Sepsis impairs alveolar epithelial function by downregulating Na-K-ATPase pump.
Widespread vascular endothelial injury is the major mechanism for multiorgan dysfunction in sepsis. Following this process, the permeability of the alveolar capillaries is augmented with subsequent increase in water content and acute respiratory distress syndrome (ARDS). Nevertheless, the role of alveolar epithelium is less known. Therefore, we examined alveolar fluid clearance (AFC) using isolated perfused rat lung model in septic rats without ARDS. Sepsis was induced by ligating and puncturing the cecum with a 21-gauge needle. AFC was examined 24 and 48 h later. The expression of Na-K-ATPase proteins was examined in type II alveolar epithelial cells (ATII) and basolateral membrane (BLM). The rate of AFC in control rats was 0.51 ± 0.02 ml/h (means ± SE) and decreased to 0.3 ± 0.02 and 0.33 ± 0.03 ml/h in 24 and 48 h after sepsis induction, respectively (P < 0.0001). Amiloride, significantly decreased AFC in sepsis; conversely, isoproterenol reversed the inhibitory effect of sepsis. The alveolar-capillary barrier in septic rats was intact; therefore the finding of increased extravascular lung water in early sepsis could be attributed to accumulation of protein-poor fluid. The expression of epithelial sodium channel and Na-K-ATPase proteins in whole ATII cells was not different in both cecal ligation and puncture and control groups; however, the abundance of Na-K-ATPase proteins was significantly decreased in BLMs of ATII cells in sepsis. Early decrease in AFC in remote sepsis is probably related to endocytosis of the Na-K-ATPase proteins from the cell plasma membrane into intracellular pools, with resultant inhibition of active sodium transport in ATII cells.


Predicting evolutionary rescue via evolving plasticity in stochastic environments.
Phenotypic plasticity and its evolution may help evolutionary rescue in a novel and stressful environment, especially if environmental novelty reveals cryptic genetic variation that enables the evolution of increased plasticity. However, the environmental stochasticity ubiquitous in natural systems may alter these predictions, because high plasticity may amplify phenotype-environment mismatches. Although previous studies have highlighted this potential detrimental effect of plasticity in stochastic environments, they have not investigated how it affects extinction risk in the context of evolutionary rescue and with evolving plasticity. We investigate this question here by integrating stochastic demography with quantitative genetic theory in a model with simultaneous change in the mean and predictability (temporal autocorrelation) of the environment. We develop an approximate prediction of long-term persistence under the new pattern of environmental fluctuations, and compare it with numerical simulations for short- and long-term extinction risk. We find that reduced predictability increases extinction risk and reduces persistence because it increases stochastic load during rescue. This understanding of how stochastic demography, phenotypic plasticity, and evolution interact when evolution acts on cryptic genetic variation revealed in a novel environment can inform expectations for invasions, extinctions, or the emergence of chemical resistance in pests.


Aquaporin-5 Expression Is Reduced in Lymphocytic Colitis.
Aquaporin-5 (AQP5) is a member of a family of water channel proteins involved in the bidirectional transfer of water across cell membranes. Lymphocytic colitis (LC) and collagenous colitis (CC) are clinically similar diseases characterized by chronic watery diarrhea in patients with usually unremarkable colonic mucosa on colonoscopy. The aim of this study was to determine whether AQP5 expression in colonic epithelium is altered in LC and CC. Sections of formalin-fixed and paraffin-embedded colorectal biopsies from three control patients (CTL), 8 patients with chronic non-bloody diarrhea with biopsies negative for active inflammation or significant distortion (CTL-D), 8 patients with LC, and 5 with CC were stained for AQP5 using immunohistochemistry. The staining intensity was scored as 3 (strong), 2 (intermediate), 1 (weak), or 0 (no staining). Statistical analysis was performed using Prism 7 Statistical Soft-ware. AQP5 was strongly expressed (score 3) in the epithelial cells in all three CTL cases and all 8 CTL-D cases. In the 5 cases of CC, 3(60%) had score 3 and 2(40%) had score 2, but none had a score of 1 or 0. Of the 8 LC cases, 2(25%) had score 3, 3 had score 2(37.5%), and 3 had score 1(37.5%) (p=0.0031). In the three cases of LC with markedly reduced AQP5 (score 1), enteric steroid treatment did not lead to significant improvement in diarrhea. Colorectal AQP5 expression is reduced in most cases of LC. Markedly reduced AQP5 expression in LC may identify a subset of patients with suboptimal response to enteric steroid treatment. Additional larger studies are needed to confirm these findings.This abstract was presented in part at Digestive Diseases Week in San Diego, CA, May 2019.


"A Vigorous Campaign against Abortion": Views of American Leaders of Eugenics v. Supreme Court Distortions.
The Supreme Court decided Box v. Planned Parenthood of Indiana and Kentucky in 2019. Justice Clarence Thomas's opinion in the case claimed there was a direct connection between the legalization of abortion, in the late 20th Century, and the beginnings of the birth control movement a full three quarters of a century earlier. "Many eugenicists," Thomas argued, "supported legalizing abortion."Justice Samuel Alito highlighted similar claims in Dobbs v. Jackson Women's Health, citing a brief entitled "The Eugenic Era Lives on through the Abortion Movement." That brief was an echo of Justice Thomas' misguided attempt at history in the Box opinion. Similar claims reoccur in Judge Matthew Kacsmaryk's opinion in the Texas mifepristone case, Alliance for Hippocratic Medicine v. U.S. Food and Drug Administration.These false claims are the focus of this article. There is no evidence that early leaders of the eugenics movement supported abortion as part of the movement for birth control. It is accurate to describe those leaders as anti-abortion, and their followers as people who condemned abortion for moral, legal, and medical reasons.


Use of stress echocardiography for the prognostic assessment of patients with stable chronic coronary artery disease.
Stress echocardiography has become an established tool for the diagnosis of coronary artery disease. However, in the current era of attention to cost effectiveness, the ability of a non-invasive test to predict outcomes, and therefore assist in clinical decision making, is paramount. As a reflection of the relative youth of this technique, there are fewer data using stress echocardiography to assess prognosis than there are using nuclear imaging. However, using both exercise and pharmacological stress echocardiography, the presence of ischaemia is strongly predictive of the recurrence of a subsequent cardiac event. Moreover, during pharmacological stress testing, the ischaemic threshold may be used to further stratify the risk of a positive test. More studies are needed in large populations to establish the prognostic role of stress echocardiography, as in independent predictor of outcome, incremental to clinical and stress testing data.


Methods for handling longitudinal outcome processes truncated by dropout and death.
Cohort data are often incomplete because some subjects drop out of the study, and inverse probability weighting (IPW), multiple imputation (MI), and linear increments (LI) are methods that deal with such missing data. In cohort studies of ageing, missing data can arise from dropout or death. Methods that do not distinguish between these reasons for missingness typically provide inference about a hypothetical cohort where no one can die (immortal cohort). It has been suggested that inference about the cohort composed of those who are still alive at any time point (partly conditional inference) may be more meaningful. MI, LI, and IPW can all be adapted to provide partly conditional inference. In this article, we clarify and compare the assumptions required by these MI, LI, and IPW methods for partly conditional inference on continuous outcomes. We also propose augmented IPW estimators for making partly conditional inference. These are more efficient than IPW estimators and more robust to model misspecification. Our simulation studies show that the methods give approximately unbiased estimates of partly conditional estimands when their assumptions are met, but may be biased otherwise. We illustrate the application of the missing data methods using data from the 'Origins of Variance in the Old-old' Twin study.


Unknown AV-fistula as reason for post-traumatic hematoma of the thigh.
A case is reported of a 28-year-old patient with gradually developing massive swelling of the right thigh after sustaining a blunt trauma. 3 1/2 months after the injury, surgery was performed because of a persisting tumor at the thigh. Intraoperatively, massive bleeding occurred, the bleeding vessel was sutured. Postoperative angiography disclosed arteriovenous (av) fistulae from the internal iliacal artery to a gluteal vein as source for the bleeding. The feeding artery was closed by coiling, the patient recovered completely. To the authors' knowledge, development of an av-fistula following blunt trauma has not been described previously. Similarly, the differential diagnosis of a posttraumatic bleeding of a congenital av-malformation was not yet reported. The authors emphasize, that prior to the surgery of inadequately behaving hematomas, an angiography should be performed.


Interleukin-20 receptor expression in the trabecular meshwork and its implication in glaucoma.
To determine whether interleukin-20 receptors (IL-20R) are expressed in trabecular meshwork cells and the effect of a T104M mutation in IL-20R2 on downstream cellular functions. Evaluation of signal transducer and activator of transcription (STAT)3 phosphorylation and generic matrix metalloproteinase (MMP) activity in primary open angle glaucoma (POAG) dermal fibroblasts (pHDF) with the T104M IL-20R2 mutation were compared with normal human dermal fibroblasts (HDF). Expression of IL-20R1 and IL-20R2 in human trabecular meshwork (HTM) cells was determined by immunohistochemistry and western immunoblotting. A T104M mutation in IL20-R2 was identified in a large POAG family in which the GLC1C locus was originally mapped. pHDFs harboring this mutation had significantly increased phosphorylated STAT3 (pSTAT3) activity compared with normal HDFs. However, stimulation with either IL-19 or IL-20 for 15 min resulted in significantly decreased levels of pSTAT3 in pHDFs compared with controls. Generic MMP activity was significantly decreased in pHDFs compared with controls after stimulation with IL-20 for 24 h. Both IL-20R1 and IL-20R2 receptors were expressed in HTM cells by western immunoblot and immunofluorescence, and they appeared to be up-regulated in response to cytokine treatment. A T104M mutation in IL-20R2 significantly impacts the function of this receptor as shown by decreased pSTAT3 levels and generic MMP activity. Reduced MMP activity may affect the ability of glaucoma patients to alter outflow resistance in response to elevated intraocular pressure.


aVR ST Segment Elevation: Acute STEMI or Not? Incidence of an Acute Coronary Occlusion.
Identification of ST elevation myocardial infarction (STEMI) is critical because early reperfusion can save myocardium and increase survival. ST elevation (STE) in lead augmented vector right (aVR), coexistent with multilead ST depression, was endorsed as a sign of acute occlusion of the left main or proximal left anterior descending coronary artery in the 2013 STEMI guidelines. We investigated the incidence of an acutely occluded coronary in patients presenting with STE-aVR with multilead ST depression. STEMI activations between January 2014 and April 2018 at the University of Arizona Medical Center were identified. All electrocardiograms (ECGs) and coronary angiograms were blindly analyzed by experienced cardiologists. Among 847 STEMI activations, 99 patients (12%) were identified with STE-aVR with multilead ST depression. Emergent angiography was performed in 80% (79/99) of patients. Thirty-six patients (36%) presented with cardiac arrest, and 78% (28/36) underwent emergent angiography. Coronary occlusion, thought to be culprit, was identified in only 8 patients (10%), and none of those lesions were left main or left anterior descending occlusions. A total of 47 patients (59%) were found to have severe coronary disease, but most had intact distal flow. Thirty-two patients (40%) had mild to moderate or no significant disease. However, STE-aVR with multilead ST depression was associated with 31% in-hospital mortality compared with only 6.2% in a subgroup of 190 patients with STEMI without STE-aVR (p<0.00001). STE-aVR with multilead ST depression was associated with acutely thrombotic coronary occlusion in only 10% of patients. Routine STEMI activation in STE-aVR for emergent revascularization is not warranted, although urgent, rather than emergent, catheterization appears to be important.


