infants from those with gastroesophageal reflux disease (GERD), and to identify potentially provocative caretaking practices, we administered the questionnaire to 100 infants attending a well-baby clinic (normals) and to 35 infants referred to the Gastroenterology Division for evaluation for GERI) and testing positive on esophageal pH probe or biopsy (GERD infants). Differences were analyzed by Chi-square, and odds ratios were defined. The diagnostic validity of a 25-point I-GERQ GERD score based on 11 items on the questionnaire was evaluated by calculating its sensitivity, specificity, and positive and negative predictive values. We found that normal infants had a high prevalence of reflux symptoms, such as daily regurgitation (40%), respiratory symptoms, crying more than an hour a day (17%), arching (10%), or daily hiccups (36%) but that many symptoms were significantly more prevalent in the GERD than in the normal infants (Chi-square P < .05), and odds ratios were above 3 for nearly 20 items. The positive and negative predictive values for the 25-point I-GERQ score were 1.00 and .94-.98, respectively. Environmental smoke exposure did not quite reach significance as a provocative factor for GERD. Although normal infants have a high prevalence of symptoms suggesting GERD, a simple questionnaire-based score is a valid diagnostic test with high positive and negative predictive values.


Inflammation of the mind. On the 300th anniversary of Gerard van Swieten.
History teaches that the ancient phrenitis concept has been used until the 19th century. After that time the concept was replaced by the word delirium. By their epigonic character the detailed descriptions of phrenitis by Van Swieten mark only the end of an uncritical use of the term. The epoch-making work of Morgagni, based on clinical-anatomical observations, provides a definitive insight into the location of the condition and into many pathologic features. Pinel is the last author who mentions phrenitis in a classification of diseases. After that time phrenitis became a vanished disease.


Soliton absorption spectroscopy.
We analyze optical soliton propagation in the presence of weak absorption lines with much narrower linewidths as compared to the soliton spectrum width using the novel perturbation analysis technique based on an integral representation in the spectral domain. The stable soliton acquires spectral modulation that follows the associated index of refraction of the absorber. The model can be applied to ordinary soliton propagation and to an absorber inside a passively modelocked laser. In the latter case, a comparison with water vapor absorption in a femtosecond Cr:ZnSe laser yields a very good agreement with experiment. Compared to the conventional absorption measurement in a cell of the same length, the signal is increased by an order of magnitude. The obtained analytical expressions allow further improving of the sensitivity and spectroscopic accuracy making the soliton absorption spectroscopy a promising novel measurement technique.


Adult onset unilateral systematized porokeratotic eccrine ostial and dermal duct nevus: a case report.
Porokeratotic eccrine ostial and dermal duct nevus (PEODDN) is an uncommon, benign dermatosis that is characterized by asymptomatic grouped keratotic papules and plaques with a linear pattern on the extremities with distinct porokeratotic histopathological features. The lesions usually appear at birth or in childhood, although rare cases of late-onset adult PEODDN have been described. Herein we report a case of adult onset PEODDN with unilateral and segmental involvement.


Dose rate and fractionation of total body irradiation in dogs: short and long term effects.
Variations of regimens of total body irradiation (TBI) were investigated in the dog as a preclinical model for bone marrow transplantation. Inactivation of hemopoietic precursor cells (CFU-GM) was studied following irradiation of marrow in vitro, following TBI at sublethal doses in vivo and following autologous transplantation of marrow obtained after sublethal TBI. Inactivation and recovery of CFU-GM as well as restoration of hemopoiesis following autologous transplantation was independent of the dose rate, but nadirs of blood counts were lower following sublethal TBI with the higher dose rate. Acute non-hemopoietic toxicity of TBI depended on the dose, the dose rate and the total treatment time and not on the fractionation regimen. At a total dose of 25 Gy acute mortality was prevented by prophylactic administration of oral, non-absorbable antibiotics. Late mortality was due to degenerative and autoimmune-like disorders with or without infections and to malignant tumors. Evaluation of long-term survival is still preliminary, since surviving dogs of two groups (10 Gy as single dose, 25 Gy as hyperfractionated TBI) have not yet reached the median survival time of their group. So far, long-term survival depended on the total dose (p = 0.05) and, possibly, the fractionation regimen (p = 0.12). The latency period until development of malignant tumors was influenced by the total doses given in the same treatment time (p = 0.05) and by the total treatment time for equal doses (p = 0.04). It was concluded that TBI at a low dose rate may give the best therapeutic ratio of inactivation of hemopoietic precursor cells to acute toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)


Expression and localisation of matrix metalloproteinases and their natural inhibitors in fistulae of patients with Crohn's disease.
Fistulae are a troublesome complication of Crohn's disease but little is known of the final effector molecules responsible for matrix degradation. Although matrix metalloproteinases (MMPs) have been strongly implicated in tissue injury in Crohn's disease, their role in fistula formation is unknown. To determine the expression pattern of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in fistulae of patients with Crohn's disease. Resected fistula specimens were obtained from patients with Crohn's disease (n = 11) and classified according to the predominant histological features-that is, acute versus chronic inflammation. Patients with fistulae due to other diseases (n = 9) and normal colon (n = 5) served as controls. MMP and TIMP protein expression was measured by single or double labelled immunohistochemistry, and mRNA expression by in situ hybridisation. MMP activity was measured by gelatin zymography. Compared with normal colon, strong MMP-3 expression was consistently observed in fistulae in Crohn's disease, irrespective of the stage of inflammatory activity. MMP-3 transcripts and protein were localised in large mononuclear cells and fibroblasts. MMP-9 transcripts and protein were expressed in granulocytes and only in fistulae with acute inflammation. Staining for MMP-1 and MMP-7 was weak and negative for MMP-10, whereas MMP-2 was equally expressed in normal colon and fistulae. TIMP-1, TIMP-2, and TIMP-3 expression was low in all samples. Similar expression patterns were found in fistulae of the disease control group. Fistulae also expressed active MMP-2 and MMP-9, as measured by gelatin zymography. MMP-3 and MMP-9 are markedly upregulated in intestinal fistulae and may contribute to fistula formation through degradation of the extracellular matrix, irrespective of the underlying disease process.


Geographic Life History Differences Predict Genomic Divergence Better than Mitochondrial Barcodes or Phenotype.
Species diversity can be inferred using multiple data types, however, results based on genetic data can be at odds with patterns of phenotypic variation. Tiger beetles of the Cicindelidiapolitula (LeConte, 1875) species complex have been taxonomically problematic due to extreme phenotypic variation within and between populations. To better understand the biology and taxonomy of this group, we used mtDNA genealogies and multilocus nuclear analyses of 34,921 SNPs to elucidate its evolutionary history and evaluate the validity of phenotypically circumscribed species and subspecies. Genetic analyses recovered two divergent species that are also ecologically distinct, based on adult life history. These patterns are incongruous with the phenotypic variation that informed prior taxonomy, and most subspecies were not supported as distinct evolutionary lineages. One of the nominal subspecies was found to be a cryptic species; consequently, we elevate C. p.laetipennis (Horn, 1913) to a full species. Although nuclear and mtDNA datasets recovered broadly similar evolutionary units, mito-nuclear discordance was more common than expected, being observed between nearly all geographically overlapping taxonomic pairs. Additionally, a pattern of 'mitochondrial displacement' was observed, where mitochondria from one species unidirectionally displace others. Overall, we found that geographically associated life history factors better predict genomic divergence than phenotype and mitochondrial genealogies, and consequently taxon identifications based on mtDNA (e.g., DNA barcodes) may be misleading.


