Identification of a gC1q-binding protein (gC1q-R) on the surface of human neutrophils. Subcellular localization and binding properties in comparison with the cC1q-R.
Human neutrophils have multiple C1q-binding proteins. Direct ligand-binding studies with the globular domain of C1q and two-dimensional Western blot analysis revealed two gC1q-binding proteins (gC1q-R): a 33,000 M(r) protein (pI 4.5) mainly in the neutrophil plasma membrane and an 80,000-90,000 M(r) protein (pI 4.1-4.2) located mainly in the granules. Direct binding studies showed that C1q bound to this higher molecular weight protein under physiological conditions. In contrast, anti-cC1q-R antibody, which recognizes a protein binding to collagenous tails of C1q, detected only a 68,000 M(r) protein in the plasma membrane. Both the 33,000 and 68,000 M(r) receptors appear early on the surface of differentiating HL-60 cells. On mature neutrophils, surface expression of both C1q receptors was evident, but no upregulation was observed upon stimulation. Phorbol myristate acetate treatment of neutrophils downregulated both the receptors from cell surface, and significant amounts of soluble gC1q-R were in cell media supernatants, suggesting receptor shedding or secretion. gC1q-R, unlike cC1q-R, did not bind to other C1q-like ligands, namely mannose binding protein, surfactant protein-A, surfactant protein-D, or conglutinin under normal ionic conditions, suggesting a greater specificity for C1q than the "collectin" type receptor (cC1q-R). Rather, gC1q-R only bound purified C1q, and the binding was enhanced under low ionic conditions and in the absence of calcium. The role of C1q receptor shedding and its biologic consequence remain to be defined, but may contribute to the diversity of C1q-mediated responses observed in many cell types.


Succinyl-κ-carrageenan Silver Nanotriangles Composite for Ammonium Localized Surface Plasmon Resonance Sensor.
This research investigates the physicochemical properties of biopolymer succinyl-κ-carrageenan as a potential sensing material for NH4+ Localized Surface Plasmon Resonance (LSPR) sensor. Succinyl-κ-carrageenan was synthesised by reacting κ-carrageenan with succinic anhydride. FESEM analysis shows succinyl-κ-carrageenan has an even and featureless topology compared to its pristine form. Succinyl-κ-carrageenan was composited with silver nanoparticles (AgNP) as LSPR sensing material. AFM analysis shows that AgNP-Succinyl-κ-carrageenan was rougher than AgNP-Succinyl-κ-carrageenan, indicating an increase in density of electronegative atom from oxygen compared to pristine κ-carrageenan. The sensitivity of AgNP-Succinyl-κ-carrageenan LSPR is higher than AgNP-κ-carrageenan LSPR. The reported LOD and LOQ of AgNP-Succinyl-κ-carrageenan LSPR are 0.5964 and 2.7192 ppm, respectively. Thus, AgNP-Succinyl-κ-carrageenan LSPR has a higher performance than AgNP-κ-carrageenan LSPR, broader detection range than the conventional method and high selectivity toward NH4+. Interaction mechanism studies show the adsorption of NH4+ on κ-carrageenan and succinyl-κ-carrageenan were through multilayer and chemisorption process that follows Freundlich and pseudo-second-order kinetic model.


Small carcinomas of the thyroid. A long-term follow-up of 867 patients.
To determine the adequate extent of surgery for small carcinomas of the thyroid. Retrospective cohort study of 867 consecutive patients with small carcinomas of the thyroid (lesions < 10 mm in diameter) who were operated on at the Noguchi Thyroid Clinic, Oita, Japan, between 1965 and 1987. Mean follow-up was 12.8 years. A center for treatment of thyroid disease, where about 1400 thyroid operations are performed per year. Thyroidectomy was performed in patients with a preoperative diagnosis of Graves' disease, Graves' disease with nodules, solitary thyroid nodules, multinodular goiters, cysts, chronic thyroiditis and small carcinomas of the thyroid, in 394, 22, 136, 193, 18, 28, and 76 patients, respectively. Operations were conservative. Three patients who had adenomatous nodular goiters underwent total thyroidectomy. Modified radical neck dissection was performed in 66 patients. Of these 66 patients, 30 had grossly noticeable nodal metastases and 17 had microscopic metastases. Another 50 patients underwent selective lymph node excision, and 28 patients had nodal metastases. Recurrence from remnants of thyroid was seen in five patients. They were treated by surgery. Recurrence in lymph nodes was observed in five patients, and four of them were successfully treated. Recurrence in bone was observed in two patients; one with recurrence in the femur was successfully treated. Two patients died with recurrent cancer. Small carcinomas of the thyroid can be fatal. Total thyroidectomy is unnecessary. Modified radical neck dissection is unnecessary unless gross nodal metastases are present. Long-term follow-up is mandatory. A


Effect of a high-fat diet on food intake and hypothalamic neuropeptide gene expression in streptozotocin diabetes.
Insulin-deficient diabetic rats are markedly hyperphagic when fed a high-carbohydrate (HC) diet, but normophagic when fed a high-fat (HF) diet. When maintained on a HC diet, diabetic rats also exhibit increased gene expression of the orexigenic peptide neuropeptide Y (NPY) in the hypothalamic arcuate nucleus, and reduced expression of the anorectic peptide corticotropin-releasing hormone (CRH) in the paraventricular nucleus, and these changes are hypothesized to contribute to diabetic hyperphagia. In this experiment we assessed whether the normophagia displayed by HF-fed diabetic rats is associated with the opposite profile of NPY and CRH expression. Our results show that relative to diabetic rats on the HC diet, the diabetic rats on the HF diet exhibited significantly reduced caloric intake (-40%), NPY expression in the arcuate nucleus (-27%), and elevated CRH expression in the paraventricular nucleus (+37%). Insulin and corticosterone, which are known to affect hypothalamic NPY and CRH expression, were not different between these two groups, making it unlikely that they can account for the differences in either feeding behavior or hypothalamic peptide expression. There was a small but significant increase in plasma leptin levels in the diabetic animals maintained on the HF, and large differences in parameters associated with elevated fat oxidation. These observations support the hypothesis that the normalization of food intake observed in diabetic rats consuming a HF diet may in part be mediated by reductions in NPY expression and elevations in CRH expression.


The profound effects of patient arm positioning on organ doses from CT procedures calculated using Monte Carlo simulations and deformable phantoms.
The purpose of this study was to evaluate the organ dose differences caused by the arms-raised and arms-lowered postures for multidetector computed tomography procedures. Organ doses were calculated using computational phantoms and Monte Carlo simulations. The arm position in two previously developed adult male and female human phantoms was adjusted to represent 'raised' and 'lowered' postures using advanced BREP-based mesh surface geometries. Organ doses from routine computed tomography (CT) scan protocols, including the chest, abdomen-pelvis, and chest-abdomen-pelvis scans, were simulated at various tube voltages and reported in the unit of mGy per 100 mAs. The CT scanner model was based on previously tested work. The differences in organ dose per unit tube current between raised and lowered arm postures were studied. Furthermore, the differences due to the tube current modulation (TCM) for these two different postures and their impact on organ doses were also investigated. For a given scan parameter, a patient having lowered arms received smaller doses to organs located within the chest, abdomen or pelvis when compared with the patient having raised arms. As expected, this is caused by the attenuation of the primary X rays by the arms. However, the skin doses and bone surface doses in the patient having lowered arms were found to be 3.97-32.12% larger than those in a patient having raised arms due to the fact that more skin and spongiosa were covered in the scan range when the arms are lowered. This study also found that dose differences become smaller with the increase in tube voltage for most of organs or tissues except the skin. For example, the liver dose differences decreased from -15.01 to -11.33% whereas the skin dose differences increased from 21.53 to 25.24% with tube voltage increased from 80 to 140 kVp. With TCM applied, the organ doses of all the listed organs in patient having lowered arms are larger due to the additional tube current necessary to overcome the presence of the arms while maintaining sufficient image quality Arm position affects the dose to internal organs from CT scans by as much as 25.3%. The presence of arms in the scan range results in a dose increase for the skin and bone surface, but a dose decrease for organs located in the torso. Considering the use of TCM, which is common in many clinics, the patient having lowered arms may receive 50% higher radiation dose to most of the organs because of the increased tube current. The use of higher tube voltage might narrow such dose differences between patients of these two postures due to the greater penetration of higher-energy X rays. Therefore, when calculating or reporting patient doses from CT scans, it is prudent to select an appropriate phantom that accurately represents the patient posture.