Transcranial magnetic stimulation: a primer.
Transcranial magnetic stimulation (TMS) is a technique for noninvasive stimulation of the human brain. Stimulation is produced by generating a brief, high-intensity magnetic field by passing a brief electric current through a magnetic coil. The field can excite or inhibit a small area of brain below the coil. All parts of the brain just beneath the skull can be influenced, but most studies have been of the motor cortex where a focal muscle twitch can be produced, called the motor-evoked potential. The technique can be used to map brain function and explore the excitability of different regions. Brief interference has allowed mapping of many sensory, motor, and cognitive functions. TMS has some clinical utility, and, because it can influence brain function if delivered repetitively, it is being developed for various therapeutic purposes.


Over-Sewing of Staple Line in Laparoscopic Sleeve Gastrectomy: Initial Experience of a Comparative Study.
The main drawback of laparoscopic sleeve gastrectomy (LSG) is the severity of postoperative complications. Staple line reinforcement (SLR) is strongly advocated. Recently, over-sewing has been proposed as a cost-effective and helpful method for reinforcing the staple line. The purpose of this study was to report our initial experience with LSG comparing over-sewing over the entire staple line with the upper-third staple line. All obese patients seen at Negrar Sacro Cuore, Don Calabria Hospital were entered into our prospective database and were retrospectively evaluated. Complications (divided as major complications: leaks and bleeding; and minor complications: dysphagia, esophagitis, and reflux disease) and reoperations were recorded for all patients. Complications were graded according to the Clavien classification system. From February 2015 to March 2016, 30 patients underwent LSG. Patients were divided in two groups according to over-sewing: Group A-over-sewing over the entire staple line; and Group B upper-third over-sewing. Mean total operative time was longer in Group A-90 minutes-compared with 85 minutes in Group B. In regard to minor complications, we reported one esophagitis and two cases of dysphagia in Group B and one dysphagia in Group A. Gastroesophageal reflux was higher in Group B than in Group A (3 vs. 1, p=0.149). Three major complications were observed (10%): two bleeding and one hematoma in Group B and no major complications occurred in Group A. All major complications were conservatively treated. No leaks were reported in both groups. No mortality was observed. Over-sewing of the staple line was associated with fewer leaks but no conclusions can be drawn regarding the effects of over-sewing on staple line bleedings. Before standardizing surgical techniques further, trials are necessary to improve our knowledge about over-sewing in LSG.


A phylogenetic model for the recruitment of species into microbial communities and application to studies of the human microbiome.
Understanding when and why new species are recruited into microbial communities is a formidable problem with implications for managing microbial systems, for instance by helping us better understand whether a probiotic or pathogen would be expected to colonize a human microbiome. Much theory in microbial temporal dynamics is focused on how phylogenetic relationships between microbes impact the order in which those microbes are recruited; for example, species that are closely related may competitively exclude each other. However, several recent human microbiome studies have observed closely related bacteria being recruited into microbial communities in short succession, suggesting that microbial community assembly is historically contingent, but competitive exclusion of close relatives may not be important. To address this, we developed a mathematical model that describes the order in which new species are detected in microbial communities over time within a phylogenetic framework. We use our model to test three hypothetical assembly modes: underdispersion (species recruitment is more likely if a close relative was previously detected), overdispersion (recruitment is more likely if a close relative has not been previously detected), and the neutral model (recruitment likelihood is not related to phylogenetic relationships among species). We applied our model to longitudinal human microbiome data, and found that for the individuals we analyzed, the human microbiome generally follows the underdispersion (i.e., nepotism) hypothesis. Exceptions were oral communities and the fecal communities of two infants that had undergone heavy antibiotic treatment. None of the datasets we analyzed showed statistically significant phylogenetic overdispersion.


The connective tissue of the female fetal pelvic region.
The spatial architecture of the female fetal pelvic region was studied with a blunt dissection technique and reconstructed from 60 mu serial thick sections of complete fetal pelves. From the analysis of these reconstructions could be concluded that the connective tissue in the fetal female pelvic region is organized into a bilateral symmetric and interindividual constant system of septa. This system of connective tissue was found continuous from the retroperitoneal space through the musculus levator ani into the fossa ischiorectalis.


Plasma and urine riboflavin and pyridoxine concentrations in enterally fed very-low-birth-weight neonates.
Preterm infant formulas (PIFs) for very-low-birth-weight (VLBW) infants (birth weight, < 1,500 g) are augmented to provide daily riboflavin and pyridoxine at levels up to five-fold greater than in term infant formula and 18-fold greater than in human milk. We evaluated plasma riboflavin and pyridoxine concentrations in VLBW infants who received PIF during their first postnatal month. Eighty-eight plasma and 124 urine samples were collected for riboflavin- and pyridoxine-concentration measurements from 57 clinically healthy VLBW infants weekly during their first postnatal month. Concentrations were measured using high-performance liquid chromatography. At the time of the sample, patients were receiving > or = 80% of their total calories via enteral feedings. Plasma riboflavin concentrations rose from 45.3 +/- 7.3 ng/ml at baseline (mean +/- SEM) to 173.5 +/- 20.3 ng/ml by 1 week of age and remained at 177.3-199.7 ng/ml during the following three weekly measurements; values were up to 14-fold above baseline concentration. Urine riboflavin concentration increased from 534 +/- 137 ng/ml at baseline to 3,521 +/- 423 ng/ml by 1 week of age and remained at 4,451-5,216 ng/ml during the next 3 weeks. In a similar pattern, baseline plasma (69.4 +/- 10.4 ng/ml) and urine (145 +/- 30 ng/ml) pyridoxine concentrations were significantly increased by 1 week postnatal age; they remained at 163-248 ng/ml (plasma) and 1,573-2,394 ng/ml (urine) through the first postnatal month. Plasma and urine riboflavin and pyridoxine concentrations in enterally fed VLBW infants increased from baseline concentrations by 1 week of postnatal age and remained elevated for the first postnatal month. High daily intake and immature renal development are probable contributing causes of the elevated plasma riboflavin and pyridoxine concentrations. We suggest that lower daily enteral administration of riboflavin and pyridoxine should maintain adequate blood concentrations and minimize potential toxicity.


Multilayered control of chromosome replication in Caulobacter crescentus.
The environmental Alphaproteobacterium Caulobacter crescentus is a classical model to study the regulation of the bacterial cell cycle. It divides asymmetrically, giving a stalked cell that immediately enters S phase and a swarmer cell that stays in the G1 phase until it differentiates into a stalked cell. Its genome consists in a single circular chromosome whose replication is tightly regulated so that it happens only in stalked cells and only once per cell cycle. Imbalances in chromosomal copy numbers are the most often highly deleterious, if not lethal. This review highlights recent discoveries on pathways that control chromosome replication when Caulobacter is exposed to optimal or less optimal growth conditions. Most of these pathways target two proteins that bind directly onto the chromosomal origin: the highly conserved DnaA initiator of DNA replication and the CtrA response regulator that is found in most Alphaproteobacteria The concerted inactivation and proteolysis of CtrA during the swarmer-to-stalked cell transition license cells to enter S phase, while a replisome-associated Regulated Inactivation and proteolysis of DnaA (RIDA) process ensures that initiation starts only once per cell cycle. When Caulobacter is stressed, it turns on control systems that delay the G1-to-S phase transition or the elongation of DNA replication, most probably increasing its fitness and adaptation capacities.


Even one voice: Teaching legislative advocacy as a core competency in family medicine.
Credentialing bodies increasingly focus on advocacy as a competency to be developed by physicians during residency. The skills of advocacy are especially important with the increased attention on social determinants of health and as restrictive state and federal health policy decisions gain widespread attention in the national news media. This movement is reflected in the ACGME's recently revised statement on the training mission of family medicine residencies and with their most recent update of the Milestones which identifies advocacy as a core competency. Additionally, the major family medicine organizations and governing bodies all similarly identify advocacy as an important professional responsibility for family physicians. Advocacy is a broad term that can be applied across a range of settings and scenarios. For the purposes of this paper we focus primarily on legislative advocacy as a specific area for growing curricular experiences in family medicine residency programs.


Actions of quinine on the rat isolated rectum.
The actions of quinine on the rat isolated rectum was studied. Quinine (2.5 X 10(-5) - 2.5 X 10(-4) M) initiated rhythmic phasic contractions (RPC) which were prevented by verapamil, lanthanum, indomethacin or Ca2+-withdrawal, but were unaffected by tetrodotoxin, L-propranolol, phentolamine, or atropine. Higher quinine concentrations (2.5 X 10(-4) - 10(-3) M) relaxed the rat rectum and inhibited the RPC induced by lower concentrations. Exposure to high Ca2+-Tyrode solution (6 Ca2+-Tyrode) increased the baseline tone of the muscle. Under this condition, quinine (2.5 X 10(-4) - 10(-3) M), but not lower concentrations relaxed the muscle. Quinine (2.5 X 10(-5) - 10(-3) M) concentration-dependently inhibited KCl and acetylcholine-induced contractions, but more readily blocked KCl than acetylcholine-induced responses; the inhibitory effect of quinine against KCl, but not acetylcholine, was largely reversed by increasing the Ca2+ concentration of the Tyrode solution. It is concluded that quinine-induced RPC occurred independently of adrenergic or cholinergic mechanisms, and are likely to be due to enhanced Ca2+ influx into the rectum, while the relaxation encountered with higher concentrations may be due to inhibition by quinine of transmembranal Ca2+ influx. Evidence was obtained that quinine may preferentially inhibit Ca2+ influx through a pathway linked to high K+ depolarisation.