Pamrevlumab, an anti-connective tissue growth factor therapy, for idiopathic pulmonary fibrosis (PRAISE): a phase 2, randomised, double-blind, placebo-controlled trial.
Connective tissue growth factor (CTGF) is a secreted glycoprotein that has a central role in the process of fibrosis. This study was designed to assess the safety, tolerability, and efficacy of pamrevlumab (FG-3019), a fully recombinant human monoclonal antibody against CTGF, in idiopathic pulmonary fibrosis. The aim was to establish whether pamrevlumab could slow, stop, or reverse progression of idiopathic pulmonary fibrosis. The phase 2, randomised, double-blind, placebo-controlled PRAISE trial was done at 39 medical centres in seven countries (Australia, Bulgaria, Canada, India, New Zealand, South Africa, and the USA). Patients with idiopathic pulmonary fibrosis and percentage of predicted forced vital capacity (FVC) of 55% or greater were enrolled and randomly assigned (1:1) by use of interactive responsive technology to intravenous infusion of pamrevlumab 30 mg/kg or placebo every 3 weeks over 48 weeks (16 infusions). The primary efficacy outcome was change from baseline in percentage of predicted FVC at week 48. Disease progression (defined as a decline from baseline in percentage of predicted FVC of ≥10%, or death) at week 48 was a key secondary efficacy outcome. All patients in the pamrevlumab group received at least one dose of the study drug and were analysed for safety. Two patients in the placebo group were excluded from the intention-to-treat population for the efficacy analyses because of enrolment error. This trial is registered with ClinicalTrials.gov, NCT01890265. Between Aug 17, 2013, and July 21, 2017, 103 patients were randomly assigned (50 to pamrevlumab and 53 to placebo). Pamrevlumab reduced the decline in percentage of predicted FVC by 60·3% at week 48 (mean change from baseline -2·9% with pamrevlumab vs -7·2% with placebo; between-group difference 4·3% [95% CI 0·4-8·3]; p=0·033). The proportion of patients with disease progression was lower in the pamrevlumab group than in the placebo group at week 48 (10·0% vs 31·4%; p=0·013). Pamrevlumab was well tolerated, with a safety profile similar to that of placebo. Treatment-emergent serious adverse events were observed in 12 (24%) patients in the pamrevlumab group and eight (15%) in the placebo group, with three patients on pamrevlumab and seven on placebo discontinuing treatment. Of the three (6%) deaths in the pamrevlumab group and six (11%) in the placebo group, none was considered treatment related. Pamrevlumab attenuated progression of idiopathic pulmonary fibrosis and was well tolerated. Now in phase 3 development, pamrevlumab shows promise as a novel, safe, and effective treatment for idiopathic pulmonary fibrosis. FibroGen.


A neural network of smooth hinge functions.
Smooth hinging hyperplane (SHH) has been proposed as an improvement over the well-known hinging hyperplane (HH) by the fact that it retains the useful features of HH while overcoming HH's drawback of nondifferentiability. This paper introduces a formal characterization of smooth hinge function (SHF), which can be used to generate SHH as a neural network. A method for the general construction of SHF is also given. Furthermore, the work proves that SHH is better than HH in functional approximation, i.e., the optimal error of SHH approximating a general function is always smaller or equal to that of HH. Particularly, in the case that the SHF is generated via the integration of a class of sigmoidal functions, it is further proven that the corresponding SHH of the 2m SHFs would outperform a neural network with m of the sigmoidal function from which the SHF is derived. Any upper bound established on the approximation error of a neural network of m sigmoidal activation functions can hence be translated to the SHH of m SHFs by replacing m with [m/2]. The work also includes an algorithm for the identification of SHH making use of its differentiability property. Simulation experiments are presented to validate the theoretical conclusions to possible extent.


High sensitivity optically pumped quantum magnetometer.
Quantum magnetometers based on optical pumping can achieve sensitivity as high as what SQUID-based devices can attain. In this paper, we discuss the principle of operation and the optimal design of an optically pumped quantum magnetometer. The ultimate intrinsic sensitivity is calculated showing that optimal performance of the magnetometer is attained with an optical pump power of 20 μW and an operation temperature of 48°C. Results show that the ultimate intrinsic sensitivity of the quantum magnetometer that can be achieved is 327 fT/Hz(½) over a bandwidth of 26 Hz and that this sensitivity drops to 130 pT/Hz(½) in the presence of environmental noise. The quantum magnetometer is shown to be capable of detecting a sinusoidal magnetic field of amplitude as low as 15 pT oscillating at 25 Hz.


A specific peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand, pioglitazone, ameliorates gastric mucosal damage induced by ischemia and reperfusion in rats.
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily, has recently been implicated as a regulator of cellular proliferation and inflammatory responses. The aim of the present study was to investigate the effects of pioglitazone on ischemia-reperfusion (I/R)-induced gastric mucosal injury in rats. Gastric ischemia was induced for 30 min by applying a small vascular clamp to the celiac artery and reperfusion was produced by removal of the clamp in male Sprague-Dawley rats treated with and without pioglitazone. Pioglitazone was given to the rats intraperitoneally 2 h before the vascular clamping. The area of gastric mucosal erosion (erosion index) significantly increased from mean basal levels after 60 min of reperfusion. This erosion index was significantly inhibited by pretreatment with pioglitazone in a dose-dependent manner. The concentration of thiobarbituric acid reactive substances (TBARS) and myeloperoxidase (MPO) activity in the gastric mucosa were both significantly increased after I/R, and pretreatment with pioglitazone significantly reduced these increases. The contents of both mucosal TNF-alpha and CINC-2beta in the I/R group were significantly increased compared with the levels in the sham-operated group. These increases in TNF-alpha and CINC-2beta were significantly inhibited by pretreatment with pioglitazone at a dose of 10 mg/kg. The results of the present study indicate that pioglitazone inhibited lipid peroxidation and reduced development of the gastric mucosal inflammation induced by I/R in rats. This investigation suggests that pioglitazone has potential as a new therapeutic agent for reperfusion injury.


FRAX-based assessment and intervention thresholds--an exploration of thresholds in women aged 50 years and older in the UK.
Under current guidelines, based on prior fracture probability thresholds, inequalities in access to therapy arise especially at older ages (≥70 years) depending on the presence or absence of a prior fracture. An alternative threshold (a fixed threshold from the age of 70 years) reduces this disparity, increases treatment access and decreases the need for bone densitometry. Several international guidelines set age-specific intervention thresholds at the 10-year probability of fracture equivalent to a woman of average BMI with a prior fracture. At older ages (≥70 years), women with prior fracture selected for treatment are at lower average absolute risk than those selected for treatment in the absence of prior fracture, prompting consideration of alternative thresholds in this age group. Using a simulated population of 50,633 women aged 50-90 years in the UK, with a distribution of risk factors similar to that in the European FRAX derivation cohorts and a UK-matched age distribution, the current NOGG intervention and assessment thresholds were compared to one where the thresholds remained constant from 70 years upwards. Under current thresholds, 45.1% of women aged ≥70 years would be eligible for therapy, comprising 37.5% with prior fracture, 2.2% with high risk but no prior fracture and 5.4% selected for treatment after bone mineral density (BMD) measurement. Mean hip fracture probability was 11.3, 23.3 and 17.6%, respectively, in these groups. Under the alternative thresholds, the overall proportion of women treated increased from 45.1 to 52.9%, with 8.4% at high risk but no prior fracture and 7.0% selected for treatment after BMD measurement. In the latter group, the mean probability of hip fracture was identical to that observed in women with prior fracture (11.3%). The alternative threshold also reduced the need for BMD measurement, particularly at older ages (>80 years). The alternative thresholds equilibrate fracture risk, particularly hip fracture risk, in those with or without prior fracture selected for treatment and reduce BMD usage at older ages.