Ketogenic diet improves and restores redox status and biochemical indices in monosodium glutamate-induced rat testicular toxicity.
This study investigated the effect of ketogenic diet on monosodium glutamate (MSG)-induced testicular dysfunction. Forty-six male rats (180 ± 40 g) were grouped into two groups (23 rats each); control group and MSG-induced group (4 mg/kg bw) for 28 days. At the 29th day, 5 rats from both group were sacrificed to establish testicular dysfunction. The remaining animals from the control group was further divided into three sub-groups and treated for 42 days; untreated group, ketogenic diet only and curcumin only as the standard drug (150 mg/kg bw). In the pre-treatment, the administration of MSG resulted in a significant (p < 0.05) decrease in the testis-body weight ratio, alkaline phosphatase (ALP), acetylcholine esterase (AChE), cholesterol, triglycerides (TG), nitric oxide (NO), glycogen, protein and antioxidant enzymes in the testis. In the post treatment, the MSG only group significantly reduced testicular cholesterol, catalase (CAT) and NO. In contrast, MSG + ketogenic diet group showed a significant increase in levels of rat testicular acid phosphatase (ACP), ALP, cholesterol, HMG-CoA, TG, malondialdehyde (MDA), reduced glutathione (GSH) and NO. The ketogenic diet showed a significant increase (p < 0.05) in the levels of NO, ALP, cholesterol, HMG CoA reductase and (TG). In addition, significant increases in levels of rat testicular ACP, ALP, HMG-CoA, (CAT), SOD and GSH were recorded for MSG + Curcumin group. Taken together, the findings support the prospects of ketogenic diet to enhance the testicular function in rats.


A Novel Polyaminocarboxylate Compound To Treat Murine Pulmonary Aspergillosis by Interfering with Zinc Metabolism.
Aspergillus fumigatus can cause pulmonary aspergillosis in immunocompromised patients and is associated with a high mortality rate due to a lack of reliable treatment options. This opportunistic pathogen requires zinc in order to grow and cause disease. Novel compounds that interfere with fungal zinc metabolism may therefore be of therapeutic interest. We screened chemical libraries containing 59,223 small molecules using a resazurin assay that compared their effects on an A. fumigatus wild-type strain grown under zinc-limiting conditions and on a zinc transporter knockout strain grown under zinc-replete conditions to identify compounds affecting zinc metabolism. After a first screen, 116 molecules were selected whose inhibitory effects on fungal growth were further tested by using luminescence assays and hyphal length measurements to confirm their activity, as well as by toxicity assays on HeLa cells and mice. Six compounds were selected following a rescreening, of which two were pyrazolones, two were porphyrins, and two were polyaminocarboxylates. All three groups showed good in vitro activity, but only one of the polyaminocarboxylates was able to significantly improve the survival of immunosuppressed mice suffering from pulmonary aspergillosis. This two-tier screening approach led us to the identification of a novel small molecule with in vivo fungicidal effects and low murine toxicity that may lead to the development of new treatment options for fungal infections by administration of this compound either as a monotherapy or as part of a combination therapy.


Excessive masturbation after epilepsy surgery.
Sexual behavior changes as well as depression, anxiety, and organic mood/personality disorders have been reported in temporal lobe epilepsy (TLE) patients before and after epilepsy surgery. The authors describe a 14-year-old girl with symptoms of excessive masturbation in inappropriate places, social withdrawal, irritability, aggressive behavior, and crying spells after selective amygdalohippocampectomy for medically intractable TLE with hippocampal sclerosis. Since the family members felt extremely embarrassed, they were upset and angry with the patient which, in turn, increased her depressive symptoms. Both her excessive masturbation behavior and depressive symptoms remitted within 2 months of psychoeducative intervention and treatment with citalopram 20mg/day. Excessive masturbation is proposed to be related to the psychosocial changes due to seizure-free status after surgery as well as other possible mechanisms such as Kluver-Bucy syndrome features and neurophysiologic changes associated with the cessation of epileptic discharges. This case demonstrates that psychiatric problems and sexual changes encountered after epilepsy surgery are possibly multifactorial and in adolescence hypersexuality may be manifested as excessive masturbation behavior.


Shape-directional growth of Pt and Pd nanoparticles.
The design and synthesis of shape-directed nanoscale noble metal particles have attracted much attention due to their enhanced catalytic properties and the opportunities to study fundamental aspects of nanoscale systems. As such, numerous methods have been developed to synthesize crystals with tunable shapes, sizes, and facets by adding foreign species that promote or restrict growth on specific sites. Many hypotheses regarding how and why certain species direct growth have been put forward, however there has been no consensus on a unifying mechanism of nanocrystal growth. Herein, we develop and demonstrate the capabilities of a mathematical growth model for predicting metal nanoparticle shapes by studying a well known procedure that employs AgNO3 to produce {111} faceted Pt nanocrystals. The insight gained about the role of auxiliary species is then utilized to predict the shape of Pd nanocrystals and to corroborate other shape-directing syntheses reported in literature. The fundamental understanding obtained herein by combining modeling with experimentation is a step toward computationally guided syntheses and, in principle, applicable to predictive design of the growth of crystalline solids at all length scales (nano to bulk).


Long-term safety and efficacy of tezepelumab in people with severe, uncontrolled asthma (DESTINATION): a randomised, placebo-controlled extension study.
Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin. The drug has been tested previously in the phase 3 NAVIGATOR (NCT03347279) and SOURCE (NCT03406078) studies, and was subsequently approved as a treatment for severe asthma. This extension study recruited from NAVIGATOR and SOURCE and aimed to evaluate the long-term safety and efficacy of tezepelumab in individuals with severe, uncontrolled asthma. DESTINATION was a phase 3, multicentre, randomised, double-blind, placebo-controlled, long-term extension study. The study was done across 182 sites (including hospitals, clinics, medical centres, clinical trial centres, and private practices) in 18 countries. Participants (aged 12-80 years) were required to have good treatment compliance in the parent study. Randomisation was stratified by the parent study and all participants were re-randomised. Those who were previously randomised to receive tezepelumab in either parent study continued treatment of subcutaneous tezepelumab (210 mg every 4 weeks); those who were previously randomised to receive placebo in either parent study were re-randomised 1:1 to receive either subcutaneous tezepelumab (210 mg every 4 weeks) or placebo (every 4 weeks) using a randomisation list prepared by a computerised system. Total treatment duration (including the parent studies) was 104 weeks for all groups. Participants, investigators, and site staff were masked to treatment assignment. The primary endpoints were exposure-adjusted incidence of adverse events and serious adverse events and the secondary endpoint was the annualised asthma exacerbation rate; these were assessed from week 0 of the parent studies to week 104 of DESTINATION in all participants who were randomised and who received at least one dose of tezepelumab or placebo in either of the parent studies. The trial is registered with ClinicalTrials.gov, NCT03706079, and is closed to new participants. Participants were recruited between Jan 7, 2019, and Oct 15, 2020. For individuals who initially received tezepelumab (n=528) in NAVIGATOR, incidence of adverse events over 104 weeks was 49·62 (95% CI 45·16 to 54·39) per 100 patient-years, compared with 62·66 (56·93 to 68·81) for those receiving placebo (n=531; difference -13·04, 95% CI -17·83 to -8·18). For serious adverse events, incidence was 7·85 (6·14 to 9·89) per 100 patient-years for individuals who initially received tezepelumab and 12·45 (9·97 to 15·35) for those who received placebo (difference -4·59, -7·69 to -1·65). In SOURCE, incidence of adverse events was 47·15 (36·06 to 60·56) per 100 patient-years for those who initially received tezepelumab (n=74) and 69·97 (54·54 to 88·40) for those who received placebo (n=76; difference -22·82, -34·77 to -10·01). For serious adverse events, incidence was 13·14 (7·65 to 21·04) per 100 patient-years for those who initially received tezepelumab and 17·99 (10·66 to 28·44) for those who received placebo (difference -4·85, -14·88 to 4·53). Tezepelumab reduced the annualised asthma exacerbation rate over 104 weeks compared with placebo. In participants initially from NAVIGATOR, the annualised asthma exacerbation rate ratio over 104 weeks was 0·42 (95% CI 0·35 to 0·51); in those initially from SOURCE, the ratio over 104 weeks was 0·61 (0·38 to 0·96). Tezepelumab treatment was well tolerated for up to 2 years and resulted in sustained, clinically meaningful reductions in asthma exacerbations in individuals with severe, uncontrolled asthma. These findings are consistent with previous randomised, placebo-controlled studies and show the long-term safety and sustained efficacy of tezepelumab in individuals with severe, uncontrolled asthma. AstraZeneca and Amgen.