Optimization and initial evaluation of 1,2-indandione as a reagent for fingerprint detection.
1,2-Indandione has been used to develop fluorescent fingerprints on porous materials such as paper. The compound reacts with amino acid residues to produce highly fluorescent fingerprint ridges. An optimized formulation and treatment protocol for using the reagent is presented here. The reagent is applied as a solution in HFE7100 containing acetic acid and ethyl acetate. Treated articles are heated at 100 degrees C for 10 min at ambient humidity and stored in the dark before recording the fingerprints using fluorescence photography or digital imaging. Photodecomposition of the fluorescent fingerprints has been observed. Storage in the dark reduces degradation, extending the lifetime of the fingerprints. Other chemical methods to stabilize the fingerprints proved unsuccessful. Comparisons of the performance of 1,2-indandione with DFO in CFC113 performed on a limited range of substrates indicated that the reagent might be an effective method for the development of latent fingerprints despite the new reagent producing less intense fluorescence.


Mapping critical cortical hubs and white matter pathways by direct electrical stimulation: an original functional atlas of the human brain.
The structural and functional organization of brain networks subserving basic daily activities (i.e. language, visuo-spatial cognition, movement, semantics, etc.) are not completely understood to date. Here, we report the first probabilistic cortical and subcortical atlas of critical structures mediating human brain functions based on direct electrical stimulation (DES), a well-validated tool for the exploration of cerebral processing and for performing safe surgical interventions in eloquent areas. We collected 1162 cortical and 659 subcortical DES responses during testing of 16 functional domains in 256 patients undergoing awake surgery. Spatial coordinates for each functional response were calculated, and probability distributions for the entire patient cohort were mapped onto a standardized three-dimensional brain template using a multinomial statistical analysis. In addition, matching analyses were performed against prior established anatomy-based cortical and white matter (WM) atlases. The probabilistic maps for each functional domain were provided. The topographical analysis demonstrated a wide spatial distribution of cortical functional responses, while subcortical responses were more restricted, localizing to known WM pathways. These DES-derived data showed reliable matching with existing cortical and WM atlases as well as recent neuroimaging and neurophysiological data. We present the first integrated and comprehensive cortical-subcortical atlas of structures essential for humans' neural functions based on highly-specific DES mapping during real-time neuropsychological testing. This novel atlas can serve as a complementary tool for neuroscientists, along with data obtained from other modalities, to improve and refine our understanding of the functional anatomy of critical brain networks.


Erdheim-Chester disease: from palliative care to targeted treatment.
Erdheim-Chester disease (ECD) is a life-threatening multi-systemic non-Langerhans histiocytosis with cardiovascular complications as the leading cause of death. ECD affects the kidneys in up to 30% of cases, with fibrotic tissue deposition in the perirenal fat and renal hilum. Diagnosis is usually based on histological analysis of the pathologic tissue, which typically shows xanthogranulomatous infiltrates of foamy CD68+/CD1a- histiocytes surrounded by fibrosis. A consistent percentage of patients affected by ECD develop renal failure and hypertension as a consequence of renal artery stenosis and hydronephrosis. These conditions have been generally treated with the placement of stents and nephrostomies that frequently led to disappointing outcomes. Before the introduction of interferon-alpha (IFNα) treatment, the mortality rate was as high as 57% in the long term. Recent studies have granted new insights into the pathogenesis of ECD, which seems to bear a dual component of clonal and inflammatory disease. These advances led to use specific therapies targeting either the oncogenes (BRAF(V600E)) or the effectors of the immune response implicated in ECD (IL-1, TNFα). Drugs such as anakinra (recombinant human IL-1 receptor antagonist), infliximab (monoclonal antibody against TNFα) and vemurafenib (inhibitor of mutant BRAF) showed promising results in small single-centre series. Although larger trials will be needed to address the impact of these drugs on ECD prognosis and to select the most effective treatment, targeted therapies hold the premises to drastically change the outcome of this condition.


Triangulating case-finding tools for patient safety surveillance: a cross-sectional case study of puncture/laceration.
To evaluate the need for triangulating case-finding tools in patient safety surveillance. This study applied four case-finding tools to error-associated patient safety events to identify and characterise the spectrum of events captured by these tools, using puncture or laceration as an example for in-depth analysis. Retrospective hospital discharge data were collected for calendar year 2005 (n=48,418) from a large, urban medical centre in the USA. The study design was cross-sectional and used data linkage to identify the cases captured by each of four case-finding tools. Three case-finding tools (International Classification of Diseases external (E) and nature (N) of injury codes, Patient Safety Indicators (PSI)) were applied to the administrative discharge data to identify potential patient safety events. The fourth tool was Patient Safety Net, a web-based voluntary patient safety event reporting system. The degree of mutual exclusion among detection methods was substantial. For example, when linking puncture or laceration on unique identifiers, out of 447 potential events, 118 were identical between PSI and E-codes, 152 were identical between N-codes and E-codes and 188 were identical between PSI and N-codes. Only 100 events that were identified by PSI, E-codes and N-codes were identical. Triangulation of multiple tools through data linkage captures potential patient safety events most comprehensively. Existing detection tools target patient safety domains differently, and consequently capture different occurrences, necessitating the integration of data from a combination of tools to fully estimate the total burden.


sgTarget: a target selection resource for structural genomics.
sgTarget (http://www.ysbl.york.ac.uk/sgTarget) is a web-based resource to aid the selection and prioritization of candidate proteins for structure determination. The system annotates user submitted gene or protein sequences, identifying sequence families with no homologues of known structure, and characterizing each protein according to a range of physicochemical properties that may affect its expression, solubility and likelihood to crystallize. Summaries of these analyses are available for individual sequences, as well as whole datasets. This type of analysis enables structural biologists to iteratively select targets from their genomic sequences of interest and according to their research needs. All sequence datasets submitted to sgTarget are available for users to select and rank using their choice of criteria. sgTarget was developed to support individual laboratories collaborating in structural and functional genomics projects and should be valuable to structural biologists wishing to employ the wealth of available genome sequences in their structural quests.


Odour and ammonia removal from pig house exhaust air using a biotrickling filter.
Odour from agricultural activities, such as the spreading of manure and the housing of animals, is increasingly being considered a nuisance in densely populated countries like the Netherlands. The objective of this research was to study the odour removal from pig house exhaust air by a biotrickling filter that had been implemented for ammonia abatement. At a regular pig production farm, the performance of a running full-scale biotrickling filter was studied for 72 days. Ammonia and odour removal efficiency were on average 79% and 49% respectively. Ammonia removal appeared to be based on an unintended accumulation of ammonium and nitrite in the system, instead of on production and discharge of nitrate. The odour removal efficiency showed a large variation that, for a major part, about 80%, could be attributed to actual changes in the performance of the biotrickling filter. These changes were probably caused by variations in the composition of the air that were not completely reflected by the olfactometrically measured odour concentration, as the many different components that make up the odour each have different removal characteristics. It seemed that the biotrickling filter was operated below its maximum absolute odour removal capacity [OUE/(m3 filter)/s], which means that the absolute odour removal will probably rise at increasing load. It was, however, not possible to distinguish between the influence of either the odour load or the odour concentration on the odour removal, because of a positive correlation between the odour concentration and the air flow. To increase the odour removal efficiency (%), the design of the filter probably needs to be optimised for both well and poorly water-soluble odour components.


Intense 99mTc-MDP Activity in an Elongated Sagging Gallbladder With a Partially Calcified Gallstone.
Intense activity was noted in the right middle abdomen on whole-body Tc-MDP bone scan images, which were obtained in a 78-year-old woman who had back pain. Further SPECT/CT images demonstrated that the intense activity was located in an elongated gallbladder. Partially calcified gallstone was also revealed on SPECT/CT images. Unexpectedly, the gallbladder activity was from the radioactive bile inside the gallbladder lumen, whereas the partially calcified gallstone was relatively photopenic.


In situ measurement of PCB pore water concentration profiles in activated carbon-amended sediment using passive samplers.
Vertical pore water profiles of in situ PCBs were determined in a contaminated mudflat in San Francisco Bay, CA, 30 months after treatment using an activated carbon amendment in the upper layer of the sediment. Pore water concentrations were derived from concentrations of PCBs measured in two passive samplers; polyethylene (PE, 51 μm thick) and polyoxymethylene (POM, 17 μm thick) at different sediment depths. To calculate pore water concentrations from PCB contents in the passive samplers, an equilibrium approach and a first-order uptake model were applied, using five performance reference compounds to estimate pore water sampling rates. Vertical pore water profiles showed good agreement among the measurement and calculation methods with variations within a factor of 2, which seems reasonable for in situ measurements. The close agreements of pore water estimates for the two sampler materials (PE and POM) and the two methods used to translate uptake in samplers to pore water concentrations demonstrate the robustness and suitability of the passive sampling approach. The application of passive samplers in the sediment presents a promising method for site monitoring and remedial treatment evaluation of sorbent amendment or capping techniques that result in changes of pore water concentrations in the sediment subsurface.


Sorting receptor SORLA--a trafficking path to avoid Alzheimer disease.
Excessive proteolytic breakdown of the amyloid precursor protein (APP) to neurotoxic amyloid β peptides (Aβ) by secretases in the brain is a molecular cause of Alzheimer disease (AD). According to current concepts, the complex route whereby APP moves between the secretory compartment, the cell surface and endosomes to encounter the various secretases determines its processing fate. However, the molecular mechanisms that control the intracellular trafficking of APP in neurons and their contribution to AD remain poorly understood. Here, we describe the functional elucidation of a new sorting receptor SORLA that emerges as a central regulator of trafficking and processing of APP. SORLA interacts with distinct sets of cytosolic adaptors for anterograde and retrograde movement of APP between the trans-Golgi network and early endosomes, thereby restricting delivery of the precursor to endocytic compartments that favor amyloidogenic breakdown. Defects in SORLA and its interacting adaptors result in transport defects and enhanced amyloidogenic processing of APP, and represent important risk factors for AD in patients. As discussed here, these findings uncovered a unique regulatory pathway for the control of neuronal protein transport, and provide clues as to why defects in this pathway cause neurodegenerative disease.