Development and characterization of immortalized ovine endometrial cell lines.
The objective of this study was to generate immortalized endometrial epithelial and stromal cell lines from the ovine uterus. Luminal (LE) and glandular epithelial (GE) cells and stromal (ST) cells were enzymatically isolated from the uterus of a Day 5 cyclic ewe (estrus on Day 0), and primary cultures were immortalized by transduction with a retroviral vector (LXSN-16E6E7) packaged by the amphotropic fibroblast line PA-317. Cells having integrated the vector were selected by resistance to the neomycin analogue G418 (0.6-0.8 mg/ml). Surviving cells were maintained in complete culture medium containing G418 (0.1 mg/ml) and subcultured for more than 40 passages. Phase-contrast microscopy revealed that LE and GE cells exhibited a cobblestone morphology whereas immortalized ST cells were spindle shaped. The epithelial origin of LE and GE was confirmed by positive cytokeratin immunostaining, and ST cells were vimentin positive. All cell lines were negative for smooth muscle alpha-actin staining. Western blot analyses of cell extracts revealed the presence of signal transducers and activators of transcription (STAT) proteins 1, 2, and 3. In the LE cells, interferon tau (IFNtau) induced nuclear translocation of STAT proteins 1 and 2 and up-regulated several IFN-inducible genes, including STATs 1, 2, and 3 and ubiquitin cross-reactive protein (UCRP/ISG17). In the LE cell line, IFN regulatory factor one was transiently up-regulated and then down-regulated by IFNtau. Immunostaining revealed the presence of nuclear estrogen receptor and progesterone receptor in all cell lines. These ovine endometrial cell lines provide useful in vitro model systems for the study of hormone and cytokine action, signal transduction pathways, cell-cell interactions, and gene expression in specific cell types of the ovine endometrium.


T cell response kinetics determines neuroinfection outcomes during murine HSV infection.
Herpes simplex virus-2 (HSV-2) and HSV-1 both can cause genital herpes, a chronic infection that establishes a latent reservoir in the nervous system. Clinically, the recurrence frequency of HSV-1 genital herpes is considerably less than HSV-2 genital herpes, which correlates with reduced neuronal infection. The factors dictating the disparate outcomes of HSV-1 and HSV-2 genital herpes are unclear. In this study, we show that vaginal infection of mice with HSV-1 leads to the rapid appearance of mature DCs in the draining lymph node, which is dependent on an early burst of NK cell-mediated IFN-γ production in the vagina that occurs after HSV-1 infection but not HSV-2 infection. Rapid DC maturation after HSV-1 infection, but not HSV-2 infection, correlates with the accelerated generation of a neuroprotective T cell response and early accumulation of IFN-γ-producing T cells at the site of infection. Depletion of T cells or loss of IFN-γ receptor (IFN-γR) expression in sensory neurons both lead to a marked loss of neuroprotection only during HSV-1, recapitulating a prominent feature of HSV-2 infection. Our experiments reveal key differences in host control of neuronal HSV-1 and HSV-2 infection after genital exposure of mice, and they define parameters of a successful immune response against genital herpes.


Oxytocin facilitates accurate perception of competition in men and kinship in women.
Despite the dominant role of the hormone oxytocin (OT) in social behavior, little is known about the role of OT in the perception of social relationships. Furthermore, it is unclear whether there are sex differences in the way that OT affects social perception. Here, we employed a double-blind, placebo-controlled crossover design to investigate the effect of OT on accurate social perception. Following treatment, 62 participants completed the Interpersonal Perception Task, a method of assessing the accuracy of social judgments that requires identification of the relationship between people interacting in real life video clips divided into three categories: kinship, intimacy and competition. The findings suggest that OT had a general effect on improving accurate perception of social interactions. Furthermore, we show that OT also involves sex-specific characteristics. An interaction between treatment, task category and sex indicated that OT had a selective effect on improving kinship recognition in women, but not in men, whereas men's performance was improved following OT only for competition recognition. It is concluded that the gender-specific findings reported here may point to some biosocial differences in the effect of OT which may be expressed in women's tendency for communal and familial social behavior as opposed to men's tendency for competitive social behavior.


The role of diarrhoeagenic Escherichia coli in acute diarrhoeal diseases in Bandar-Abbas, Iran.
The prevalance of different types of diarrhoea-producing Escherichia coli was measured in 273 patients attending 12 out-patient clinics in Bandar-Abbas, State of Hormozgan, Iran, during March 1984. Enteropathogenic E. coli (EPEC) belonging to 12 different serogroups, of which O128 and O126 were the most common, were found in almost 31% of the patients. Enterotoxigenic strains of E. coli (ETEC) were the next most frequent group (21.9%); among these, 36 (60%) strains produced heat-stable enterotoxin (ST), 14 (23.3%) strains produced both heat-labile enterotoxin (LT) and ST, and 10 (16.7%) strains produced LT only. The same pattern of toxigenicity was observed among the EPEC isolates. Ten of the 12 serogroups encountered in this study contained toxin producers, amongst which strains producing ST were dominant. Enteroinvasive E. coli (EIEC) strains were not isolated. These findings suggest that enterotoxin-producing E. coli may be an important cause of diarrhoea in this part of Iran.


Procainamide, N-acetylprocainamide, antinuclear antibody and systemic lupus erythematosus.
Long-term therapy with procainamide (PA) leads to the systemic lupus erythematosus syndrome (SLE) in about 30% of patients and 80% develop antinuclear antibodies. Acetylation of procainamide results in the formation of N-acetylprocainamide (NAPA) the propensity of which to induce SLE and to increase antinuclear antibodies is negligible while its antiarrhythmic properties remain. Slow acetylators of PA have a greater tendency to induce SLE consistent with the observation that it is the level of PA that is responsible for the observed immunologically-mediated side effects of the compound. This is also suggested by the remission of PA-induced SLE when PA is replaced with NAPA for the control of cardiac arrhythmias. Thus, NAPA, compared to the parent compound, has little tendency to induce SLE.


The Importance of Multidisciplinary Trauma-Informed Training in Addressing Campus-Based Sexual Violence.
This study investigates the impact of a professional development training series among a multidisciplinary team (MDT) during establishment of a trauma-informed sexual assault response and prevention program at a midsized university in the southeastern United States. MDT members included forensic nurses, advocates, counselors, law enforcement officers, and relevant faculty and staff. After completion of a baseline survey assessing attitudes toward trauma-informed care and perceptions of the team climate within the MDT, team members engaged in a trauma-informed care (TIC) professional development training series consisting of (a) 4-hour-long didactic lectures with incorporated group discussion and (2) one 2-hour in-situ simulation-based training exercise. MDT members subsequently completed 3-month and long-term follow-up surveys to assess the immediate and enduring impacts of the training series.The TIC training series significantly increased MDT members' perceptions of participative safety, task orientation, and support for innovation within the group at the 3-month assessment. No long-term differences were found, likely because of a small sample size and low statistical power.Intensive TIC MDT professional development at the beginning of a campus-wide sexual assault prevention and response initiative enhances psychological safety within the group, evidenced by increased perceptions of participative safety and support for innovation, and builds team cohesiveness around a shared set of tasks. Within the present MDT, the professional development training series also appeared to facilitate adoption of a shared set of values for accomplishing the team's goal of preventing and responding to sexual assault on campus. Recommendations for MDTs with similar goals are discussed.