A DNA polymerase with unusual properties from the slime mold Physarum polycephalum.
Two forms of a DNA polymerase have been purified from microplasmodia of Physarum polycephalum by poly(ethyleneimine) precipitation and chromatography on DEAE-Sephacel, phosphocellulose, heparin Sepharose, hydroxyapatite, DNA-agarose, blue-Sepharose. They were separated from DNA polymerase alpha on phosphocellulose and from each other on heparin-Sepharose. Form HS1 enzyme was 30-40% pure and form HS2 enzyme 60% with regard to protein contents of the preparations. Form HS2 enzyme was generated from form HS1 enzyme on prolonged standing of enzyme preparations. The DNA polymerases were obtained as complexes of a 60-kDa protein associated with either a 135-kDa (HS1) or a 110-kDa (HS2) DNA-polymerizing polypeptide in a 1:1 molar stoichiometry. The biochemical function of the 60-kDa protein remained unknown. The complexes tended to dissociate during gradient centrifugation and during partition chromatography as well as during polyacrylamide gradient gel electrophoresis under nondenaturing conditions at high dilutions of samples. Both forms existed in plasmodia extracts, their proportions depending on several factors including those which promoted proteolysis. The DNA polymerases resembled eucaryotic DNA polymerase beta by several criteria and were functionally indistinguishable from each other. It is suggested that lower eucaryotes contain repair DNA polymerases, which are similar to those of eubacteria on a molecular mass basis.


Approach to Rickets: Is It Calciopenic or Phosphopenic?
Rickets is a childhood disorder of decreased mineralization of bone tissue. It is either calciopenic or phosphopenic, according to the deficient mineral. Calcium, phosphate, and vitamin D metabolism should be known to understand the pathophysiology of rickets. A deficiency of calcium or vitamin D can be caused by several conditions. These conditions lead to defective osteoid mineralization, impaired chondrocyte differentiation, and apoptosis in the growth plate, resulting in clinical and radiological findings of rickets. Rickets developing as a result of vitamin D deficiency is the most frequently encountered form. Vitamin D-dependent rickets classification is made according to genetic abnormalities of enzymes that are involved in vitamin D metabolism. Phosphopenic rickets is divided mainly into 2 categories that are FGF23 related or not. A systemic approach that includes a detailed history, physical examination, and laboratory evaluation is required when performing a diagnostic evaluation. Vitamin D and calcium supplementation should be used to treat nutritional rickets. To prevent rickets and its morbidities, vitamin D prophylaxis in the newborn period is suggested. High dose of vitamin D3, 1.25(OH)2D, and calcium are treatment choices in vitamin D-dependent rickets according to its subgroup. If conventional treatment consisting of phosphate and calcitriol is ineffective in the treatment of phosphopenic rickets, Burosumab is the new treatment option.


Three-dimensional evaluation of mandibular canine impaction characteristics and their relationship with lower incisor root morphometry.
To three-dimensionally evaluate the characteristics of mandibular canine impaction with the morphometry of the roots of the lower incisors. Cone-beam computed tomography (CBCT) scans of 35 individuals (18 males and 17 females) with a mean age of 14.37± 10.26 years were evaluated. Forty-three impacted mandibular canines (IMbC) were evaluated. Their location, sector and level of impaction were determined. Likewise, the distances of the canines to the occlusal plane, the angulations with respect to the midline and adjacent lateral incisors, the length of the impacted canines, and of the lower incisors were measured. Finally, the presence of incisor root resorption was determined. Chi-square and Kruskal Wallis tests were employed (P<0.05). The buccal position of the IMbCs was the most predominant (65.1%), and the location below the apical middle third of the lower incisor root was the most frequent (32.6%). No statistical significance was found between root resorption and location, level and impaction sector. Only mild root resorption and impaction sector 5 was significant (66.70%; P<0.001). The proximity of the follicle and crown of the IMbC did not affect the root structure of the lower incisors. 72.1% and 52.2% of mandibular canines did not present contact of the impacted canine or its follicle with the adjacent tooth respectively. Root lengths were similar in the different types of impactions (P>0.05). IMbCs are mostly positioned buccally and below the apical middle third of the root of the lower incisors. Likewise, the proximity of their follicles and crowns does not seem to affect the root structure of the lower incisors, producing minimal and infrequent root resorption. Key words:Mandibular canine impaction, incisor root morphometry, cone-beam CT.


A new microvascular anastomosis technique using muscle graft.
A novel microvascular anastomosis technique is described. Forty-five male Sprague-Dawley rats were divided equally into three groups before undergoing femoral artery anastomosis. The first group received standard eight-suture anastomotic repair. Group 2 (muscle group) received three sutures plus autogenous muscle graft wrapped around the anastomosis. In group 3 (fascial surface group), a muscle graft was wrapped around the anastomosis with the fascial side of the graft facing the anastomosis. Significantly less time and suture usage were noted using both fascial surface and muscle groups compared with controls (p < 0.05). No significant difference regarding patency rates or aneurysm formation existed among the three groups (p > 0.05). Additionally, grade 2 anastomotic leakage was less frequent in the study groups compared with the control group (p < 0.05). This new microvascular anastomosis technique took less time and achieved better performance than standard anastomotic repair.


Macrophages modulate the viability and growth of human mesenchymal stem cells.
Following myocardial infarction, tissue repair is mediated by the recruitment of monocytes and their subsequent differentiation into macrophages. Recent findings have revealed the dynamic changes in the presence of polarized macrophages with pro-inflammatory (M1) and anti-inflammatory (M2) properties during the early (acute) and late (chronic) stages of cardiac ischemia. Mesenchymal stem cells (MSCs) delivered into the injured myocardium as reparative cells are subjected to the effects of polarized macrophages and the inflammatory milieu. The present study investigated how cytokines and polarized macrophages associated with pro-inflammatory (M1) and anti-inflammatory (M2) responses affect the survival of MSCs. Human MSCs were studied using an in vitro platform with individual and combined M1 and M2 cytokines: IL-1β, IL-6, TNF-α, and IFN-γ (for M1), and IL-10, TGF-β1, TGF-β3, and VEGF (for M2). In addition, polarization molecules (M1: LPS and IFN-γ; M2: IL-4 and IL-13) and common chemokines (SDF-1 and MCP-1) found during inflammation were also studied. Indirect and direct co-cultures were conducted using M1 and M2 polarized human THP-1 monocytes. M2 macrophages and their associated cytokines supported the growth of hMSCs, while M1 macrophages and their associated cytokines inhibited the growth of hMSCs in vitro under certain conditions. These data imply that an anti-inflammatory (M2) environment is more accommodating to the therapeutic hMSCs than a pro-inflammatory (M1) environment at specific concentrations.


The erythropoietin receptor is a downstream effector of Klotho-induced cytoprotection.
Although the role of the erythropoietin (EPO) receptor (EpoR) in erythropoiesis has been known for decades, its role in nonhematopoietic tissues is still not well defined. Klotho has been shown and EPo has been suggested to protect against acute ischemia-reperfusion injury in the kidney. Here we found in rat kidney and in a rat renal tubular epithelial cell line (NRK cells) EpoR transcript and antigen, and EpoR activity signified as EPo-induced phosphorylation of Jak2, ErK, Akt, and Stat5 indicating the presence of functional EpoR. Transgenic overexpression of Klotho or addition of exogenous recombinant Klotho increased kidney EpoR protein and transcript. In NRK cells, Klotho increased EpoR protein, enhanced EPo-triggered phosphorylation of Jak2 and Stat5, the nuclear translocation of phospho-Stat5, and protected NRK cells from hydrogen peroxide cytotoxicity. Knockdown of endogenous EpoR rendered NRK cells more vulnerable, and overexpression of EpoR more resistant to peroxide-induced cytotoxicity, indicating that EpoR mitigates oxidative damage. Knockdown of EpoR by siRNA abolished Epo-induced Jak2, and Stat5 phosphorylation, and blunted the protective effect of Klotho against peroxide-induced cytotoxicity. Thus in the kidney, EpoR and its activity are downstream effectors of Klotho enabling it to function as a cytoprotective protein against oxidative injury.


Heterochromatin polymorphism and physical mapping of 5S and 18S ribosomal DNA in four populations of Hypostomus strigaticeps (Regan, 1907) from the Paraná River basin, Brazil: evolutionary and environmental correlation.
A cytogenetic analysis was performed on four populations of Hypostomus strigaticeps from the Paraná River basin, Brazil. Two populations were collected from the large channel river at the Itaipu reservoir area and the other two were from the upper stretches of tributaries of the Paraná River. All populations showed 2n=72 chromosomes (12m+12sm+18st+30a), intra- and interpopulation 18S rDNA site polymorphisms (two to three acrocentric chromosome pairs), and multiple 5S rDNA sites in three chromosome pairs (4, 21, and 28). C-banding revealed heterochromatin located in the centromere and pericentromere regions of most chromosome; however, large heterochromatic blocks (CMA3(-)/DAPI(+)) on the long arm of acrocentric chromosomes identified intra- and interpopulation polymorphism. The amount and distribution of heterochromatin seem to be correlated to biogeographical characteristics of H. strigaticeps along the Paraná River. Morphometric results also showed diversity among the populations, suggesting phenotypic plasticity of this species. Evolutionary, taxonomy, and biogeographical approaches with regard to H. strigaticeps and interrelationships in Hypostomus are discussed.