Congenital disseminated malignant rhabdoid tumor: a distinct clinicopathologic entity demonstrating abnormalities of chromosome 22q11.
The clinical, pathologic, and immunohistochemical features of a widely disseminated tumor with rhabdoid phenotype are described in nine infants < or = 3 months of age. Five neonates had tumor evident at birth, two of which had placental metastases. The average survival following diagnosis was < 6 weeks. None of the infants had an apparent primary tumor in either the kidney or brain. In four cases, the dominant mass involved the head and neck region, and in two cases, the primary mass was paraspinal. The histologic features were those of a high-grade, round cell neoplasm with abundant cytoplasm and containing cells with cytoplasmic filamentous inclusions. Immunohistochemical studies revealed polyphenotypic antigen expression. Genetic information was available from eight of nine cases. Karyotype analysis revealed abnormalities of chromosome band 22q11-12 in three of six tumors. Fluorescence in situ hybridization studies or molecular studies demonstrated 22q11.2 deletions in all five cases with available frozen tissue, two of which had translocations involving 22q by karyotype analysis. The similar clinical and pathologic findings in these rapidly fatal tumors in infants and the demonstration of abnormalities of chromosome 22q11 in a majority of the cases supports their histogenetic and nosologic relationship to the family of malignant rhabdoid tumors that typically occur in young children in several anatomic sites, including kidney, soft tissues, liver, and brain. Like neuroblastoma and rhabdomyosarcoma, malignant rhabdoid tumor can appear as disseminated disease at birth or shortly thereafter.


Rapid bioassay for the determination of dioxins and dioxin-like PCDFs and PCBs in meat and animal feeds.
Over the past several years, the numerous contamination incidents have raised concerns over the presence of halogenated aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and related chemicals in foods and feeds. Here we applied a sensitive recombinant mouse hepatoma cell (H1L1.1c2) bioassay for the determination of dioxins and dioxin-like polychlorinated dibenzofurans (PCDFs) and biphenyls (PCBs) in meat and animal feeds. These cells responded to TCDD-like chemicals with dose-dependent induction of firefly luciferase activity, and the minimal detection limit of TCDD in the cell was 16 fg. Induction equivalency factors determined for pure TCDD-like polychlorinated dibenzo-p-dioxins (PCDDs), PCDFs, and PCBs in the bioassay were well-correlated with the World Health Organization's toxic equivalency factors. To determine the applicability of the bioassay system to detect those compounds presence in meat and feed samples, cell bioassays for 17 TCDD-like PCDDs and PCDFs congeners-spiked lipid extracted from beef or animal feed were performed. Mean recoveries of TCDD-like chlorinated PCDDs and PCDFs congeners from spiked beef or feed fat ranged from 61.2 to 122.3%. Within-laboratory coefficients of variation for analysis as index of precision were lower than 5.2%, and the calculated limits of detection and quantitation were 0.33 and 1 pg toxicity equivalency quantity (TEQ)/0.5 g fat, respectively. Correlation between bioassay- and high-resolution gas chromatography-mass spectrometry (HR-GC-MS)-determined TEQs for 10 meat samples was 0.85, with 1.2 times higher in bioassay than HR-GC-MS. The correlation between bioassay- and HR-GC-MS-determined TEQs in 10 animal feed products was 0.81, with 2.1 times higher in bioassay than HR-GC-MS. Overall, these results demonstrated that the recombinant cell bioassay can be used for the rapid detection and quantitation of PCDDs and dioxin-like PCDFs and PCBs in meats and animal feeds.


Vancomycin-resistant streptococci or Leuconostoc sp.
Two strains of gram-positive cocci highly resistant to vancomycin (MICs of 512 and 1,024 micrograms/ml) were isolated from blood cultures in two compromised patients. These organisms were identified as Leuconostoc spp. Leuconostoc spp. are gram-positive cocci found in vegetables and dairy products; they had not been isolated previously from clinical specimens. The susceptibility of eight Leuconostoc spp. strains, including the two clinical isolates, to 23 antimicrobial agents was determined.


Age-specific oncogenic pathways in head and neck squamous cell carcinoma - are elderly a different subcategory?
In recent clinical practice, an increasing number of elderly patients suffering from head and neck squamous cell carcinoma (HNSCC) of unknown pathophysiology is observed. The majority of HNSCC patients can roughly be divided into three subcategories. First, a small group of young patients who present with variants of genomic aberrations and inheritable diseases like Fanconi anaemia. Second, an increasing population of HPV-related HNSCCs that are regarded as genomic stable tumours with a more favourable prognosis. Though HPV-related tumours used to be more common among younger males, a notable rise in the elderly population is observed. The third subcategory, that of HPV-negative tumours, has been shown to be more heterogeneous with involvement of a variety of oncogenic pathways related to lifestyle factors like smoking and alcohol consumption, often seen in middle-aged males. Some of these pathways could be related to age, such as TP53 alterations, EGFR activation, apoptotic pathway alterations and field cancerization. In this narrative review, we provide an overview of established and newly discovered age-specific pathophysiological mechanisms underlying HNSCC. We propose a fourth subcategory of patients with a suspected different pathophysiology: elderly (HPV-negative) HNSCC patients without a history of tobacco and alcohol consumption. In this subcategory, carcinogenesis seems to be a multi-step process based on genomic instability, immunosenescence, cell cycle disruption and telomere shortening. To conclude, we discuss suggestions for future research to fill the knowledge gap about age-dependent HNSCC carcinogenesis.


Selection of cyanobacteria isolated from mosquito breeding sites as a potential food source for mosquito larvae.
One way to increase the persistence of larvicidal toxins in mosquito breeding sites is to clone the corresponding genes in microorganisms, such as cyanobacteria, which could serve as a source of food for the larvae. We isolated and cultured 10 strains of cyanobacteria from three mosquito breeding sites along the French Mediterranean coast. Most of the strains were tolerant to a relatively wide range of salt concentrations, and all of them were totally or partially resistant to at least four of the five biological or chemical larvicides used in the local mosquito control program. Six unicellular strains from these habitats and Synechococcus strain PCC 7942, a strain maintained for more than 10 years under laboratory conditions, were assessed for ingestion and digestion by larvae Culex pipiens and Anopheles gambiae mosquitoes. The numbers of cells ingested and digested were dependent on the cyanobacterial strain and varied with the mosquito species. Three of the new isolates, Synechococcus strain PCC 8905 and Synechocystis strains PCC 8906 and PCC 8912, were ingested and digested rapidly by larvae of both mosquito species. Since these strains are also tolerant to larvicides and relatively resistant to elevated salt concentrations, they meet the basic requirements for potential recipients of bacterial genes that encode endotoxins.


Evaluation of an adapted version of the Diabetes Prevention Program for low- and middle-income countries: A cluster randomized trial to evaluate "Lifestyle Africa" in South Africa.
Low- and middle-income countries (LMICs) are experiencing major increases in diabetes and cardiovascular conditions linked to overweight and obesity. Lifestyle interventions such as the United States National Diabetes Prevention Program (DPP) developed in high-income countries require adaptation and cultural tailoring for LMICs. The objective of this study was to evaluate the efficacy of "Lifestyle Africa," an adapted version of the DPP tailored for an underresourced community in South Africa compared to usual care. Participants were residents of a predominantly Xhosa-speaking urban township of Cape Town, South Africa characterized by high rates of poverty. Participants with body mass index (BMI) ≥ 25 kg/m2 who were members of existing social support groups or "clubs" receiving health services from local nongovernmental organizations (NGOs) were enrolled in a cluster randomized controlled trial that compared Lifestyle Africa (the intervention condition) to usual care (the control condition). The Lifestyle Africa intervention consisted of 17 video-based group sessions delivered by trained community health workers (CHWs). Clusters were randomized using a numbered list of the CHWs and their assigned clubs based on a computer-based random allocation scheme. CHWs, participants, and research team members could not be blinded to condition. Percentage weight loss (primary outcome), hemoglobin A1c (HbA1c), blood pressure, triglycerides, and low-density lipoprotein (LDL) cholesterol were assessed 7 to 9 months after enrollment. An individual-level intention-to-treat analysis was conducted adjusting for clustering within clubs and baseline values. Trial registration is at ClinicalTrials.gov (NCT03342274). Between February 2018 and May 2019, 782 individuals were screened, and 494 were enrolled. Participants were predominantly retired (57% were receiving a pension) and female (89%) with a mean age of 68 years. Participants from 28 clusters were allocated to Lifestyle Africa (15, n = 240) or usual care (13, n = 254). Fidelity assessments indicated that the intervention was generally delivered as intended. The modal number of sessions held across all clubs was 17, and the mean attendance of participants across all sessions was 61%. Outcome assessment was completed by 215 (90%) intervention and 223 (88%) control participants. Intent-to-treat analyses utilizing multilevel modeling included all randomized participants. Mean weight change (primary outcome) was -0.61% (95% confidence interval (CI) = -1.22, -0.01) in Lifestyle Africa and -0.44% (95% CI = -1.06, 0.18) in control with no significant difference (group difference = -0.17%; 95% CI = -1.04, 0.71; p = 0.71). However, HbA1c was significantly lower at follow-up in Lifestyle Africa compared to the usual care group (mean difference = -0.24, 95% CI = -0.39, -0.09, p = 0.001). None of the other secondary outcomes differed at follow-up: systolic blood pressure (group difference = -1.36; 95% CI = -6.92, 4.21; p = 0.63), diastolic blood pressure (group difference = -0.39; 95% CI = -3.25, 2.30; p = 0.78), LDL (group difference = -0.07; 95% CI = -0.19, 0.05; p = 0.26), triglycerides (group difference = -0.02; 95% CI = -0.20, 0.16; p = 0.80). There were no unanticipated problems and serious adverse events were rare, unrelated to the intervention, and similar across groups (11 in Lifestyle Africa versus 13 in usual care). Limitations of the study include the lack of a rigorous dietary intake measure and the high representation of older women. In this study, we found that Lifestyle Africa was feasible for CHWs to deliver and, although it had no effect on the primary outcome of weight loss or secondary outcomes of blood pressure or triglycerides, it had an apparent small significant effect on HbA1c. The study demonstrates the potential feasibility of CHWs to deliver a program without expert involvement by utilizing video-based sessions. The intervention may hold promise for addressing cardiovascular disease (CVD) and diabetes at scale in LMICs. ClinicalTrials.gov NCT03342274.