Vestibular Function Change in a Vasopressin-Induced Hydrops Model.
A vasopressin-induced endoymphatic hydrops model can represent an acute vertiginous attack in Menière's disease (MD). Previous animal models are not appropriate to evaluate the efficacy of new treatments for hydrops because they cannot represent an acute attack of MD. Recently, a new dynamic model was introduced for acute hydrops exacerbation using the vasopressin type 2 receptor agonist, desmopressin (1-deamino-8-D-Arginine vasopressin, VP); however, resulting changes in vestibular function have not been investigated. A total of 37 guinea pigs were used. Two to 4 weeks after surgical ablation of endolymphatic sacs in 33 guinea pigs, acute exacerbation of hydrops was induced by a single VP injection in 18 animals (group A). Next, two VP injections at 1 hour interval were administered to investigate the effect of multiple VP doses on vestibular function in the other 15 animals (group B). In the remaining four animals, VP was injected without surgery for the control group (control). Bidirectional sinusoidal harmonic acceleration (SHA) tests of vestibular function were performed. "Type I response" was defined as when the maximum slow-phase velocity (SPV) during left rotation (toward the operated ear) was lower than that during right rotation (toward the normal ear). In contrast, "Type II response" was defined as when maximum SPV at the left rotation was higher than that at the right rotation. Vestibular symmetry scores were analyzed at baseline and after each of two VP injections given 1 hour apart. Vestibular symmetry scores increased at 1 hour after VP injection in all 18 animals in group A (p < 0.001). Two hours after VP injection, symmetry score decreased to the initial score. Two different types of vestibular response were observed after VP. However, the symmetry scores between type I and II responses were not significantly different (p = 0.173). In all 15 animals of Group B, vestibular asymmetry was sustained over 3 hours when two VP injections were given 1 hour apart. In three of Group B, the type of vestibular response changed from type II response to type I response after the 2nd VP injection; however, no animal demonstrated a shift from type I to type II response. VP can transiently induce an acute exacerbation of hydrops and asymmetric vestibular dysfunction in guinea pigs. This model could help in studying new treatments for acute hydrops and in explaining the mechanism of bidirectional nystagmus in MD.


2-amino-4-phosphonobutyric acid: a new pharmacological tool for retina research.
Information processing in the vertebrate retina occurs in two separate channels known as ON and OFF channels. When intracellular electrophysiological recordings were obtained from the perfused retina-eyecup preparation of the mud-puppy (Necturus maculosus), the addition of 2-amino-4-phosphonobutyric acid to the bathing medium blocked all responses in the ON channel but left intact the OFF responses including OFF ganglion cell discharge. 2-Amino-4-phosphonobutyric acid blocks the light response of the ON bipolar cell by mimicking the endogenous photoreceptor transmitter.


Central circulation during exercise after venesection and reinfusion of red blood cells.
To study central circulation at different levels of hemoglobin (Hb) concentration, five subjects performed submaximal and maximal exercise in three different situations: 1) control, 2) after venesection of 800 ml of whole blood, and 3) after reinfusion of the red blood cells about 30-35 days after venesection. Maximal oxygen uptake (VO2 max) decreased from 4.27 l-min-1) at control to 4.03 l-min-1 after venesection (P less than 0.05) and increased to 4.61 l-min-1 after reinfusion (P less than 0.05). Maximal values on cardiac output (Q), heart rate (HR), and stroke volume (SV) were the same in the three situations. Thus, there was no compensatory increase in Qmax due to the lowered arterial oxygen content (Cao2) after venesection. An increase of the Cao2 (Hb concentration) and a lowering of the Cvo2 contributed equally to the increased VO2 max after reinfusion. At a given submaximal VO2, HR and blood lactates were increased at lowered Hb concentration and decreased at increased Hb concentration over control levels. Correlation coefficient for the change in Q in relation to the acute change in Hb concentration at a given submaximal VO2 was -0.49 (P less than 0.05).


Committed change of real-time quantitative PCR to droplet digital PCR for monitoring BCR::ABL1 transcripts in tyrosine kinase inhibitor treated CML.
We performed a feasibility study of an FDA-approved commercial ddPCR assay to measure BCR::ABL1 in CML patients treated using TKI therapy. Assay performance of standard RQ-PCR and commercially available FDA-approved ddPCR were compared to measure BCR::ABL1 p210 transcripts in RNA samples from 100 CML patients who received TKI therapy. %BCR::ABL1/ABL1IS levels obtained from both methods were not statistically significant difference after normalization with batch-specific conversion factor (p = 0.0651). The correlation and agreement of %BCR::ABL1/ABL1IS between the two assays were high. Molecular response stratification data showed 56% concordance between RQ-PCR and ddPCR, and 37% higher residual disease detection using ddPCR. Furthermore, 21.21% (7/33) of RQ-PCR undetectable samples were detected by ddPCR, representing high sensitivity to quantify the low abundance of BCR::ABL1 transcripts. ddPCR was proven to be a highly sensitive method with the potential to overcome some limitations of traditional RQ-PCR, and has the potential of being a valuable tool for monitoring BCR::ABL1 transcripts in CML during TKI therapy. (163 words).


Measurement of Circulating Filarial Antigen Levels in Human Blood with a Point-of-Care Test Strip and a Portable Spectrodensitometer.
The Alere Filariasis Test Strip (FTS) is a qualitative, point-of-care diagnostic tool that detects Wuchereria bancrofti circulating filarial antigen (CFA) in human blood, serum, or plasma. The Global Program to Eliminate Lymphatic Filariasis employs the FTS for mapping filariasis-endemic areas and assessing the success of elimination efforts. The objective of this study was to explore the relationship between the intensity of positive test lines obtained by FTS with CFA levels as determined by enzyme-linked immunosorbent assay (ELISA) with blood and plasma samples from 188 individuals who live in a filariasis-endemic area. The intensity of the FTS test line was assessed visually to provide a semiquantitative score (visual Filariasis Test Strip [vFTS]), and line intensity was measured with a portable spectrodensitometer (quantitative Filariasis Test Strip [qFTS]). These results were compared with antigen levels measured by ELISA in plasma from the same subjects. qFTS measurements were highly correlated with vFTS scores (ρ = 0.94; P < 0.001) and with plasma CFA levels (ρ = 0.91; P < 0.001). Thus, qFTS assessment is a convenient method for quantifying W. bancrofti CFA levels in human blood, which are correlated with adult worm burdens. This tool may be useful for assessing the impact of treatment on adult filarial worms in individuals and communities.