Reconstitution of a thermophilic Cu+ importer in vitro reveals intrinsic high-affinity slow transport driving accumulation of an essential metal ion.
Acquisition of the trace element copper (Cu) is critical to drive essential eukaryotic processes such as oxidative phosphorylation, iron mobilization, peptide hormone biogenesis, and connective tissue maturation. The Ctr1/Ctr3 family of Cu importers, first discovered in fungi and conserved in mammals, are critical for Cu+ movement across the plasma membrane or mobilization from endosomal compartments. Whereas ablation of Ctr1 in mammals is embryonic lethal, and Ctr1 is critical for dietary Cu absorption, cardiac function, and systemic iron distribution, little is known about the intrinsic contribution of Ctr1 for Cu+ permeation through membranes or its mechanism of action. Here, we identify three members of a Cu+ importer family from the thermophilic fungus Chaetomium thermophilum: Ctr3a and Ctr3b, which function on the plasma membrane, and Ctr2, which likely functions in endosomal Cu mobilization. All three proteins drive Cu and isoelectronic silver (Ag) uptake in cells devoid of Cu+ importers. Transport activity depends on signature amino acid motifs that are conserved and essential for all Ctr1/3 transporters. Ctr3a is stable and amenable to purification and was incorporated into liposomes to reconstitute an in vitro Ag+ transport assay characterized by stopped-flow spectroscopy. Ctr3a has intrinsic high-affinity metal ion transport activity that closely reflects values determined in vivo, with slow turnover kinetics. Given structural models for mammalian Ctr1, Ctr3a likely functions as a low-efficiency Cu+ ion channel. The Ctr1/Ctr3 family may be tuned to import essential yet potentially toxic Cu+ ions at a slow rate to meet cellular needs, while minimizing labile intracellular Cu+ pools.


Diagnosis and Workup of Intellectual Disability in Adults: Suggested Strategies for the Adult Neurologist.
Etiologic investigations for adults with intellectual disability (ID) pose a special challenge to many adult neurologists. The adaptability of pediatric guidelines for workup of ID to adult populations has not been clearly established. We review the current recommendations on etiologic workup of ID in children and adults and provide initial guidance for adult neurologists who care for individuals with ID of unknown etiology. Etiologic workup, including genetic testing, is recommended in individuals with ID of unknown origin. Workup should be guided by a thoughtful history and physical examination, which can help identify certain causes of ID. Specific diagnoses may help guide management and surveillance of comorbid conditions in individuals with ID. Etiologic investigations of adults with ID include genetic and metabolic testing and brain imaging in the appropriate clinical setting.


Characterization of protein-protein interfaces.
We analyze the characteristics of protein-protein interfaces using the largest datasets available from the Protein Data Bank (PDB). We start with a comparison of interfaces with protein cores and non-interface surfaces. The results show that interfaces differ from protein cores and non-interface surfaces in residue composition, sequence entropy, and secondary structure. Since interfaces, protein cores, and non-interface surfaces have different solvent accessibilities, it is important to investigate whether the observed differences are due to the differences in solvent accessibility or differences in functionality. We separate out the effect of solvent accessibility by comparing interfaces with a set of residues having the same solvent accessibility as the interfaces. This strategy reveals residue distribution propensities that are not observable by comparing interfaces with protein cores and non-interface surfaces. Our conclusions are that there are larger numbers of hydrophobic residues, particularly aromatic residues, in interfaces, and the interactions apparently favored in interfaces include the opposite charge pairs and hydrophobic pairs. Surprisingly, Pro-Trp pairs are over represented in interfaces, presumably because of favorable geometries. The analysis is repeated using three datasets having different constraints on sequence similarity and structure quality. Consistent results are obtained across these datasets. We have also investigated separately the characteristics of heteromeric interfaces and homomeric interfaces.


Case Report: Anaplasmosis in Canada: Locally Acquired Anaplasma phagocytophilum Infection in Alberta.
Human granulocytic anaplasmosis is an obligate intra-granulocytic parasite that is transmitted by Ixodes scapularis and Ixodes pacificus in North America. We report on the second laboratory-confirmed case of Anaplasma phagocytophilum acquired within the province of Alberta, Canada. A 67-year-old woman from the Edmonton health zone developed nonspecific systemic symptoms including fatigue, night sweats, myalgia, headaches, and fever 6 days after noticing a tick on her left upper arm in May of 2017 (day 0). On day 13, she was found to have thrombocytopenia. Her symptoms progressed until day 16 when she was treated empirically with doxycycline, at which time she slowly improved over the subsequent 2 months. The tick was later identified as a partially engorged female blacklegged tick, I. scapularis, and it was positive for A. phagocytophilum DNA by PCR. Anaplasma serology performed retrospectively on blood samples collected on days 13, 31, and 52 showed a greater than 4-fold increase in A. phagocytophilum (IgG titers from less than 1:64 on day 13 to 1:2048 on days 31 and 52), consistent with an acute infection. Although populations of blacklegged ticks are not yet established in Alberta, suspicion should remain for tick-borne diseases because infected ticks are introduced into the province by migrating birds. This case report highlights the need to remind physicians and other public health professionals that rare, non-endemic tick-borne diseases can occasionally occur in low-risk jurisdictions.


Developmental differentiation of executive functions on the NIH Toolbox Cognition Battery.
The NIH Toolbox Cognition Battery (NTCB) is a brief computerized method for evaluating neuropsychological functions in children, adolescents, and adults. We examined how performance on the 2 executive function measures of cognitive flexibility and inhibitory control was related to performance on the other NTCB measures across development. Participants were 1,020 typically developing individuals between the ages of 3 and 21 from the Pediatric Imaging, Neurocognition, and Genetics Study who were divided into 5 age groups (3-6, 7-9, 10-13, 14-17, and 18-21). Scores were adjusted for sex, level of parental education, and family income. Although the correlations between the 2 executive function measures were moderate and consistent across age groups, their correlations with the other 5 cognitive measures were highest in the youngest age group and decreased across the older age groups. Exploratory factor analysis revealed that all NTCB measures loaded onto a single factor for the 3- to 6-year-olds. Across the older age groups, the executive function and processing speed measures loaded onto one factor, and the vocabulary knowledge, oral reading, and working memory measures loaded onto a second factor. These results indicate that younger children's performance on the NTCB is more intercorrelated and less differentiated, while performance on the NTCB executive function measures becomes more differentiated from performance on the other measures with development. These results support the hypothesis that executive functions become increasingly differentiated from other cognitive functions with development as the functional specialization of neural systems progresses throughout childhood and young adulthood. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Regulation of Gene Expression by Thyroid Hormone in Primary Astrocytes: Factors Influencing the Genomic Response.
Astrocytes mediate the action of thyroid hormone in the brain on other neural cells through the production of the active hormone triiodothyronine (T3) from its precursor thyroxine. T3 has also many effects on the astrocytes in vivo and in culture, but whether these actions are directly mediated by transcriptional regulation is not clear. In this work, we have analyzed the genomic response to T3 of cultured astrocytes isolated from the postnatal mouse cerebral cortex using RNA sequencing. Cultured astrocytes express relevant genes of thyroid hormone metabolism and action encoding type 2 deiodinase (Dio2), Mct8 transporter (Slc16a2), T3 receptors (Thra1 and Thrb), and nuclear corepressor (Ncor1) and coactivator (Ncoa1). T3 changed the expression of 668 genes (4.5% of expressed genes), of which 117 were responsive to T3 in the presence of cycloheximide. The Wnt and Notch pathways were downregulated at the posttranscriptional level. Comparison with the effect of T3 on astrocyte-enriched genes in mixed cerebrocortical cultures isolated from fetal cortex revealed that the response to T3 is influenced by the degree of astrocyte maturation and that, in agreement with its physiological effects, T3 promotes the transition between the fetal and adult patterns of gene expression.


Three unusual cases of parasites in eye.
A 17-year-old male patient presented with cellulitis and mass in the eye noticed approximately 3 months back. The mass was about 1 cm in size and situated at the limbus. All preoperative routine investigations were normal. Surgical exploration revealed a sub-conjunctival cystic mass near the lateral rectus muscle about 1 cm in diameter; the mass was excised. Gross pathological examination revealed a thin-walled cystic mass. There was a hard nodule in the center. Microscopy revealed a wall of cysticercosis. Scolex was also seen. Surrounding tissue revealed sparse acute and chronic inflammatory cells. The case was confirmed by CDC, Atlanta, and was also included in their departmental presentation as an interesting case. A 60-year-old lady presented with complaints of itching over the forehead and right eye for 5 days. She was prescribed steroid eyedrops and antihistaminics. The itching aggravated with eyedrops along with watering and foreign body sensation. On revisit, the ophthalmologist noticed a worm in the right upper subconjunctival space. The worm was carefully removed in toto and sent to the laboratory for identification. The worm was thin, cylindrical, 8-10 cm long and white in color. After microscopic and gross examination of the worm, it was identified as Dirofilaria spp. CDC (Atlanta) confirmed the diagnosis of Dirofilaria. The patient was treated with antihistaminics and was relieved of symptoms without recurrence. A 45-year-old male patient had a painless mass in the eye for the last 3 months. He had no systemic illness. He gave a history of swimming pool use during that time. The mass was excised and submitted for histopathology. Numerous globular cysts representing thick-walled sporangia containing numerous spores diagnostic of Rhinosporidiosis were seen.