The benefits of exercise training in multiple sclerosis.
Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammatory demyelination and neurodegeneration within the CNS. This damage of CNS structures leads to deficits of body functions, which, in turn, affect patient activities, such as walking, and participation. The pathogenesis and resulting consequences of MS have been described as concepts within the International Classification of Functioning, Disability and Health (ICF) model--an international standard to describe and measure health and disability. Evidence suggests that exercise training in people with MS has the potential to target and improve many of the components outlined in the ICF model. Although the body of research examining the effects of exercise training on depression, cognition and participatory outcomes is not sufficiently developed, some preliminary evidence is promising. Exercise training is proposed to affect inflammation, neurodegeneration, and CNS structures, but current evidence is limited. In this Review, we discuss evidence from clinical trials that suggests beneficial effects of exercise training on muscle strength, aerobic capacity and walking performance, and on fatigue, gait, balance and quality of life. Issues with current studies and areas of future research are highlighted.


Novel three dimensional human endocervix cultures respond to 28-day hormone treatment.
The endocervix has both anatomical and biological functions that participate in the delicate balance between tolerance necessary for conception and protection from pathogens. Our goal was to develop a robust 3-dimensional (3D) endocervix model that was a reliable representation of the in vivo tissues and to identify the physiological responses to changing levels of steroid hormones during a 28-day time period. Human endocervical cells were grown on polystyrene scaffolds, and the morphologic and hormonal responses of cultured cells were assessed in response to fluctuating levels of estradiol (E2) or progesterone (P4). Morphologically, the 3D cultures were composed of a mixed population of cells, including epithelial and stromal cells. Treatment with E2 and P4 (d 28) increased cell growth and proliferation as compared with no treatment control. Cells expressed estrogen receptor and P4 receptor and produced both neutral and acidic mucins, including Mucin 16. In addition, a 45-plex Luminex assay identified numerous factors secreted and regulated by hormones. Specifically, IL-1β and leukemia inhibitory factor significantly decreased in the presence of E2 and P4 as compared with the no hormone control at day 26. Cotreatment with RU486 (mifepristone) attenuated the inhibition of IL-1β and leukemia inhibitory factor secretion. In summary, a robust, novel 3D endocervical culture was developed, and physiologic responses to the menstrual cycle mimic of E2 and P4 levels for a period of 28 days were identified.


Anterior urethral strictures.
The surgical treatment of adult anterior urethral strictures has developed continuously. Recently considerable changes have been introduced, involving the cause of the urethral disease and surgical techniques. The criteria for selecting the reconstructive surgical technique are presented according to the cause and a new classification of urethral strictures. The main surgical procedures are presented and fully illustrated, with an updated and comprehensive review of recent publications.


Efficacy and complications of intradetrusor injection with botulinum toxin A in patients with refractory idiopathic detrusor overactivity.
To evaluate the efficacy and complications of botulinum A toxin (Dysport, Ipsen Ltd, Slough, UK) 500 U in refractory idiopathic detrusor overactivity (IDO). In a prospective study of 25 patients with refractory IDO, the baseline evaluation included an assessment of symptoms, a 7-day voiding diary, 24-h pad test, record of symptoms on a visual analogue scale (VAS) (0-10), the Kings Health Questionnaire (KHQ) and urodynamics. Dysport 500 U was administered at 20 sites in the bladder, sparing the trigone. Patients were followed at 6 weeks and 3, 6 and 9 months; the urodynamic assessment was repeated at 3 months. Fifteen (63%) patients reported being continent from 1 week after treatment; at 3 months, six (32%) (P = 0.01) patients were still dry, remaining so at 6 months (P = 0.025). Weekly leakage episodes decreased from 5.5 to 1.8 (P = 0.044) at 6 weeks and this was sustained, at 2.7 episodes (P = 0.012), at 9 months. The mean VAS score (0-10) decreased from 8.3 to 5.0 (P = 0.001) at 1 week, to 5.0 at 6 weeks (P = 0.001) and 3 months (P = 0.03) and to 6.1 (P = 0.013) at 6 months. On the KHQ there was a significant improvement in the severity measures domain (P = 0.021) and incontinence impact domain (P = 0.015) up to 9 months. The volume at first desire to void increased from 177 to 251 mL (P = 0.04) at 3 months. At 6 weeks and 3 months, 35% of patients required catheterization, as did 22% at 6 months, but only one at 9 months. Intradetrusor Dysport 500 U was associated with significant subjective and objective improvements in refractory IDO. The present patients initially had a significant increase in voiding dysfunction that resolved by 9 months.


NF-AT-mediated expression of TGF-beta1 in tolerant T cells.
During T cell development in the thymus, a certain population of self-reactive thymocytes differentiates into regulatory T cells that suppress otherwise harmful self-reactive T cells. In transgenic mice expressing both TCR that specifically recognizes moth cytochrome c and the moth cytochrome c ligand, a large proportion of CD4+ T cells expresses CD25 and secretes TGF-beta1 upon Ag stimulation. Because TGF-beta1 expression by these T cells can be decreased by cyclosporin A, a NF-AT inhibitor, NF-AT-mediated TGF-beta1 expression in T cells was addressed by characterizing a NF-AT response element in the TGF-beta1 promoter. Analysis of the mouse TGF-beta1 promoter (-1799 to +793) in transfection experiments in T cell 68-41 hybridoma cells detected NF-AT binding sites at positions +268 and +288 in the proximal promoter region. Binding of NF-AT to this region was detected only in tolerant CD4+ T cells, but not in fully activated CD4+ T cells by chromatin immunoprecipitation assays. Activation of these NF-AT sites was sufficient to induce TGF-beta1 promoter activity; however, additional signaling due to full Ag stimulation blocked NF-AT-mediated TGF-beta1 expression. This suppression of the TGF-beta1 promoter is mediated by the -1079 to -406 region, in which deletion of a GATA-binding motif at position -821 abrogates NF-AT-mediated activation of the TGF-beta1 promoter. Therefore, TGF-beta1 expression in T cells is controlled by multiple regulatory factors that have distinct functions in response to partial or full TCR activation.


The Quantification of Injectability by Mechanical Testing.
Injectable biomaterials are becoming increasingly popular for the minimally invasive delivery of drugs and cells. These materials are typically more viscous than traditional aqueous injections and may be semi-solid, therefore, their injectability cannot be assumed. This protocol describes a method to objectively assess the injectability of these materials using a standard mechanical tester. The syringe plunger is compressed by the crosshead at a set rate, and the force is measured. The maximum or plateau force value can then be used for comparison between samples, or to an absolute force limit. This protocol can be used with any material, and any syringe and needle size or geometry. The results obtained may be used to make decisions about formulations, syringe and needle sizes early in the translational process. Further, the effects of altering formulations on injectability may be quantified, and the optimum time to inject temporally changing materials determined. This method is also suitable as a reproducible way to examine the effects of injection on a material, to study phenomena such as self-healing and filter pressing or study the effects of injection on cells. This protocol is faster and more directly applicable to injectability than rotational rheology, and requires minimal post processing to obtain key values for direct comparisons.


Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart.
We tested the hypothesis that left ventricular (LV) remodeling late after myocardial infarction (MI) is associated with myocyte apoptosis in myocardium remote from the infarcted area and is related temporally to LV dilation and contractile dysfunction. One, four, and six months after MI caused by coronary artery ligation, LV volume and contractile function were determined using an isovolumic balloon-in-LV Langendorff technique. Apoptosis and nuclear morphology were determined by terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) and Hoechst 33258 staining. Progressive LV dilation 1-6 mo post-MI was associated with reduced peak LV developed pressure (LVDP). In myocardium remote from the infarct, there was increased wall thickness and expression of atrial natriuretic peptide mRNA consistent with reactive hypertrophy. There was a progressive increase in the number of TUNEL-positive myocytes from 1 to 6 mo post-MI (2.9-fold increase at 6 mo; P < 0. 001 vs. sham). Thus LV remodeling late post-MI is associated with increased apoptosis in myocardium remote from the area of ischemic injury. The frequency of apoptosis is related to the severity of LV dysfunction.


A_16_C haplotype in the FcepsilonRIbeta gene confers a higher risk for atopic asthma in the Indian population.
We conducted a case-control study aimed at identifying polymorphisms and haplotypes in the FcepsilonRIbeta gene associated with asthma and its associated phenotypes such as serum IgE levels. A G/A polymorphism in intron 2, a (CA)n repeat polymorphism in intron 5, and a C/T polymorphism in 3'-UTR, encompassing a length of 8.74 Kb, were genotyped, and haplotypes were generated for unrelated patients and healthy volunteers in two independent cohorts. A significant association was observed at the level of alleles and genotypes studied with asthma independently in the two cohorts (p < 0.05). A change in CC_AA genotype combination to a non-CC_AA genotype was associated with reduced risk for asthma. Interestingly, a three-locus haplotype, A_16_C, was found to be significantly associated with asthma (p = 10(-5) in cohort A and p = 0.004 in cohort B). On the other hand, the haplotype G_18_T was found to be negatively associated with asthma (p = 0.007 in cohort A and p = 0.0004 in cohort B). This is the first study identifying a haplotype A_16_C that predisposes individuals to asthma in the Indian population.


Adaptive governance, ecosystem management, and natural capital.
To gain insights into the effects of adaptive governance on natural capital, we compare three well-studied initiatives; a landscape in Southern Sweden, the Great Barrier Reef in Australia, and fisheries in the Southern Ocean. We assess changes in natural capital and ecosystem services related to these social-ecological governance approaches to ecosystem management and investigate their capacity to respond to change and new challenges. The adaptive governance initiatives are compared with other efforts aimed at conservation and sustainable use of natural capital: Natura 2000 in Europe, lobster fisheries in the Gulf of Maine, North America, and fisheries in Europe. In contrast to these efforts, we found that the adaptive governance cases developed capacity to perform ecosystem management, manage multiple ecosystem services, and monitor, communicate, and respond to ecosystem-wide changes at landscape and seascape levels with visible effects on natural capital. They enabled actors to collaborate across diverse interests, sectors, and institutional arrangements and detect opportunities and problems as they developed while nurturing adaptive capacity to deal with them. They all spanned local to international levels of decision making, thus representing multilevel governance systems for managing natural capital. As with any governance system, internal changes and external drivers of global impacts and demands will continue to challenge the long-term success of such initiatives.