Neuropathological Comparison of Adult Onset and Juvenile Huntington's Disease with Cerebellar Atrophy: A Report of a Father and Son.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a trinucleotide (CAG) repeat expansion in huntingtin (HTT) on chromosome 4. Anticipation can cause longer repeat expansions in children of HD patients. Juvenile Huntington's disease (JHD), defined as HD arising before age 20, accounts for 5-10% of HD cases, with cases arising in the first decade accounting for approximately 1%. Clinically, JHD differs from the predominately choreiform adult onset Huntington's disease (AOHD) with variable presentations, including symptoms such as myoclonus, seizures, Parkinsonism, and cognitive decline. The neuropathologic changes of AOHD are well characterized, but there are fewer reports that describe the neuropathology of JHD. Here we report a case of a six-year-old boy with paternally-inherited JHD caused by 169 CAG trinucleotide repeats who presented at age four with developmental delay, dysarthria, and seizures before dying at age 6. The boy's clinical presentation and neuropathological findings are directly compared to those of his father, who presented with AOHD and 54 repeats. A full autopsy was performed for the JHD case and a brain-only autopsy was performed for the AOHD case. Histochemically- and immunohistochemically-stained slides were prepared from formalin-fixed, paraffin-embedded tissue sections. Both cases had neuropathology corresponding to Vonsattel grade 3. The boy also had cerebellar atrophy with huntingtin-positive inclusions in the cerebellum, findings not present in the father. Autopsies of father and son provide a unique opportunity to compare and contrast the neuropathologic findings of juvenile and adult onset HD while also providing the first immunohistochemical evidence of cerebellar involvement in JHD. Additionally this is the first known report to include findings from peripheral tissue in a case of JHD.


TNM classification of malignant tumors (Breast Cancer Study Group).
The eighth editions of the primary tumor, lymph node and metastasis classifications for breast cancer issued by the American Joint Commission of Cancer and the Union for International Cancer Control were revised in 2017. The major change made by the American Joint Commission of Cancer is to incorporate biological factors such as estrogen and progesterone receptor, human epidermal growth factor receptor 2, histological grade and multigene prognostic assays, into the staging system. Tumor biomarkers and low recurrence scores confirmed by multigene prognostic assays change the staging. Minor changes are to add the post-neoadjuvant therapy clinical and pathological classification and to define the size of tumor, lymph node and metastasis components more precisely. Little has changed in the Union for International Cancer Control. We have identified key points of change in both eighth editions of the tumor, lymph node and metastasis classifications and we discuss possible problems which may arise when they are adopted in Japanese practice, as well as future directions.


Kynurenine pathway metabolites in humans: disease and healthy States.
Tryptophan is an essential amino acid that can be metabolised through different pathways, a major route being the kynurenine pathway. The first enzyme of the pathway, indoleamine-2,3-dioxygenase, is strongly stimulated by inflammatory molecules, particularly interferon gamma. Thus, the kynurenine pathway is often systematically up-regulated when the immune response is activated. The biological significance is that 1) the depletion of tryptophan and generation of kynurenines play a key modulatory role in the immune response; and 2) some of the kynurenines, such as quinolinic acid, 3-hydroxykynurenine and kynurenic acid, are neuroactive. The kynurenine pathway has been demonstrated to be involved in many diseases and disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, AIDS dementia complex, malaria, cancer, depression and schizophrenia, where imbalances in tryptophan and kynurenines have been found. This review compiles most of these studies and provides an overview of how the kynurenine pathway might be contributing to disease development, and the concentrations of tryptophan and kynurenines in the serum, cerebrospinal fluid and brain tissues in control and patient subjects.


Effect of Hospital Volume on In-hospital Morbidity and Mortality Following Pancreatic Surgery in Germany.
We aimed to determine the effect of hospital volume on in-hospital mortality, and failure to rescue following major pancreatic resections using hospital discharge data of every inpatient case in Germany. Several studies have found strong volume-outcome relationships in pancreatic surgery, with high mortality in low-volume facilities. However, their datasets were only based on portions of national populations. In addition, these studies did not assess the effect of hospital volume according to other crucial variables such as medical indications, postoperative complications, and failure to rescue. We studied all inpatient cases of major pancreatic surgery (n = 60,858) in Germany from 2009 to 2014, using national hospital discharge data. We evaluated the association between hospital volume and in-hospital mortality following major pancreatic resections by using multivariate regression methods. In addition, we analyzed rates of major complications and failure to rescue across hospital volume quintiles. Risk-adjusted in-hospital mortality varied widely across hospital volume quintiles, from 6.5% (95% CI 6.0-7.0) in very high volume hospitals to 11.5% (95% CI 10.9-12.1) in very low volume hospitals (OR 0.47, 95% CI 0.41-0.54). Rates of postoperative interventions necessary for complications and failure to rescue were lower in higher volume hospitals [eg, mortality following septic complications in very high volume hospitals: 24.2% (95% CI 22.4-26.1) vs. very low volume hospitals: 36.8% (34.9-38.7)]. Moreover, we estimated that centralization of surgical care to the minimum volume and mortality risk of the medium volume quintile could prevent at least 94 deaths per year. In Germany, patients who are undergoing major pancreatic resections have improved outcomes if they are admitted to higher volume hospitals. As current health policies failed to centralize pancreatic surgery procedures in Germany, new strategies to initiate a sufficient centralization process in the field of pancreatic surgery are needed.


The use and disposal of household pesticides.
Most pesticides are synthetic chemicals manufactured specifically for their toxic properties to the target species, and widely used globally. Several epidemiological studies in the United States have suggested health concerns arising from the chronic exposure of young children to pesticides in the domestic environment. In the UK very little is currently known about how nonoccupational pesticides are being used or disposed of. Any use of pesticides is a potential risk factor for children's exposure, and any potential exposure is likely to be reduced by the parents' adopting precautionary behaviour when using these pesticide products. This was investigated using a sample of 147 parents from the Avon Longitudinal Study of Parents and Children cohort in and around Bristol, through an in-depth interview between August and November 2001. The results of this study add to the understanding of the underlying behaviour of parents applying pesticide products in the home environment in the UK. Pesticides are readily available, and are normally purchased in do-it-yourself shops and supermarkets and mostly disposed of in domestic waste. Safety was stated by 45% of parents to be the most important factor to consider when buying a pesticide. When buying pesticide products, labels were stated to be the most important source of information about pesticides. However, a third of parents stated they would not follow the product label exactly when using a product, just under half felt labels were both inadequate and hard to understand, and about 10% of parents would not take notice of warnings on the pesticide label. Less than half of parents would use gloves when applying a pesticide, although the use of protective equipment such as gloves during the application of pesticides could greatly reduce the exposure. It is a public health concern that the instructions on the labels of products may not always be understood or followed, and further understanding of user behaviour is needed.


Effects of weight, temperature and behaviour on the circadian rhythm of salivary cortisol in growing pigs.
In farm animals, salivary cortisol has become a widely used parameter for measuring stress responses. However, only few studies have dealt with basal levels of concentration of cortisol in pigs and its circadian rhythm. The aim of this study was to examine the effects of ambient temperature and thermoregulatory behaviour on the circadian rhythm of salivary cortisol levels in fattening pigs. Subjects were 30 fattening pigs of different weight (60 to 100 kg), kept in six groups in an uninsulated building in pens with partly slatted floors. Saliva samples were taken every 2 h over periods of 24 h at different ambient temperatures at two times in winter and four times in summer. Thermoregulatory behaviour was recorded in the same 24-h time periods. The effect of time of day, body weight, ambient temperature and behaviour on the cortisol level was analysed using a mixed-effects model. Two peaks of cortisol levels per day were found. This circadian pattern became more pronounced with increasing weight and on days where thermoregulatory behaviour was shown. Mean cortisol levels per day were affected by weight but not by thermoregulatory behaviour. From our data, we conclude that long-term variations in cortisol concentration may be influenced by increasing age and weight more than by the respective experimental situation. In assessing animal welfare, it seems more reliable to consider the circadian pattern of cortisol concentration instead of only one value per day.