Selective extinction through cognitive evaluation: Linking emotion regulation and extinction.
The extinction of a previously conditioned response can be modulated through cognitive processes, including feature-based information, and explicit instruction. Here, we introduce a selective extinction through cognitive evaluation (SECE) task in which information is cognitively evaluated on a trial-by-trial basis to ascertain the extinction contingencies. Participants were conditioned to expect an electric shock during the presentation of one of two letters (CS+/CS-). During the SECE task, the letters were presented within words belonging to two categories, one of which indicated safety (COG-_CS+ trials), while risk of shock was maintained for the other category (COG+_CS+ trials). Skin conductance responses indicated that participants reduced their response to COG-_CS+ trials compared to COG+_CS+ trials. Clusters in bilateral insula and anterior cingulate cortex showed activation for COG+_CS+ trials that was reduced for COG-_CS+ trials. A network of brain regions, including left inferior frontal gyrus, and bilateral temporal and parietal cortices showed greater activation for COG-_CS+ versus COG+_CS+ trials. This is consistent with the semantic processing and decision-making necessary to evaluate the trial contingencies. We compared activation in the SECE task to activation in a cognitive reappraisal task in which participants were asked to attend to, or regulate their emotional reactions to affective IAPS images. This task replicated prefrontal activation seen in previous reappraisal studies. A voxelwise conjunction analysis found no overlap between the cognitive reappraisal and the SECE task, but we did find evidence for common activation in follow-up ROI analyses, supporting the idea of common lateral prefrontal mechanisms involved in both processes.


In vivo Serial Passaging of Human-Simian Immunodeficiency Virus Clones Identifies Characteristics for Persistent Viral Replication.
We previously reported that a human immunodeficiency virus type 1 with a simian immunodeficiency virus vif substitution (HSIV-vifNL4-3) could replicate in pigtailed macaques (PTMs), demonstrating that Vif is a species-specific tropism factor of primate lentiviruses. However, infections did not result in high-peak viremia or setpoint plasma viral loads, as observed during simian immunodeficiency virus (SIV) infection of PTMs. Here, we characterized variants isolated from one of the original infected animals with CD4 depletion after nearly 4years of infection to identify determinants of increased replication fitness. In our studies, we found that the HSIV-vif clones did not express the HIV-1 Vpr protein due to interference from the vpx open reading frame (ORF) in singly spliced vpr mRNA. To examine whether these viral genes contribute to persistent viral replication, we generated infectious HSIV-vif clones expressing either the HIV-1 Vpr or SIV Vpx protein. And then to determine viral fitness determinants of HSIV-vif, we conducted three rounds of serial in vivo passaging in PTMs, starting with an initial inoculum containing a mixture of CXCR4-tropic [Vpr-HSIV-vifNL4-3 isolated at 196 (C/196) and 200 (C/200) weeks post-infection from a PTM with depressed CD4 counts] and CCR5-tropic HSIV (Vpr+ HSIV-vif derivatives based NL-AD8 and Bru-Yu2 and a Vpx expressing HSIV-vifYu2). Interestingly, all infected PTMs showed peak plasma viremia close to or above 105 copies/ml and persistent viral replication for more than 20weeks. Infectious molecular clones (IMCs) recovered from the passage 3 PTM (HSIV-P3 IMCs) included mutations required for HIV-1 Vpr expression and those mutations encoded by the CXCR4-tropic HSIV-vifNL4-3 isolate C/196. The data indicate that the viruses selected during long-term infection acquired HIV-1 Vpr expression, suggesting the importance of Vpr for in vivo pathogenesis. Further passaging of HSIV-P3 IMCs in vivo may generate pathogenic variants with higher replication capacity, which will be a valuable resource as challenge virus in vaccine and cure studies.


Pulmonary Hypertension in Adults with Congenital Heart Disease: Real-World Data from the International COMPERA-CHD Registry.
Pulmonary hypertension (PH) is a common complication in patients with congenital heart disease (CHD), aggravating the natural, post-operative, or post-interventional course of the underlying anomaly. The various CHDs differ substantially in characteristics, functionality, and clinical outcomes among each other and compared with other diseases with pulmonary hypertension. To describe current management strategies and outcomes for adults with PH in relation to different types of CHD based on real-world data. COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) is a prospective, international PH registry comprising, at the time of data analysis, >8200 patients with various forms of PH. Here, we analyzed a subgroup of 680 patients with PH due to CHD, who were included between 2007 and 2018 in 49 specialized centers for PH and/or CHD located in 11 European countries. At enrollment, the patients´ median age was 44 years (67% female), and patients had either pre-tricuspid shunts, post-tricuspid shunts, complex CHD, congenital left heart or aortic disease, or miscellaneous other types of CHD. Upon inclusion, targeted therapies for pulmonary arterial hypertension (PAH) included endothelin receptor antagonists, PDE-5 inhibitors, prostacyclin analogues, and soluble guanylate cyclase stimulators. Eighty patients with Eisenmenger syndrome were treatment-naïve. While at inclusion the primary PAH treatment for the cohort was monotherapy (70% of patients), with 30% of the patients on combination therapy, after a median observation time of 45.3 months, the number of patients on combination therapy had increased significantly, to 50%. The use of oral anticoagulants or antiplatelets was dependent on the underlying diagnosis or comorbidities. In the entire COMPERA-CHD cohort, after follow-up and receiving targeted PAH therapy (n = 511), 91 patients died over the course of a 5-year follow up. The 5-year Kaplan-Meier survival estimate for CHD associated PH was significantly better than that for idiopathic PAH (76% vs. 54%; p < 0.001). Within the CHD associated PH group, survival estimates differed particularly depending on the underlying diagnosis and treatment status. In COMPERA-CHD, the overall survival of patients with CHD associated PH was dependent on the underlying diagnosis and treatment status, but was significantly better as than that for idiopathic PAH. Nevertheless, overall survival of patients with PAH due to CHD was still markedly reduced compared with survival of patients with other types of CHD, despite an increasing number of patients on PAH-targeted combination therapy.


Prevalence and diagnostic distribution of medically unexplained painful somatic symptoms across 571 major depressed outpatients.
To assess the prevalence and distribution of medically unexplained painful somatic symptoms (PSSs) versus nonpainful somatic symptoms (NPSSs) in patients diagnosed with major depressive episode (MDE). A total of 571 outpatients diagnosed with MDE according to DSM-IV-TR criteria were consecutively enrolled into a cross-sectional, multicentric, observational study over a period of 7 months. Subjects were evaluated by means of the ad hoc validated 30-item Somatic Symptoms Checklist (SSCL-30) and Zung's questionnaires for depression and anxiety. The 32-item Hypomania Checklist (HCL-32) was also administered in order to explore any eventual association of PSSs or NPSSs with sub-threshold (DSM-IV-TR [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision] not recognized) bipolar disorder (BD). In our sample, just 183 patients (32%) did not report painful somatic symptoms (NPSSs). Of these, 90 patients (15.76%) had no somatic symptoms at all. The remaining 388 (68%) had at least one PSS being subdivided as follows: 248 (43%) had one or two PSSs, while 140 (25%) experienced two or more. Patients with at least one PSS also reported a greater number of nonpainful somatic symptoms than NPSS. Bipolar patients (associated with higher HCL-32 scores) were less represented across PSS cases than NPSS subjects. Conversely, females were more prone to having a higher number of total somatic symptoms (and bipolar features). PSSs are common in patients with MDE, especially among those patients reporting fewer somatic symptoms in general as opposed to those patients who exhibit more somatic symptoms (both PSSs and NPSSs) with lower relative number of PSSs. A major therapeutic implication is that antidepressant monotherapy could be used with more confidence in unexplained PSS patients than in NPSS patients because of the latter group's lower frequency of (sub)-threshold bipolar features.


Organizer and regulatory role of colonic isolated lymphoid follicles in inflammation.
Gut-associated lymphoid tissue (GALT) is supposed to play an integral role in the organization of colonic repair mechanisms. Majority of the GALT is composed of isolated and aggregated lymphoid follicles distributed throughout the intestines. These lymphoid follicles, including Peyer's patches of the small, and isolated lymphoid follicles (ILFs) of both the small and large intestines, are composed of a specialised follicle associated epithelium overlying a subepithelial dome containing numerous dendritic cells, macrophages, T and B cells. Within inflammatory conditions the number, the diameter and the density of ILFs are increasing. Follicles are involved not just in immune surveillance, but their presence is also indispensable for normal colonic mucosal regeneration. Regarding mucosal repair the relation of ILFs to bone marrow derived stem cells, follicular dendritic cells, subepithelial myofibroblasts and crypt formations, and the putative organizer role of ILFs have not been clarified yet.