Climate analogues suggest limited potential for intensification of production on current croplands under climate change.
Climate change could pose a major challenge to efforts towards strongly increase food production over the coming decades. However, model simulations of future climate-impacts on crop yields differ substantially in the magnitude and even direction of the projected change. Combining observations of current maximum-attainable yield with climate analogues, we provide a complementary method of assessing the effect of climate change on crop yields. Strong reductions in attainable yields of major cereal crops are found across a large fraction of current cropland by 2050. These areas are vulnerable to climate change and have greatly reduced opportunity for agricultural intensification. However, the total land area, including regions not currently used for crops, climatically suitable for high attainable yields of maize, wheat and rice is similar by 2050 to the present-day. Large shifts in land-use patterns and crop choice will likely be necessary to sustain production growth rates and keep pace with demand.


Recognizing an index case of type 1 neurofibromatosis.
Neurofibromatosis is a relatively common autosomal dominant disorder with variable penetrance. The disorder usually presents in childhood. Hallmarks of type 1 neurofibromatosis are café-au-lait macules and neurofibromas. Neurologic complications include mental retardation, learning disabilities and seizures. Tumors of the eighth cranial nerve, as well as other intracranial and spinal neoplasms, are the typical lesions in type 2 neurofibromatosis. Both forms of neurofibromatosis have a highly variable course and may result in progressive neurologic deterioration, disfigurement and impingement syndromes. In the 50 percent of cases that represent new mutations, diagnosis may be delayed if the physician is not familiar with the salient features of the disorder. Thorough initial evaluation, genetic counseling and close follow-up are important aspects of management.


Associations of primary and secondary organic aerosols with airway and systemic inflammation in an elderly panel cohort.
Exposure-response information about particulate air-pollution constituents is needed to protect sensitive populations. Particulate matter <2.5 mm (PM2.5) components may induce oxidative stress through reactive-oxygen-species generation, including primary organics from combustion sources and secondary organics from photochemically oxidized volatile organic compounds. We evaluated differences in airway versus systemic inflammatory responses to primary versus secondary organic particle components, particle size fractions, and the potential of particles to induce cellular production of reactive oxygen species. A total of 60 elderly subjects contributed up to 12 weekly measurements of fractional exhaled nitric oxide (NO; airway inflammation biomarker), and plasma interleukin-6 (IL-6; systemic inflammation biomarker). PM2.5 mass fractions were PM0.25 (<0.25 μm) and PM0.25-2.5 (0.25-2.5 μm). Primary organic markers included PM2.5 primary organic carbon, and PM0.25 polycyclic aromatic hydrocarbons and hopanes. Secondary organic markers included PM2.5 secondary organic carbon, and PM0.25 water soluble organic carbon and n-alkanoic acids. Gaseous pollutants included carbon monoxide (CO) and nitrogen oxides (NOx; combustion emissions markers), and ozone (O3; photochemistry marker). To assess PM oxidative potential, we exposed rat alveolar macrophages in vitro to aqueous extracts of PM0.25 filters and measured reactive-oxygen-species production. Biomarker associations with exposures were evaluated with mixed-effects models. Secondary organic markers, PM0.25-2.5, and O3 were positively associated with exhaled NO. Primary organic markers, PM0.25, CO, and NOx were positively associated with IL-6. Reactive oxygen species were associated with both outcomes. Particle effects on airway versus systemic inflammation differ by composition, but overall particle potential to induce generation of cellular reactive oxygen species is related to both outcomes.


Multiple Lymph Node Basin Drainage in Trunk Melanoma Is Not Associated with Survival of Sentinel Lymph Node-Positive Patients.
This study was aimed at investigating the prognostic role of multiple lymph node basin drainage (MLBD) in patients with positive sentinel lymph node (SLN) biopsy. MLBD is frequently observed in patients with trunk melanoma undergoing SLN. The prognostic value of MLBD in SLN-positive patients is still debated. Retrospective data from 312 trunk melanoma patients with positive SLN biopsy (1991-2012) at 6 Italian referral centres were gathered in a multicentre database. MLBD was defined at preoperative lymphoscintigraphy. Clinical and pathological data were analysed for their association with disease-free interval (DFI) and disease-specific (DSS) survival. MLBD was identified in 34.6% of patients (108/312) and was significantly associated with >1 positive SLN (37 vs. 15.2%; p < 0.001) and with >1 positive lymph node (LN) after complete lymph node dissection (CLND) (50.9 vs. 34.8%; p = 0.033). No differences were observed according to drainage pattern in patients who had negative and positive non-SLN at CLND. MLBD was not associated with either DFI or DSS. Multivariate analyses showed that tumour thickness, ulceration, and number of metastatic LNs were associated with worse DFI and DSS, while regression confirmed its protective role in survival. In positive SLN patients, MLBD has no association with survival, which is mainly related to American Joint Committee on Cancer (AJCC) prognostic factors. Since the overall number of positive LNs drives the prognosis, the importance of a CLND in all the positive basins is confirmed.


Vascular smooth muscle: availability of calcium through alpha-adrenoceptor stimulation.
In strip preparations from the rabbit main pulmonary artery, it was not possible to differentiate convincingly between alpha 1- and alpha 2-adrenoceptors, when selective agonists such as methoxamine, St 587, B-HT 920, and clonidine, as well as selective antagonists such as prazosin and yohimbine were used for receptor characterization. Measurements of the membrane potential of the vascular smooth-muscle cells with intracellular glass micropipettes showed similar depolarizations in response to the alpha 1-selective methoxamine and the alpha 2-selective B-HT 920. These observations suggest the occurrence of a uniform alpha-adrenoceptor population in the rabbit main pulmonary artery. However, in contrast to alpha 1-agonists, contractile responses to alpha 2-agonists differed considerably in their dependence on external Ca, as revealed in Ca withdrawal experiments, as well as by the use of Ca antagonists. Furthermore, inactivation of the guanine nucleotide-binding inhibitory protein (Ni protein) by pertussis toxin impaired vasoconstriction, in response to alpha 2-agonists, but left that to alpha 1-agonists unaffected. It is suggested that alpha 1- and alpha 2-agonists induce two distinct conformational changes in an otherwise uniform alpha-adrenoceptor of the rabbit main pulmonary artery. By the mediation of Ni protein, alpha 2-agonists appear to allow influx of Ca into the vascular muscle cells through a type of Ca channel that is unlikely to be controlled by voltage.


Effects of repeated intravenous doses of tranexamic acid on closed tibial fracture healing: Experimental study based on the rat model.
The aim of this study was to assess the effects of tranexamic acid on fracture healing in the rat tibia closed fracture model. Sixty-four male Sprague-Dawley rats were included in this study, where closed fracture and intramedullary nailing were performed on their right tibial diaphyses. They were divided into 2 main groups, the experimental group, which was given weekly tranexamic acid injections, and the control group, which received no additional treatment. Eight rats from each group were sacrificed and evaluated for fracture healing at the first experimental group and control group, second experimental group and control group, third experimental group and control group, and fourth experimental group and control group weeks. Fracture healing was radiologically assessed according to the "Spencer Index" and "Lane and Sandhu Scoring System," and histologically evaluated according to the scoring system devised by Huo et al. Results: According to the Spencer Index, the mean union score was statistically significantly higher in the E3 group than in the third con- trol group (P = .014). Furthermore, the mean union score was statistically significantly higher in the fourth experimental group compared to the fourth control group (P=.047). According to the Lane and Sandhu Scoring System, only the mean union scores of the E3-4 groups were statistically significantly higher than the mean union scores of the C3-4 groups (P=.048). There was no histological difference between groups in terms of union, according to the criteria defined by Huo et al (P > .05). This study showed us that repeated intravenous administrations of tranexamic acid had no negative effect on fracture heal- ing in the rat tibia fracture model. Although tranexamic acid demonstrated better radiological healing in the late period, it had no effect on histological union.


["Separation delay" on random flap: an experimental and clinical practice on delayed flap].
A new technique of delayed flap, that is called "Separation delay" by the authors, has succeeded in animal experiment and clinical practice. In the years of 1985-1989, 11 cases of random skin flaps on the patients had been performed with the new method. All the flaps look like table tennis rackets. It's pedicle is very narrow, simultaneously, the flap itself is very large. So it is quite suitable for repairing a neighbouring wound surface. It can be rotated 180 degrees. "The Separation delay" is a handy way without microsurgical technique. It is also an useful and reliable technique for resurfacing wound on plastic and reconstructive surgery.


Association of estrogen receptor-α A908G (K303R) mutation with breast cancer risk.
Genetic mutations in premalignant breast lesions may have a role in malignancy progression or influence the behavior of subsequent disease. A point mutation in estrogen receptor-α (ER-α) as A908G (Lys303→Arg) was originally involved to hypersensitive to estrogen breast hyperplasia. We detected this mutation among Iranian women with invasive breast cancer. A population-based case-control study was conducted in 150 newly diagnosed invasive breast cancer and 147 healthy control individuals controls to screen for presence of the ER-α A908G mutation by using single-strand conformation polymorphism (SSCP) analysis and 33Pcycle DNA sequencing. We detected the 10.7% ER-α A908G mutation in the form of heterozygote genotype only among cancer patients (χ(2)=22.752, P=0.00). The allelic frequency of mutant allele AGG in codon 303 was significantly (χ(2)=29.709, P=0.001) higher in patients with the family history of breast cancer (28.9%) than those without the family history of breast cancer (1.9%). Our data suggest that ER-α codon 303 mutation is correlated with various aspects of breast cancer in Iran. ER-α genotype might represent a surrogate marker for predicting breast cancer developing later in life.


Slice imaging of methyl bromide photofragmentation at 193 nm.
The photodissociation of methyl bromide at 193 nm is studied using slice imaging. From the measured photofragment translational energy and angular distributions we were able to extract methyl-state-specific dissociation channel yields and crossing probabilities between (3)Q0 and (1)Q1 surfaces. The angular distributions for the Bromine photofragments show a strong dependence on the total translational energy release. Nonadiabatic transition probabilities from the (3)Q0 to (1)Q1 surface dominate the dynamics in this excitation energy region and for most of the methyl vibrational states probed.