[Estimation of the glomerular filtration rate in 2014 by tests and equations: strengths and weaknesses].
The accurate estimation of the glomerular filtration rate (GFR) is a goal of multiple interests regarding clinical, research and public health aspects. The strong relationship between progressive loss of renal function and mortality underlines the need for early diagnosis and close follow-up of renal diseases. Creatinine is the commonest biomarker of GFR in use. By reason of non-renal determinants of GFR, it is required to integrate creatinine values within equations that take in account its most important determinants (i.e., age, sex). The CKD-EPI 2009 equation is now recommended as the first line equation to estimate GFR within the general population. In this indication, it should replace MDRD that tends to overestimate the prevalence of stage 3 chronic kidney disease with GFR around 60 ml/min. However, many questions remain about the accuracy of GFR equations in specific situations such as extremes of age or body weight. The identification of new biomarkers, less determined by non-renal determinants, is of importance. Among these biomarkers, cystatin-C is more accurate to estimate GFR when it is combined to creatinine (i.e., equation CKD-EPI 2012). However the indica. tions for using cystatin-C instead of creatinine alone are still unclear and its use remains limited in routine practice. In conclusion, neither biomarker nor equation gives an accurate estimation for the whole range of GFR and for all patient populations. Limits of prediction are relying on both biomarker's properties and the range of GFR that is concerned, but also rely on the measurement methods. Therefore, it is crucial to interpret the estimated GFR according to the strengths and weaknesses of the equation in use.


Generation of self-clusters of galectin-1 in the farnesyl-bound form.
Ras protein is involved in a signal transduction cascade in cell growth, and cluster formation of H-Ras and human galectin-1 (Gal-1) complex is considered to be crucial to achieve its physiological roles. It is considered that the complex is formed through interactions between Gal-1 and the farnesyl group (farnesyl-dependent model), post-translationally modified to the C-terminal Cys, of H-Ras. We investigated the role of farnesyl-bound Gal-1 in the cluster formation by analyzing the structure and properties of Gal-1 bound to farnesyl thiosalicylic acid (FTS), a competitive inhibitor of the binding of H-Ras to Gal-1. Gal-1 exhibited self-cluster formation upon interaction with FTS, and small- and large-size clusters were formed depending on FTS concentration. The galactoside-binding pocket of Gal-1 in the FTS-bound form was found to play an important role in small-size cluster formation. Large-size clusters were likely formed by the interaction among the hydrophobic sites of Gal-1 in the FTS-bound form. The present results indicate that Gal-1 in the FTS-bound form has the ability to form self-clusters as well as intrinsic lectin activity. Relevance of the self-clustering of FTS-bound Gal-1 to the cluster formation of the H-Ras-Gal-1complex was discussed by taking account of the farnesyl-dependent model and another (Raf-dependent) model.


Stress responses to repeated captures in a wild ungulate.
While capture-mark-recapture studies provide essential individual-level data in ecology, repeated captures and handling may impact animal welfare and cause scientific bias. Evaluating the consequences of invasive methodologies should be an integral part of any study involving capture of live animals. We investigated short- and long-term stress responses to repeated captures within a winter on the physiology, behaviour, and reproductive success of female Svalbard reindeer (Rangifer tarandus platyrhynchus). Short-term responses were evaluated using serum concentrations of glucocorticoids and catecholamines during handling, and post-release recovery times in heart rate and activity levels. Repeated captures were associated with an increase in measured catecholamines and glucocorticoids, except cortisone, and delayed recovery in heart rate but not activity. Four months later, in summer, individuals captured repeatedly in winter exhibited a small increase in behavioural response to human disturbance and had a lower probability of being observed with a calf, compared to animals not captured, or captured only once. Our findings imply that single annual capture events have no significant negative consequences for Svalbard reindeer, but repeated captures within a season may impact offspring survival in the same year. Such unanticipated side effects highlight the importance of addressing multiple indicators of animal responses to repeated captures.


Denoising and decoding spontaneous vagus nerve recordings with machine learning.
Neural interfaces that electrically stimulate the peripheral nervous system have been shown to successfully improve symptom management for several conditions, such as epilepsy and depression. A crucial part for closing the loop and improving the efficacy of implantable neuromodulation devices is the efficient extraction of meaningful information from nerve recordings, which can have a low Signal-to-Noise ratio (SNR) and non-stationary noise. In recent years, machine learning (ML) models have shown outstanding performance in regression and classification problems, but it is often unclear how to translate and assess these for novel tasks in biomedical engineering. This paper aims to adapt existing ML algorithms to carry out unsupervised denoising of neural recordings instead. This is achieved by applying bandpass filtering and two novel ML algorithms to in-vivo spontaneous, low-SNR vagus nerve recordings. The performance of each approach is compared using the task of extracting respiratory afferent activity and validated using cross-correlation, MSE, and accuracy in terms of extracting the true respiratory rate. A variational autoencoder (VAE) model in particular produces results that show better correlation with respiratory activity compared to bandpass filtering, highlighting that these models have the potential to preserve relevant features in complex neural recordings.


Microtubule targeting agents: from biophysics to proteomics.
This review explores various aspects of the interaction between microtubule targeting agents and tubulin, including binding site, affinity, and drug resistance. Starting with the basics of tubulin polymerization and microtubule targeting agent binding, we then highlight how the three-dimensional structures of drug-tubulin complexes obtained on stabilized tubulin are seeded by precise biological and biophysical data. New avenues opened by thermodynamics analysis, high throughput screening, and proteomics for the molecular pharmacology of these drugs are presented. The amount of data generated by biophysical, proteomic and cellular techniques shed more light onto the microtubule-tubulin equilibrium and tubulin-drug interaction. Combining these approaches provides new insight into the mechanism of action of known microtubule interacting agents and rapid in-depth characterization of next generation molecules targeting the interaction between microtubules and associated modulators of their dynamics. This will facilitate the design of improved and/or alternative chemotherapies targeting the microtubule cytoskeleton.


Cell-cell channel formation and lectins.
The oocyte cell-cell channel assay was used to investigate determinants of the rate of channel formation. After injection of connexin-specific mRNA, oocytes accumulate a pool of precursors from which cell-cell channels can form after oocytes are paired. Channel formation was found to be increased if oocytes are pretreated with lectins before pairing. Several lectins differing in their carbohydrate binding affinities can exert this effect. Lectin-specific sugars suppress the effect on cell-cell channel formation only if the sugar is mixed with the lectin before application to the oocyte. If the lectin is first bound to the oocyte and then the sugar is added, no significant inhibition is seen. The promotion of channel formation by lectins is enhanced by adding an incubation period in regular medium after lectin treatment, before pairing of the oocytes. Electron microscopic studies with gold-conjugated lectins show that the lectin receptors are clustered on the free membrane surface and are taken up in endocytotic vesicles. These data suggest that the observed acceleration of cell-cell channel formation by lectins can be attributed to the removal of steric hindrance, which is a consequence of clustering of the bulky glycoprotein lectin receptors as well as of the removal from the surface by endocytosis.