Acute myocardial infarction being the presentation of dengue myocarditis.
Dengue fever is one of the most common vector-borne viral infections in tropical countries. Myocarditis is an uncommon complication of severe dengue fever. Sometimes, dengue myocarditis masquerades as acute myocardial infarction. We report here a case of a 22-year-old female, who presented with acute chest pain five days after the onset of a febrile episode. Initially she was diagnosed as acute myocardial infarction depending on the biochemical and echocardiography evidence. However, later investigation confirmed she was suffering from myocarditis due to dengue fever, which mimicked acute myocardial infarction. A Medline search revealed only few other reported cases of dengue myocarditis that mimicked of acute myocardial infarction.


Gain-of-function mutations in granulocyte colony-stimulating factor receptor (CSF3R) reveal distinct mechanisms of CSF3R activation.
Granulocyte colony-stimulating factor (G-CSF or CSF3) and its receptor CSF3R regulate granulopoiesis, neutrophil function, and hematopoietic stem cell mobilization. Recent studies have uncovered an oncogenic role of mutations in the CSF3R gene in many hematologic malignancies. To find additional CSF3R mutations that give rise to cell transformation, we performed a cellular transformation assay in which murine interleukin 3 (IL-3)-dependent Ba/F3 cells were transduced with WT CSF3R plasmid and screened for spontaneous growth in the absence of IL-3. Any outgrowth clones were sequenced to identify CSF3R mutations with transformation capacity. We identified several novel mutations and determined that they transform cells via four distinct mechanisms: 1) cysteine- and disulfide bond-mediated dimerization (S581C); 2) polar, noncharged amino acid substitution at the transmembrane helix dimer interface at residue Thr-640; 3) increased internalization by a Glu-524 substitution that mimics a low G-CSF dose; and 4) hydrophobic amino acid substitutions in the membrane-proximal residues Thr-612, Thr-615, and Thr-618. Furthermore, the change in signaling activation was related to an altered CSF3R localization. We also found that CSF3R-induced STAT3 and ERK activations require CSF3R internalization, whereas STAT5 activation occurred at the cell surface. Cumulatively, we have expanded the regions of the CSF3R extracellular and transmembrane domains in which missense mutations exhibit leukemogenic capacity and have further elucidated the mechanistic underpinnings that underlie altered CSF3R expression, dimerization, and signaling activation.


Effects of hypocaloric diet, low-intensity resistance exercise with slow movement, or both on aortic hemodynamics and muscle mass in obese postmenopausal women.
This study aims to examine the independent and combined impact of hypocaloric diet and low-intensity resistance exercise training (LIRET) on aortic hemodynamics and appendicular skeletal muscle mass (ASM) in obese postmenopausal women. Forty-one obese postmenopausal women (mean [SD] age, 54 [1] y) were randomly assigned to LIRET (n = 13), diet (n = 14), or diet + LIRET (n = 14). Body weight, waist circumference, aortic systolic blood pressure, aortic pulse pressure, augmentation index, subendocardial viability ratio (SEVR; myocardial perfusion), and heart rate (HR) were measured before and after 12 weeks. ASM was assessed by dual-energy x-ray absorptiometry. Body weight (P < 0.001) and waist circumference (P < 0.01) decreased similarly after diet and diet + LIRET compared with no changes after LIRET. ASM did not change after diet + LIRET, and the decrease observed after diet (P < 0.001) was significant compared with LIRET. Aortic systolic blood pressure decreased similarly after LIRET (P < 0.05), diet (P < 0.01), and diet + LIRET (P < 0.01). Aortic pulse pressure (P < 0.05) decreased similarly after diet and diet + LIRET, but not after LIRET. SEVR (P < 0.01) increased similarly in both diet groups, whereas HR (P < 0.01) decreased only after diet. Changes in SEVR (P < 0.05) and HR (P< 0.01) with diet were different compared with LIRET. The augmentation index did not change in any group. Our findings suggest that diet-induced weight loss may reduce cardiovascular risk by improving SEVR via HR and aortic pulse pressure reductions in obese postmenopausal women. LIRET prevents ASM loss associated with hypocaloric diet but has no additive effects on aortic hemodynamics.


Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: a randomized, double-blinded, placebo-controlled clinical trial. The Multiple Sclerosis Study Group.
Patients with clinically definite multiple sclerosis, mild to moderately severe neurological disability (entry score on the Expanded Disability Status Scale (EDSS) between 3.0 and 7.0), and a progressive course defined by an increase in the EDSS of between 1 and 3 grades in the year prior to entry were randomized to receive either cyclosporine (n = 273) or placebo (n = 274) in a 2-year, double-blinded, multicenter trial. Treatment groups at entry proved balanced for age, gender, duration of illness, and neurological disability. Cyclosporine dosage was adjusted for toxicity and a median trough whole-blood level was maintained between 310 and 430 ng/ml. The mean increase in EDSS score was 0.39 +/- 1.07 grades for cyclosporine-treated patients and 0.65 +/- 1.08 grades for placebo-treated patients from entry until the time of early withdrawal or completion of the study (p = 0.002). Of three primary efficacy criteria, cyclosporine delayed the time to becoming wheelchair bound (p = 0.038; relative risk, 0.765), but statistically significant effects were not observed for "time to sustained progression" or on a composite score of "activities of daily living." Active treatment did have a favorable effect on several secondary measures of disease outcome. A large and differential withdrawal rate (44% for cyclosporine-treated patients, 32% for placebo-treated patients) complicated the analysis but did not appear to explain the observed effect of cyclosporine in delaying disease progression. Multivariate analysis did not show institutional effects but did demonstrate substantial effects of baseline neurological disability on outcome. Nephrotoxicity and hypertension were common troublesome toxicities and accounted for most of the excess loss of patients in the cyclosporine arm of the study. Thus, chronic cyclosporine therapy was associated with a statistically significant but clinically modest delay of progression of disability in a group of patients with multiple sclerosis selected for moderately severe and progressive disease. Close supervision by physicians familiar with cyclosporine is mandatory to minimize known adverse effects, particularly nephrotoxicity, when considering the use of this immunosuppressant.


Allocation of spatial attention to emotional stimuli depends upon arousal and not valence.
Attentional allocation to emotional stimuli is often proposed to be driven by valence and in particular by negativity. However, many negative stimuli are also arousing leaving the question whether valence or arousal accounts for this effect. The authors examined whether the valence or the arousal level of emotional stimuli influences the allocation of spatial attention using a modified spatial cueing task. Participants responded to targets that were preceded by cues consisting of emotional pictures varying on arousal and valence. Response latencies showed that disengagement of spatial attention was slower for stimuli high in arousal than for stimuli low in arousal. The effect was independent of the valence of the pictures and not gender-specific. The findings support the idea that arousal affects the allocation of attention.


Morbidity, mortality, and quality of life following surgery for intracranial meningiomas. A retrospective study in 257 cases.
The authors report 257 patients who underwent 338 craniotomies for the removal of meningiomas. The average duration of observed survival was 9.0 years, while that with acceptable quality of life was 8.3 years. Multiple factors including the size and location of tumors, the degree of tumor excision, the histological features, and the preoperative condition of the patients are important in both duration of survival and quality of life following surgery for intracranial meningiomas. Computerized tomography permits early diagnosis and is invaluable in follow-up assessment. It allows for recognition of small recurrent tumors, and offers a better opportunity for complete removal and, subsequently, a longer duration of reasonable survival. Radiation therapy may prolong survival time in patients with malignant meningiomas, but it fails to delay further tumor recurrences following its delivery to patients with recurrent tumors. There are multiple predisposing factors responsible for the development of postoperative seizures. These include tumor recurrence involving highly functional anatomical areas of the brain, history of preoperative seizures, and intraoperative factors such as excessive brain retraction and the sacrifice of major draining or bridging veins. Intraoperative complications may be decreased by using osmotic diuretics and subarachnoid drains, meticulous dissection, and with the increased awareness and preservation of the important venous structures.


Gene regulation by the act of long non-coding RNA transcription.
Long non-protein-coding RNAs (lncRNAs) are proposed to be the largest transcript class in the mouse and human transcriptomes. Two important questions are whether all lncRNAs are functional and how they could exert a function. Several lncRNAs have been shown to function through their product, but this is not the only possible mode of action. In this review we focus on a role for the process of lncRNA transcription, independent of the lncRNA product, in regulating protein-coding-gene activity in cis. We discuss examples where lncRNA transcription leads to gene silencing or activation, and describe strategies to determine if the lncRNA product or its transcription causes the regulatory effect.