Processing of nerve biopsies: a practical guide for neuropathologists.
Nerve biopsy is a valuable tool in the diagnostic work-up of peripheral neuropathies. Currently, major indications include interstitial pathologies such as suspected vasculitis and amyloidosis, atypical cases of inflammatory neuropathy and the differential diagnosis of hereditary neuropathies that cannot be specified otherwise. However, surgical removal of a piece of nerve causes a sensory deficit and - in some cases - chronic pain. Therefore, a nerve biopsy is usually performed only when other clinical, laboratory and electrophysiological methods have failed to clarify the cause of disease. The neuropathological work-up should include at least paraffin and resin semithin histology using a panel of conventional and immunohistochemical stains. Cryostat section staining, teased fiber preparations, electron microscopy and molecular genetic analyses are potentially useful additional methods in a subset of cases. Being performed, processed and read by experienced physicians and technicians nerve biopsies can provide important information relevant for clinical management.


Outbreak of Campylobacteriosis Associated with Raccoon Contact at a Wildlife Rehabilitation Centre, Minnesota, 2013.
Campylobacteriosis is an enteric illness caused by bacteria of the genus Campylobacter. There are approximately 900 culture-confirmed cases of campylobacteriosis reported annually to the Minnesota Department of Health (MDH). Case patients are interviewed about risk factors, including foods eaten, recreational and drinking water exposures and animal contact. In September 2013, MDH identified two Campylobacter jejuni cases who reported working at the same wildlife rehabilitation centre before illness onset. This report describes the investigation, which used a case-control study design, and identified 16 additional ill persons, for a total of 18 ill persons. Both cases and controls reported working with a variety of animals, including squirrels, chipmunks, mice, raccoons, opossums, rabbits, songbirds, waterfowl and reptiles. In univariate analyses, contact with a number of different animal species was significantly associated with illness, including raccoons (odds ratio [OR], 11.1; P < 0.001), chipmunks (OR, 3.65; P = 0.01), opossums (OR, 4.38; P = 0.005), mice (OR, 4.18; P = 0.01) and rabbits (OR, 4.36; P = 0.003). In a multivariate model, contact with raccoons was the only exposure independently associated with illness (adjusted OR, 12.2; P = 0.01). Bacterial culture and subtyping of the outbreak strain of C. jejuni from raccoon faecal samples further implicated raccoons as the source of the outbreak. Not all of the cases reported handling raccoons, suggesting that environmental contamination contributed to transmission. MDH worked with the wildlife rehabilitation centre's management to strengthen biosecurity and infection control protocols.


Posttranslational regulation of self-renewal capacity: insights from proteome and phosphoproteome analyses of stem cell leukemia.
We recently generated 2 phenotypically similar Hoxa9+Meis1 overexpressing acute myeloid leukemias that differ by their in vivo biologic behavior. The first leukemia, named FLA2, shows a high frequency of leukemia stem cells (LSCs; 1 in 1.4 cells), whereas the second, FLB1, is more typical with a frequency of LSCs in the range of 1 per several hundred cells. To gain insights into possible mechanisms that determine LSC self-renewal, we profiled and compared the abundance of nuclear and cytoplasmic proteins and phosphoproteins from these leukemias using quantitative proteomics. These analyses revealed differences in proteins associated with stem cell fate, including a hyperactive p38 MAP kinase in FLB1 and a differentially localized Polycomb group protein Ezh2, which is mostly nuclear in FLA2 and predominantly cytoplasmic in FLB1. Together, these newly documented proteomes and phosphoproteomes represent a unique resource with more than 440 differentially expressed proteins and 11 543 unique phosphopeptides, of which 80% are novel and 7% preferentially phosphorylated in the stem cell-enriched leukemia.


All over or overall - Do we understand allostery?
Allostery is probably the most important concept in the regulation of cellular processes. Models to explain allostery are plenty. Each sheds light on different aspects but their entirety conveys an ambiguous feeling of comprehension and disappointment. Here, I discuss the most popular allostery models, their roots, similarities, and limitations. All of them are thermodynamic models. Naturally this bears a certain degree of redundancy, which forms the center of this review. After sixty years, many questions remain unanswered, mainly because our human longing for causality as base for understanding is not satisfied by thermodynamics alone. A description of allostery in terms of pathways, i.e., as a temporal chain of events, has been-, and still is-, a missing piece of the puzzle.


Histamine H(2) receptor activated chloride conductance in myenteric neurons from guinea pig small intestine.
Whole cell perforated patch-clamp methods were used to investigate ionic mechanisms underlying histamine-evoked excitatory responses in small intestinal AH-type myenteric neurons. When physiological concentrations of Na(+), Ca(2+), and Cl(-) were in the bathing medium, application of histamine significantly increased total conductance as determined by stepping to 50 mV from a holding potential of -30 mV. The current reversed at a membrane potential of -30 +/- 5 (SE) mV and current-voltage relations exhibited outward rectification. The reversal potential for the histamine-activated current was unchanged by removal of Na(+) and Ca(2+) from the bathing medium. Reduction of Cl(-) from 155 mM to 55 mM suppressed the current when the neurons were in solutions with depleted Na(+) and Ca(2+). Current-voltage curves in solutions with reduced Cl(-) were linear and the reversal potential was changed from -30 +/- 5 mV to 7 +/- 4 mV. Niflumic acid, but not anthracene-9-carboxylic acid (9-AC) nor 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), suppressed the histamine-activated current. A membrane permeable analogue of cAMP evoked currents similar to those activated by histamine. A selective histamine H(2) receptor agonist (dimaprit) mimicked the action of histamine and a selective histamine H(2) receptor antagonist (cimetidine) blocked the conductance increase evoked by histamine. A selective adenosine A(1) receptor agonist (CCPA) reduced the histamine-activated current and a selective adenosine A(1) receptor antagonist (CPT) reversed the inhibitory action. The results suggest that histamine acts at histamine H(2) receptors to increase Cl(-) conductance in AH-type enteric neurons. Cyclic AMP appears to be a second messenger in the signal transduction process. Results with a selective adenosine A(1) receptor agonist and antagonist add to existing evidence for co-coupling of inhibitory adenosine A(1) receptors and histamine H(2) receptors to adenylate cyclase in AH-type enteric neurons.


All-optical switching of silicon disk resonator based on photothermal effect in metal-insulator-metal absorber.
Efficient narrowband light absorption by a metal-insulator-metal (MIM) structure can lead to high-speed light-to-heat conversion at a micro- or nanoscale. Such a MIM structure can serve as a heater for achieving all-optical light control based on the thermo-optical (TO) effect. Here we experimentally fabricated and characterized a novel all-optical switch based on a silicon microdisk integrated with a MIM light absorber. Direct integration of the absorber on top of the microdisk reduces the thermal capacity of the whole device, leading to high-speed TO switching of the microdisk resonance. The measurement result exhibits a rise time of 2.0 μs and a fall time of 2.6 μs with switching power as low as 0.5 mW; the product of switching power and response time is only about 1.3 mW·μs. Since no auxiliary elements are required for the heater, the switch is structurally compact, and its fabrication is rather easy. The device potentially can be deployed for new kinds of all-optical applications.


Effective colostomy irrigation.
The ultimate goal of the cone method of colostomy irrigation is to return patients with colostomies to their former role in society with confidence in themselves to the extent that having a colostomy is not considered a handicap. The results have generally been excellent. We believe all patients with stomas should be afforded the opportunity to attempt colostomy irrigation.


Knowledge, Attitudes, Beliefs, and Practices Regarding Dengue in La Réunion Island, France.
Since 2017, La Réunion island has been facing a major epidemic of dengue. Despite actions carried out by the anti-vector control department, public authorities have failed to contain this epidemic. As individual involvement is key to success in vector control, we carried out a mixed-methods study on population knowledge, attitudes, beliefs, and practices (KABP) regarding dengue infection risk in La Réunion. The study combined quantitative data collected through a questionnaire administered to a representative sample of 622 people to assess the use of protective measures and the perception of severity and risk of dengue, and a sample of 336 people to assess the level of knowledge and concern about dengue, as well as qualitative data collected through semi-structured interviews among 11 individuals who had previously completed the questionnaire. The study results show that 63% of the surveyed population had a good level of knowledge associated with age, education, and socio-professional category variables-78% considered dengue to be a serious threat, and concern was estimated at 6/10, while 71% were likely to use protective measures. The interviews revealed contradictory behaviors in the implementation of recommended actions, in conflict with personal beliefs regarding respect of human body and nature. The study also revealed a loss of confidence in public authorities.


Using life-history information to assess potential effects of shrimp trawling on small fishes.
The current study presents information on size distributions, size at recruitment to the fishery, size at maturity and patterns of reproduction for several small benthic fishes caught as by-catch in the southern Gulf of California (Mexico) shrimp trawl fishery: sand perch Diplectrum spp., lumptail searobin Prionotus stephanophrys, bigscale goatfish Pseudupeneus grandisquamis and silver stardrum Stellifer illecebrosus. Pseudupeneus grandisquamis, P. stephanophrys and S. illecebrosus populations were all sexually dimorphic in size. Total-length (L(T))-based analyses did not provide reliable information on survival and growth. The majority of sampled P. grandisquamis and S. illecebrosus were caught before reproductive maturity, whereas the majority of Diplectrum spp. and almost all P. stephanophrys were mature when caught. L(T) at 50% gear retention (L(Tc), mm) v. 50% maturity (L(Tm), mm): Diplectrum spp. 124.53 v. 131.43; P. grandisquamis 90.98 v. 135.20; S. illecebrosus 82.55 v. 137.30. L(Tc) for P. stephanophrys was 104.73, but L(Tm) could not be modelled for this species as almost all captured individuals were mature. Diplectrum spp., P. grandisquamis and S. illecebrosus were indeterminate spawners, whereas P. stephanophrys appeared to be a determinate spawner. Sex ratios were equal for each of the gonochoristic species. In general, the gonado-somatic index (I(G)) increased with increasing L(T) for all except P. stephanophrys, where I(G) decreased with increasing L(T) for both males and females. Mature individuals of all taxa were found throughout the sampling period (September to March), and I(G) increased with sample day for all except females of P. grandisquamis. The current data suggest the potential for fishery effects on sampled populations of P. grandisquamis and S. illecebrosus.