Identification of novel COX-2 / CYP19A1 axis involved in the mesothelioma pathogenesis opens new therapeutic opportunities.
Based on previous studies highlighting that the induction of cyclooxygenase-2 (COX-2) and high prostaglandin E2 (PGE2) levels contribute to the pathogenesis of malignant pleural mesothelioma (MPM), and that aromatase (CYP19A1), an enzyme that plays a key role in estrogen biosynthesis, along with estradiol (E2) were expressed in MPM, this study aimed to investigate the possible interplay between COX-2 and CYP19A1 in the pathogenesis of mesothelioma, as well as the underlying mechanism. The interaction between COX-2 and CYP19A1 was first investigated on different MPM lines upon PGE2, and COX-2 inhibitor (rofecoxib) treatment by western blot, RT-PCR. The key regulatory pathways involved in the COX-2 and CYP19A1 axis were further studied in MPM cells, after rofecoxib and exemestane (CYP19A1 inhibitor) treatment in monotherapy and in combination, by cell cycle distribution, western blot, and combination index analysis. To explore the role of COX-2/CYP19A1 axis in 3D preclinical models of MPM cells, we analyzed the effect of combination of COX-2 and CYP19A1 inhibitors in mesosphere formation. Immunohistochemical analysis of MPM mesosphere and specimens was utilized to evaluate the involvement of COX-2 on the CYP19A1 activity and the relationship between E2 and COX-2. PGE2 or rofecoxib treatment caused in MPM cells an increased or decreased, respectively, CYP19A1 expression at mRNA and protein levels. The effect of rofecoxib and exemestane combination in MPM cell proliferation was synergistic. Activation of caspase-3 and cleavage of PARP confirmed an apoptotic death for MPM cell lines. Increased expression levels of p53, p21, and p27, downregulation of cyclin D1 and inhibition of Akt activation (pAKT) were also found. The antagonistic effect of rofecoxib and exemestane combination found only in one cell line, was reverted by pretreatment with MK2206, a pAKT inhibitor, indicating pAKT as an actionable mediator in the COX-2-CYP19A1 axis. Reduction of size and sphere-forming efficiency in MPM spheres after treatment with both inhibitor and a decrease in COX-2 and E2 staining was found. Moreover, immunohistochemical analysis of 46 MPM samples showed a significant positive correlation between COX-2 and E2. Collectively, the results highlighted a novel COX-2/CYP19A1 axis in the pathogenesis of MPM that can be pharmacologically targeted, consequently opening up new therapeutic options.


Clinical features of hypertriglyceridemia-induced acute pancreatitis in an international, multicenter, prospective cohort (APPRENTICE consortium).
The clinical features and outcomes of hypertriglyceridemia-induced acute pancreatitis (HTG-AP) are not well-established. To evaluate the clinical characteristics of HTG-AP in an international, multicenter prospective cohort. Data collection was conducted prospectively through APPRENTICE between 2015 and 2018. HTG-AP was defined as serum TG levels >500 mg/dl in the absence of other common etiologies of AP. Three multivariate logistic regression models were performed to assess whether HTG-AP is associated with SIRS positive status, ICU admission and/or moderately-severe/severe AP. 1,478 patients were included in the study; 69 subjects (4.7%) were diagnosed with HTG-AP. HTG-AP patients were more likely to be younger (mean 40 vs 50 years; p < 0.001), male (67% vs 52%; p = 0.018), and with a higher BMI (mean 30.4 vs 27.5 kg/m2; p = 0.0002). HTG-AP subjects reported more frequent active alcohol use (71% vs 49%; p < 0.001), and diabetes mellitus (59% vs 15%; p < 0.001). None of the above risk factors/variables was found to be independently associated with SIRS positive status, ICU admission, or severity in the multivariate logistic regression models. These results were similar when including only the 785 subjects with TG levels measured within 48 h from admission. HTG-AP was found to be the 4th most common etiology of AP. HTG-AP patients had distinct baseline characteristics, but their clinical outcomes were similar compared to other etiologies of AP.


Temporal phenotypic heterogeneity as a substrate for selection.
The interaction of temporal phenotypic heterogeneity with a population level fitness function was explored through the use of a simple model. The model, based upon experimental data, assumes that the exploitation of pollinators, and seed-set within plant populations are dependent upon the frequency of a pink flower morph in populations composed of pink and white morphs. An increase in pink frequency is accompanied by an increase in seed-set for both morphs. The model also assumes that seed-set within a population is the same for pink and white individuals. In perennials and annuals with long-lived seeds, fluctuations in morph balance from one season to another may lead to reproductive pulses or drags, depending upon which morph was in excess. The reproductive differential which stems from different levels of pollinator service leads to an increase in pink frequency and an attendant fitness gain. The perennial habit and long-lived seeds provide a population with a memory which permits the current population image to compete with images of previous years. As a consequence, fitness gains may be achieved in the absence of interplant or interpopulation selection.


Identification and characterization of Aplysia adducin, an Aplysia cytoskeletal protein homologous to mammalian adducins: increased phosphorylation at a protein kinase C consensus site during long-term synaptic facilitation.
Structural changes at synapses are associated with long-term facilitation (LTF) of synaptic transmission between sensory and motor neurons in Aplysia. We have cloned a cDNA encoding Aplysia adducin (ApADD), the Aplysia homolog of mammalian adducins that are regulatory components of the membrane cytoskeleton. ApADD is recovered in the particulate fraction of nervous system extracts and is localized predominantly in the submembraneous region of Aplysia neurons. ApADD is phosphorylated in vitro by protein kinase C (PKC) at a site homologous to the in vivo PKC phosphorylation site in mammalian adducins. Phosphorylation of ApADD at this site is also detected in vivo in the intact Aplysia nervous system and is increased 18 hr after serotonin-induced LTF. In contrast, there is no change in phosphorylation during short-term facilitation or 1 hr after initial LTF induction. Thus, ApADD is modulated specifically with later phases of LTF and provides an attractive candidate protein that contributes to structural changes accompanying long-lasting synaptic alteration.


Healthcare resource utilisation for chronic kidney disease and other major non-communicable chronic diseases in China: a cross-sectional study.
To evaluate the healthcare resource utilisation for chronic kidney disease (CKD) and other major non-communicable chronic diseases (NCDs) in China. A cross-sectional study. A national inpatient database of tertiary hospitals in China. The study included a total of 19.5 million hospitalisations of adult patients from July 2013 to June 2014. Information on CKD and other major NCDs, including coronary heart disease (CHD), stroke, hypertension, diabetes, chronic obstructive pulmonary disease (COPD) and cancer, was extracted from the unified discharge summary form. Cost, length of hospital stay and in-hospital mortality. The percentages of hospitalisations with CKD, CHD, stroke, hypertension, diabetes, COPD and cancer were 4.5%, 9.2%, 8.2%, 18.8%, 7.9%, 2.3% and 19.4%, respectively. For each major NCD, the presence of CKD was independently associated with longer hospital stay, with increased percentages ranging from 7.69% (95% CI 7.11% to 8.28%) for stroke to 21.60% (95% CI 21.09% to 22.10%) for CHD. Hospital mortality for other NCDs was also higher in the presence of CKD, with fully adjusted relative risk ranging from 1.91 (95% CI 1.82 to 1.99) for stroke to 2.65 (95% CI 2.55 to 2.75) for cancer. Compared with other NCDs, CKD was associated with the longest hospital stay (22.1% increase) and resulted in the second highest in-hospital mortality, only lower than that of cancer (relative risk, 2.23 vs 2.87, respectively). The presence of diagnosed CKD alongside each major NCD was associated with an additional burden on the healthcare system. Healthcare resource utilisation and prognosis of CKD were comparable with those of other major NCDs, which highlights the importance of CKD as a major public health burden.