Approaches to setting organism-based ballast water discharge standards.
As a vector by which foreign species invade coastal and freshwater waterbodies, ballast water discharge from ships is recognized as a major environmental threat. The International Maritime Organization (IMO) drafted an international treaty establishing ballast water discharge standards based on the number of viable organisms per volume of ballast discharge for different organism size classes. Concerns that the IMO standards are not sufficiently protective have initiated several state and national efforts in the United States to develop more stringent standards. We evaluated seven approaches to establishing discharge standards for the > 50-microm size class: (1) expert opinion/management consensus, (2) zero detectable living organisms, (3) natural invasion rates, (4) reaction-diffusion models, (5) population viability analysis (PVA) models, (6) per capita invasion probabilities (PCIP), and (7) experimental studies. Because of the difficulty in synthesizing scientific knowledge in an unbiased and transparent fashion, we recommend the use of quantitative models instead of expert opinion. The actual organism concentration associated with a "zero detectable organisms" standard is defined by the statistical rigor of its monitoring program; thus it is not clear whether such a standard is as stringent as other standards. For several reasons, the natural invasion rate, reaction-diffusion, and experimental approaches are not considered suitable for generating discharge standards. PVA models can be used to predict the likelihood of establishment of introduced species but are limited by a lack of population vital rates for species characteristic of ballast water discharges. Until such rates become available, PVA models are better suited to evaluate relative efficiency of proposed standards rather than predicting probabilities of invasion. The PCIP approach, which is based on historical invasion rates at a regional scale, appears to circumvent many of the indicated problems, although it may underestimate invasions by asexual and parthenogenic species. Further research is needed to better define propagule dose-responses, densities at which Allee effects occur, approaches to predicting the likelihood of invasion from multi-species introductions, and generation of formal comparisons of approaches using standardized scenarios.


Evaluation of a peer coach-led intervention to improve pain symptoms (ECLIPSE): Rationale, study design, methods, and sample characteristics.
Chronic pain is prevalent, costly, and a leading cause of disability. Pain self-management (i.e., employing self-management strategies including behavioral modifications) is an effective, evidence-based treatment. However, implementation and delivery of a pain self-management model is challenging because of time and resources. Peer supported pain self-management offers a promising approach to implementing pain self-management programs using fewer clinical resources. Evaluation of a Peer Coach-Led Intervention for the Improvement of Pain Symptoms (ECLIPSE) is a randomized controlled trial testing effectiveness of peer coach-delivered pain self-management intervention versus controls receiving a class on pain and pain self-management. ECLIPSE is a Hybrid Type 1 study testing effectiveness while examining implementation factors. ECLIPSE enrolled 215 veterans randomly assigned to the peer coaching (N = 120) or control (N = 95) arm. The peer coaching intervention lasts 6 months, with patient-peer coach pairs instructed to talk twice per month. Coaches attend initial training, are provided a detailed training manual, and attend monthly booster sessions. Outcomes are assessed at baseline, 6 months, and 9 months. The primary outcome is overall pain (intensity and interference), measured by the Brief Pain Inventory (BPI). Secondary outcomes are self-efficacy, social support, pain catastrophizing, patient activation, health-related quality of life, and health care utilization. To maximize implementation potential of pain self-management, innovative delivery methods are needed that do not require additional resources from healthcare teams. A novel and promising approach is a peer-coaching model, in which patients who are successfully managing their pain offer information, ongoing support, and advice to other patients with pain. Clinical Trials Registration: NCT02380690.


Comparative cytotoxicity of monocrotaline and its metabolites in cultured pulmonary artery endothelial cells.
Metabolites of the pyrrolizidine alkaloid monocrotaline cause progressive development of pulmonary hypertension in rats. The putative reactive intermediate monocrotaline pyrrole (MCTP) has been shown to cause cytotoxicity, hypertrophy, decreased proliferation, and altered synthetic capability in cultured pulmonary endothelial cells. We compared effects of monocrotaline (MCT) at 60 micrograms/ml (0.185 mM) with previously identified metabolites, MCTP 10 micrograms/ml (0.031 mM) and glutathione-conjugated dihydropyrrolizine (GSH-DHP) 60 micrograms/ml (0.135 mM), in cultured bovine pulmonary artery endothelial cells (BPAECs). To determine whether endothelial metabolism might contribute to the mechanism of this toxicity, we used markers of cytotoxicity (LDH release), synthetic activity (PGI2 synthesis), hypertrophy (planimetry), cell density (cell count/area), and Evans blue albumin (EBA) transudation as a marker for loss of fluid barrier integrity. We found changes in all endothelial markers with MCTP only. MCTP caused increased LDH release by 48 hr, augmented PGI2 synthesis by 96 hr, and resulted in hypertrophy and decreased cell density by 48 hr that persisted at least 21 days. There was increased EBA transudation at 24 hr posttreatment. We concluded that, based on markers of endothelial damage, BPAECs showed no apparent ability to metabolize MCT to a reactive intermediate nor to further metabolize GSH-DHP to a toxic species. We also concluded that MCTP can cause a direct effect on fluid barrier integrity of endothelial cell monolayers in the absence of inflammation.


Diagnosis and management of atypical fibroxanthoma.
A 90-year-old Caucasian man with a history of basal cell carcinoma and squamous cell carcinoma presented with a friable erythematous nodule on his scalp that had been present for several months. The lesion measured 1.4 x 1.8 cm. What is your diagnosis? How would you proceed?


A bistable model of cell polarity.
Ultrasensitivity, as described by Goldbeter and Koshland, has been considered for a long time as a way to realize bistable switches in biological systems. It is not as well recognized that when ultrasensitivity and reinforcing feedback loops are present in a spatially distributed system such as the cell plasmamembrane, they may induce bistability and spatial separation of the system into distinct signaling phases. Here we suggest that bistability of ultrasensitive signaling pathways in a diffusive environment provides a basic mechanism to realize cell membrane polarity. Cell membrane polarization is a fundamental process implicated in several basic biological phenomena, such as differentiation, proliferation, migration and morphogenesis of unicellular and multicellular organisms. We describe a simple, solvable model of cell membrane polarization based on the coupling of membrane diffusion with bistable enzymatic dynamics. The model can reproduce a broad range of symmetry-breaking events, such as those observed in eukaryotic directional sensing, the apico-basal polarization of epithelium cells, the polarization of budding and mating yeast, and the formation of Ras nanoclusters in several cell types.


Anxious Attachment Mediates the Associations Between Early Recollections of Mother's Own Parental Bonding and Mother-Infant Bonding: A 2-Month Path Analysis Model.
Parental bonding (recollection of own parents' parenting), adult attachment, and mother-infant bonding are all closely related yet distinct concepts of the parent-child relationship, sometimes used interchangeably in the literature. This study aimed to examine the associations between these concepts in a longitudinal path analysis design. A total of 262 postpartum women who gave birth at the maternity ward of a large tertiary health center in Israel completed a demographic questionnaire, the Experiences in Close Relationships Scale (ECR), the Parental Bonding Instrument (PBI) at 1-4 days postpartum, and the Postpartum Bonding Questionnaire (PBQ) at 2 months postpartum. Parental care factor (PBI) was found to be associated with mother-infant bonding (PBQ), directly and indirectly through insecure anxious attachment (ECR). Denial of autonomy factor (PBI) was found to be associated with mother-infant bonding (PBQ) only through insecure anxious attachment (ECR). Encouragement of behavioral freedom factor (PBI) was found to be associated with mother-infant bonding (PBQ) in a simple correlation but not in the complete model. The results highlight the intergenerational aspects of parenting and suggest that early childhood interventions with parents may have a long-term impact on child-rearing though generations, and by that on children's development.


Rational Control on Quantum Emitter Formation in Carbon-Doped Monolayer Hexagonal Boron Nitride.
Single-photon emitters (SPEs) in hexagonal boron nitride (hBN) are promising candidates for quantum light generation. Despite this, techniques to control the formation of hBN SPEs down to the monolayer limit are yet to be demonstrated. Recent experimental and theoretical investigations have suggested that the visible wavelength single-photon emitters in hBN originate from carbon-related defects. Here, we demonstrate a simple strategy for controlling SPE creation during the chemical vapor deposition growth of monolayer hBN via regulating surface carbon concentration. By increasing the surface carbon concentration during hBN growth, we observe increases in carbon doping levels by 2.4-fold for B-C bonds and 1.6-fold for N-C bonds. For the same samples, we observe an increase in the SPE density from 0.13 to 0.30 emitters/μm2. Our simple method enables the reliable creation of hBN SPEs in monolayer samples for the first time, opening the door to advanced two-dimensional (2D) quantum state engineering.