A totally implantable drug infusion defice: laboratory and clinical experience using a model with single flow rate and new design for modulated insulin infusion.
The Infusaid implantable infusion pump with a single delivery rate has maintained chronic intravenous heparin infusion in man for greater than 35 mo and for greater than 5 yr in the dog. Intra-arterial infuson of fluorodeoxyuridine has been maintained for greater than 8 mo in man. In a pilot study using a commercially available, transcutaneously controllable, magnetically activated valve for baseline superimposed bolus insulin infusion, the feasibility of maintaining near normal serum glucose in diabetic dogs was demonstrated. The effect of long-term intravenous cannulation was investigated; it was found that the intimal tissues of the vena cava surrounding the cannulae were largely unaltered and microemboli could not be detected in the lungs of the animals studied. Cannula plugging, which occurred on several occasions due to thrombus formation in the final centimeter of the cannula, has been solved by changes in pump design and refilling procedures. The problem of insulin precipitation in flow passages of the pump remains unsolved, but there are indications that substances entering the cannula from the blood may be involved. A new pump design for modulated insulin infusion is described.


The role of natural selection in the origin of life.
It is commonly accepted among origin-of-life scientists that the emergence of life was an evolutionary process involving at one stage or other the working of natural selection. Researchers disagree, however, on the nature of the chemical infrastructure that could have formed prebiotically, enabling the evolutionary process. The division of the origin-of-life research community into 'geneticists' and 'metabolists' usually revolves around the issue whether the first to arise prebiotically was a genetic polymer or a primitive metabolic system. In this paper I offer an alternative classification based on the attitude to the onset of natural selection. From this perspective I add to the conventional division between gene-first and metabolism-first groups a position I call "preparatory metabolism". By this line of thought, an RNA or an RNA-like polymer could not have emerged prebiotically. Nevertheless, the onset of natural selection had to wait until such a polymer had arised. This paper examines the RNA-first, RNA-later, metabolism-first and preparatory-metabolism scenarios, assessing the weaknesses and strengths of each. I conclude that despite the recent theoretical advances in all these lines of research, and despite experimental breakthroughs, especially in overcoming several RNA-first hurdles, none of the examined paradigms has yet attained decisive experimental support. Demonstrating the evolvability of a potentially prebiotic infrastructure, whether genetic or metabolic, is a most serious challenge. So is the experimental demonstration of the emergence of such an infrastructure under prebiotic conditions. The current agenda before origin-of-life researchers of all stripes and colors is the search for the experimental means to tackle all these difficulties.


Maximizing response: a case report of salvage chemotherapy after immune checkpoint inhibition in a patient with previous chemo-refractory metastatic esophageal carcinoma.
Esophageal carcinoma is an aggressive malignancy and outcomes remain poor. Immune checkpoint inhibitors are a standard-of-care in the third-line and beyond settings, although benefit is modest. Herein, we report the case of a patient who achieved a partial response to salvage chemotherapy following treatment with an immune checkpoint inhibitor despite having chemo-refractory disease. A 41-year-old male, with a history of Crohn's disease, was diagnosed with Her2-positive metastatic esophageal adenocarcinoma to lungs and lymph nodes. The patient received multiple lines of systemic therapy including: first-line modified DCF (docetaxel/cisplatin/5-fluorouracil) with trastuzumab, second-line trastuzumab/afatinib on a clinical study, third-line carboplatin/irinotecan/ramucirumab and fourth-line treatment with a Her2 antibody-drug conjugate, DS-8201A, on a phase I study. While the patient was not a candidate for clinical trials evaluating immune checkpoint inhibitors due to his history of Crohn's disease, the latter was well controlled. Thus, the patient commenced pembrolizumab as fifth-line of treatment 2 years since diagnosis. After 3 cycles of therapy, the patient developed grade 3 immune-related colitis and treatment was discontinued. The patient maintained a good performance status and commenced a sixth-line of carboplatin/irinotecan/ramucirumab. Subsequent imaging demonstrated a partial response which was maintained over a 6-month period. This case demonstrates a response to previously administered chemotherapy following immune checkpoint inhibitor therapy, despite prior progression on this chemotherapy regimen. To our knowledge, this has not been previously reported in esophagogastric carcinoma (EGC). Post-immune checkpoint inhibitor chemotherapy may be a feasible treatment strategy. Research is needed to evaluate the role of post-immune checkpoint inhibitor chemotherapy in patients with metastatic EGC.


Large lessons learned from small vessels: coronary microvascular dysfunction in HIV.
Large cohort studies have consistently shown the presence of heart failure is approximately doubled among persons with HIV (PWH). Early studies of cardiovascular disease (CVD) in HIV were primarily focused on atherosclerotic burden, and we now have a greater understanding of large vessel disease in HIV. More recent studies have begun to inform us about small vessel disease, or coronary microvascular dysfunction (CMD), in HIV. CMD is recognized to be an important risk factor for adverse events related to heart failure, associated with cardiovascular mortality, and often presents without overt atherosclerotic disease. In this review, we highlight implications for CMD and relevant clinical studies in HIV. Inflammation and endothelial dysfunction, well known risk factors in HIV, may mediate the pathogenesis of CMD. Initial studies suggest that CMD worsens with ART initiation. Newer studies reveal CMD is present among well treated PWH without known CVD. In addition, myocardial flow reserve (MFR), a marker of CMD, is reduced in HIV similar to diabetes. There also appears to be sex differences, such that CMD is worse among women vs. men with HIV. Alterations in the coronary microvasculature may be an important mediator of subclinical myocardial dysfunction that deserves further clinical attention among PWH without known CVD.


A Review on AA 6061 Metal Matrix Composites Produced by Stir Casting.
In recent years, many alloys as well as composites of aluminium were developed for enhanced material performance. AA 6061 is an aluminium alloy that has extensive applications due to its superior material characteristics. It is a popular choice of matrix for aluminium matrix composite (AMC) fabrication. This study provides a review on AA 6061 aluminium alloy matrix composites produced through the stir-casting process. It focusses on conventional stir-casting fabrication, process parameters, various reinforcements used, and the mechanical properties of the AA 6061 composites. Several research studies indicated that the stir-casting method is widely used and suitable for fabricating AA 6061 composites with reinforcements such as SiC, B4C, Al2O3, TiC, as well as other inorganic, organic, hybrid, and nanomaterials. The majority of the studies showed that an increase in the reinforcement content enhanced the mechanical and tribological properties of the composites. Furthermore, hybrid composites showed better material properties than single reinforcement composites. The usage of industrial and agricultural residues in hybrid composites is also reported. Future studies could focus on the fabrication of AA 6061 nanocomposites through stir casting and their material characterisation, since they have great potential as advanced materials.


Effectiveness of two rotary instrumentation techniques for cleaning the root canal.
An in vitro study was undertaken to compare the efficiency of two rotary endodontic devices for cleaning the root canal wall(s). Only mesial roots of mandibular first molar were used. Forty roots were classified into two equal groups. Group (I) was instrumented using the Canal Finder system, Group (II) was instrumented using Nickel Titanium files. In both groups half of the specimens received a final flush of 17% EDTA and 5.25% NaOCl solutions. Roots were sectioned longitudinally and Scanning Electron Micrographs were taken at three levels (Coronal, Middle and Apical) of each section of the prepared roots. Statistical analysis of the results showed that the Canal Finder system produced a clean canal surface when 17% EDTA and 5.25% NaOCL were used as an irrigating solutions, while Nickel Titanium files had a superior cleaning efficiency than the Canal Finder with either irrigating solution.


Effect of hindlimb unloading on rat soleus fiber force, stiffness, and calcium sensitivity.
The purpose of this study was to examine the time course of change in soleus muscle fiber peak force (N), tension (Po, kN/m2), elastic modulus (Eo), and force-pCa and stiffness-pCa relationships. After 1, 2, or 3 wk of hindlimb unloading (HU), single fibers were isolated and placed between a motor arm and a transducer, and fiber diameter, peak absolute force, Po, Eo, and force-pCa and stiffness-pCa relationships were characterized. One week of HU resulted in a significant reduction in fiber diameter (68 +/- 2 vs 57 +/- 1 microns), force (3.59 +/- 0.15 vs. 2.19 +/- 0.12 x 10(-4) N), Po (102 +/- 4 vs. 85 +/- 2 kN/m2), and Eo (1.96 +/- 0.12 vs. 1.37 +/- 0.13 x 10(7) N/m2), and 2 wk of HU caused a further decline in fiber diameter (45 +/- 1 microns), force (1.31 +/- 0.06 x 10(-4) N), and Eo (0.96 +/- 0.09 x 10(7) N/m2). Although the mean fiber diameter and absolute force continued to decline through 3 wk of HU, Po recovered to values not significantly different from control. The Po/Eo ratio was significantly increased after 1 (5.5 +/- 0.3 to 7.1 +/- 0.6), 2, and 3 wk of HU, and the 2-wk (9.5 +/- 0.4) and 3-wk (9.4 +/- 0.8) values were significantly greater than the 1-wk values. The force-pCa and stiffness-pCa curves were shifted rightward after 1, 2, and 3 wk of HU. At 1 wk of HU, the Ca2+ sensitivity of isometric force, assessed by Ca2+ concentration required for half-maximal force, was increased from the control value of 1.83 +/- 0.12 to 2.30 +/- 0.10 microM. In conclusion, after HU, the decrease in soleus fiber Po can be explained by a reduction in the number of myofibrillar cross bridges per cross-sectional area. Our working hypothesis is that the loss of contractile protein reduces the number of cross bridges per cross-sectional area and increases the filament lattice spacing. The increased spacing reduces cross-bridge force and stiffness, but Po/Eo increases because of a quantitatively greater effect on stiffness.


[Electron microscopic diagnosis of human synovial tumors].
The present study was aimed at the analysis of the ultrastructure of synovial tissue tumors and the determination of a set of signs of synovial differentiation for electron microscopic diagnosis of these neoplasias. Three benign giant cell synoviomas and 10 synovial sarcomas of different structures were studied. The results showed both benign and malignant synoviomas to have similar signs of synovial differentiation: cellular (signs of A- and B-cells of normal synovial membrane) and tissue signs (specific intercellular cavities). In benign synoviomas cellular signs are more marked, in malignant tumors tissue signs are more manifest but the detection of histioid and epithelioid components in the latter at the electron microscopic level has no principal significance. A hypothesis that A- and B-cells in synovial tumors and normal synovial membrane represent the same cellular form (synoviocyte) in different functional stages is discussed.