Using qualitative synthesis to explore heterogeneity of complex interventions.
Including qualitative evidence on patients' perspectives in systematic reviews of complex interventions may reveal reasons for variation in trial findings. This is particularly the case when the intervention is for a long-term disease, as management may rely heavily on the efforts of the patient. Inclusion though seldom happens, possibly because of methodological challenges, and when it does occur the different forms of evidence are often kept separate. To explore heterogeneity in trial findings, we tested a novel approach to integrate qualitative review evidence on patients' perspectives with evidence from a Cochrane systematic review. We used, as a framework for a matrix, evidence from a qualitative review on patients' perspectives on helping them manage their disease. We then logged in the matrix whether the interventions identified in a Cochrane review corresponded with the patient perspectives on how to help them. We then explored correspondence.The Cochrane review we used included 19 trials of interventions to improve adherence to therapy in HIV/AIDS patients. The qualitative review we used included 23 studies on HIV/AIDS patients' perspectives on adherence; it translated the themes identified across the studies into recommendations in how to help patients adhere.Both reviews assessed quality. In the qualitative review they found no difference in findings between the better quality studies and the weaker ones. In the Cochrane review they were unable to explore the impact of quality in subgroup analysis because so few studies were of good quality. Matrix tabulation of interventions and patients' perspectives identified a range of priorities raised by people infected with HIV-1 that were not addressed in evaluated interventions. Tabulation of the more robust trials revealed that interventions that significantly improved adherence contained more components considered important by patients than interventions where no statistically significant effect was found. This simple approach breaks new ground in cross tabulating qualitative evidence with the characteristics of trialled interventions. In doing so it tests the assumption that patients are more likely to adhere to interventions that match more closely with their concerns. The potential of this approach in exploring varying content and rates of success in trialled complex interventions deserves further evaluation.


An ultrasensitive electrochemical immunosensor based on the synergistic effect of quaternary Cu2SnZnS4 NCs and cyclodextrin-functionalized graphene.
In this study, highly monodispersed Cu2SnZnS4 NCs with a quasi-spherical structure were prepared to construct a sandwich-type electrochemical immunosensor for alpha-fetoprotein detection. Quaternary Cu2SnZnS4 NCs as novel biomimetic catalysts show an efficient intrinsic peroxidase-like activity for H2O2 reduction. This excellent catalytic activity is ascribed to the higher electroconductivity than those of the binary Cu2S and ternary Cu2SnS3 NCs. Moreover, β-cyclodextrin-functionalized graphene sheets are used as substrate materials that can capture large amounts of primary antibodies due to host-guest interaction and high surface area. Under the optimized conditions, the electrochemical immunosensor exhibites a wide working range from 0.5 pg mL-1 to 10 ng mL-1 and a detection limit of 0.16 pg mL-1 at a signal-to-noise ratio of 3. Good sensitivity, reproducibility, and stability demonstrate its potential application in clinical diagnostics.


Effectiveness of group aerobic and/or resistance exercise programs associated with pelvic floor muscle training during prenatal care for the prevention and treatment of urinary incontinence: A systematic review.
To evaluate the effectiveness of aerobic and/or resistance group exercise programs associated with pelvic floor muscle training (PFMT) during prenatal care for the prevention and treatment of urinary incontinence (UI) using the best level of evidence. A search was carried out in the MEDLINE/PubMed, LILACS, PEDro, CENTRAL, and SCOPUS databases, without restrictions. The terms "urinary incontinence" and "pregnant woman" were used. Randomized and quasi-randomized clinical trials were included using aerobic and/or resistance exercise programs plus PFMT as an intervention compared to usual care. The Cochrane tool (RoB 2.0) and GRADE were used to assess risk of bias and certainty of evidence, respectively. Quantitative analysis was assessed by meta-analyses. Five publications were included. There was a reduction in the reports of UI postintervention at 16 weeks (RR: 0.83; 95% CI: 0.74-0.93, one study, 762 women, random effects: p = 0.002) and after 3 months (RR: 0.76; 95% CI: 0.60-0.95, one study, 722 women, random effects: p = 0.02), based on moderate certainty of evidence and improvement in UI-specific quality of life (MD: -2.42; 95% CI: -3.32 to -1.52, one study, 151 women, random effects: p < 0.00001), based on low quality of evidence. Other results showed no difference between the postintervention groups, with low and very low evidence. There is moderate evidence that the aerobic and/or resistance exercise program associated with PFMT compared to usual care can reduce postintervention UI, as well as 3 months postintervention, and that it can improve UI-specific quality of life, but with low-evidence certainty.


Potent Influence of Exogenous Melatonin on In Vitro Oocyte Maturation in the Longchin Goby, Chaenogobius annularis.
Effects of changes in photoperiod on the reproductive events in fish are suggested to be mediated mainly via the action of melatonin (MEL). Changing levels of plasma MEL throughout the day and year are suggested to influence the hypothalamus-pituitary-gonadal axis in fish. Therefore, in this study, we aimed to investigate the effects of MEL on oocyte maturation and germinal vesicle breakdown (GVBD) in the marine fish, Chaenogobius annularis, in vitro. Oocytes at three different stages (pre-, mid-, and late-vitellogenesis) were incubated with (a) only MEL (5, 10, 50, 100, 500, and 1,000 pg/mL) and (b) 50 pg/mL of 17α,20β-dihydroxy-4-pregnen-3-one (17α20βP), maturation-inducing hormone (MIH) of this species, and MEL (4-h incubation before addition of MIH). Any single MEL treatment did not significantly induce GVBD. However, treatment with 50 pg/mL MEL or MIH significantly induced GVBD. These results suggest that preincubation with MEL accelerates the effect of MIH on longchin goby oocyte maturation.


Effect of self-efficacy enhancement program on self-care behaviors in chronic obstructive pulmonary disease.
Given the importance of the chronic obstructive pulmonary disease (COPD) and role of different factors in self-care behaviors of COPD patients, this study was conducted to determine the effect of self-efficacy program on self-care behaviors of COPD patients. In this semi-experimental study, 62 COPD patients were recruited in which 31 subjects were in control group and 31 were in experimental group. Subjects were selected based on purposive sampling from Imam Hospital affiliated to the Urmia University of Medical Sciences, Iran, in 2011. Two valid and reliable questionnaires were filled after completing informed consent form. A month later, and after implementing the planned intervention, the questionnaires were completed by the subjects again. The mean standard deviation of age were 64.1 (9.1) years in the control group and 65.2 (8.0) years in the experimental group. There was a statistically significant difference between self-efficacy state before and after intervention. Self-care scores in the experimental group were significantly higher after intervention (t = 25.18, P < 0.0001). Given the high potency of self-efficacy factors on self-care behaviors of the COPD patients, enhancement of self-efficacy in these patients can be very effective in disease control, prevention of complications, reduction of hospitalization costs, and improve their quality of life. Hence, it is suggested that in empowerment programs of these patients, special emphasis will put on the strengthening of their self-efficacy.