The Tetragnatha kauaiensis Genome Sheds Light on the Origins of Genomic Novelty in Spiders.
Spiders (Araneae) have a diverse spectrum of morphologies, behaviors, and physiologies. Attempts to understand the genomic-basis of this diversity are often hindered by their large, heterozygous, and AT-rich genomes with high repeat content resulting in highly fragmented, poor-quality assemblies. As a result, the key attributes of spider genomes, including gene family evolution, repeat content, and gene function, remain poorly understood. Here, we used Illumina and Dovetail Chicago technologies to sequence the genome of the long-jawed spider Tetragnatha kauaiensis, producing an assembly distributed along 3,925 scaffolds with an N50 of ∼2 Mb. Using comparative genomics tools, we explore genome evolution across available spider assemblies. Our findings suggest that the previously reported and vast genome size variation in spiders is linked to the different representation and number of transposable elements. Using statistical tools to uncover gene-family level evolution, we find expansions associated with the sensory perception of taste, immunity, and metabolism. In addition, we report strikingly different histories of chemosensory, venom, and silk gene families, with the first two evolving much earlier, affected by the ancestral whole genome duplication in Arachnopulmonata (∼450 Ma) and exhibiting higher numbers. Together, our findings reveal that spider genomes are highly variable and that genomic novelty may have been driven by the burst of an ancient whole genome duplication, followed by gene family and transposable element expansion.


South american geochronology: radiometric time scale for middle to late tertiary mammal-bearing horizons in patagonia.
Radiometric (potassium-argon) age determinations for basalts and tuffs associated with middle to late Tertiary mammal-bearing horizons in Patagonia, southern Argentina, permit refinement of boundaries and hiatuses between beds of Deseadan (early Oligocene) through Friasian (middle to late Miocene) age. At two localities beds of Deseadan age are overlain by basalts, which gave dates of 33.6 and 35.4 million years ago; 34.0 million years ago is tentatively accepted as a terminal date for known Deseadan. At several localities beds of Colhuehuapian age are underlain by basalts, which gave dates ranging from 28.8 to 24.3 million years ago; 25.0 million years is tentatively taken as a basal age for known Colhuehuapian. The paleontological hiatus between known Deseadan and known Colhuehuapian is thus in the order of 9.0 million years. Two tuffs from the Santa Cruz Formation (Santacrucian) gave ages of 21.7 and 18.5 million years. Plagioclase and biotite concentrates of an ignimbrite from the Collón Curá Formation (Friasian) gave ages ranging from 15.4 to 14.0 million years.


Progressive update approach to real-time cutting of finite element models in surgical simulation.
We present an extension of our work on topology modification and deformation for Finite Element Models, in which the inverse stiffness matrix is updated rather than recomputed entirely. Previously we integrated condensation to allow for realistic interaction with larger models. We improve on this by redistributing computational load to increase the system's real-time response. Removing a tetrahedron only requires data associated with the nodes of that tetrahedron, and the surface nodes, to be updated, in order to drive the simulation. However, the update procedure itself needs the entire data structure to be updated. The equations used to update the inverse stiffness matrix are split up such that calculations are only performed for the affected nodes. Data regions corresponding to the surface nodes necessary for deformation calculations are computed immediately, whilst remaining regions can be computed as required, resulting in up to a ten-fold improvement in system response times.


Cerebroelectrical depression following surfactant treatment in preterm neonates.
During surfactant treatment of respiratory distress syndrome, 23 premature newborns were investigated with continuous amplitude-integrated electroencephalography (cerebral function monitors). Simultaneously, arterial blood pressure and transcutaneous blood gas values were recorded. A short (less than 10 minutes) but significant decrease in cerebral activity was seen in almost all neonates immediately after the surfactant instillation, in spite of an improved pulmonary function. In 21 of 23 neonates, a transient fall in mean arterial blood pressure of 9.3 mm Hg (mean) occurred coincidently with the cerebral reaction. Neonates in whom intraventricular hemorrhage developed tended to have lower presurfactant mean arterial blood pressure (P greater than .05), but they had a significantly lower mean arterial blood pressure after surfactant instillation (P less than .05). No other differences were found between neonates in whom intraventricular hemorrhage developed and those without intraventricular hemorrhage. The present findings demonstrate that an acute cerebral dysfunction may occur after surfactant instillation. In some vulnerable neonates with arterial hypotension and severe pulmonary immaturity, the fall in mean arterial blood pressure may increase the risk of cerebral complications and could be related to an unchanged rate of intraventricular hemorrhage after surfactant treatment.


Presence of connectin-like protein in white blood cells and platelets.
Connectin is known to be an anchoring protein of actomyosin filaments in skeletal muscle. Attempts were made to extract this protein from white blood cells and platelets in order to investigate its properties. The purified connectin-like protein obtained had a rubbery appearance and was insoluble in water and immobile on SDS gel-electrophoresis. Amino acid composition and electron microscopic features of the protein were similar to those of skeletal muscles. FITC-labeled antibody to the protein showed a positive reaction to the membrane fractions of red cells, white cells and platelets. In moving cells fluorescence was observed not only in pseudopod, but also in whole cytoplasm. No changes in the fluorescence patterns were observed with respect to moving stages or cell types. The presence of the protein beneath the cell membrane was also confirmed electron micrographically.


Fluorosilicone oil in the treatment of retinal detachment.
We evaluated the use of a heavier-than-water fluorinated silicone oil in the treatment of 30 selected cases of complicated retinal detachment from January 1988 to July 1989. Proliferative vitreoretinopathy grade C-2 or greater accounted for 19 cases, proliferative diabetic retinopathy with traction detachment for two cases, giant retinal tears five, ruptured globe with retinal detachment two, massive choroidal effusion with retinal detachment one, and acute retinal necrosis with retinal detachment one. Initial retinal reattachment was achieved in all cases. Complications included redetachment seven (23%), cataract six (75% of phakic patients), raised intraocular pressure four (13%), hypotony four (13%), keratopathy three (10%), uveitis-synechia formation three (10%), phthisis two (3%), choroidal haemorrhage one (3%), and vitreous haemorrhage one (3%). Postoperative visual acuities with at least six months' follow-up range from no light perception to 20/50, with seven patients (23%) 20/400 or better.


Morphine-induced epidermal growth factor pathway activation in non-small cell lung cancer.
Epidermal growth factor receptor (EGFR) is coactivated by the μ-opioid receptor (MOR), expressed on non-small cell lung cancer (NSCLC) cells and human lung cancer. We hypothesized that clinically used opioid analgesics that are MOR agonists coactivate EGFR, resulting in growth- and survival-promoting signaling. We used H2009, a human adenocarcinoma NSCLC cell line, with constitutive EGFR phosphorylation, which showed increased expression of MOR and the δ-opioid receptor by reverse transcriptase polymerase chain reaction. We used Western immunoblotting, magnetic bead-based Bio-Plex cytokine assay, immunofluorescent staining, BrdU incorporation enzyme-linked immunosorbent assay, and BioCoat™ Matrigel™ invasion assay to examine cell signaling, cytokine expression, colocalization of MOR and EGFR in human lung cancer, and cell proliferation and invasion, respectively. Similar to epidermal growth factor (EGF), morphine stimulated phosphorylation of EGFR, Akt/protein kinase B (Akt), and mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) signaling in H2009 cells. Opioid receptor (OR) antagonist, naloxone, EGFR tyrosine kinase inhibitor, erlotinib, and silencing of MOR and δ-opioid receptor abrogated morphine- and EGF-induced phosphorylation of signaling, suggestive of OR-mediated coactivation of EGFR. H2009 cells secreted significantly higher levels of cytokines compared with control Beas2B epithelial cells. H2009-conditioned medium stimulated MOR expression in Beas2B cells, suggesting that cytokines secreted by H2009 may be associated with increased OR expression in H2009. We observed colocalization of EGFR and MOR, in human NSCLC tissue. Functionally, morphine- and EGF-induced proliferation and invasion of H2009 cells was ameliorated by naloxone as well as erlotinib. Morphine-induced phosphorylation of EGFR occurs via ORs, leading to downstream MAPK/ERK, Akt phosphorylation, cell proliferation, and increased invasion. Notably, ORs are also associated with EGF-induced phosphorylation of EGFR. Increased coexpression of MOR and EGFR in human lung cancer suggests that morphine may have a growth-promoting effect in lung cancer.


Sclerosing cholangitis.
PSC is an unusual disease of unknown etiology. In fact, sclerosis of the bile ducts may be the result of multiple factors, including autoimmune, bacterial, congenital, drug, or viral agents. The most commonly associated diseases are ulcerative colitis and chronic pancreatitis. Except for the earliest stages of the disease, liver histology is not specific. Most patients present with jaundice, pain, and pruritus, although an increasing number of asymptomatic patients with inflammatory bowel disease and abnormal liver function are being diagnosed. Cholangiography is the key to the diagnosis and is usually pathognomonic except in the unusual case where PSC is confused with cholangiocarcinoma. Multiple forms of medical therapy have been tried, including steroids, azothiaprine, D-penicillamine, colchicine, cholestyramine, and antibiotics. To date, however, none of these medications has altered the course of this disease. In recent years, balloon dilation of biliary strictures has been accomplished via endoscopic and percutaneous transhepatic approaches. However, in patients with PSC these nonoperative manipulations must be done repeatedly, may require multiple general anesthetics, and are difficult to perform. A direct surgical approach to the biliary tree with prolonged transhepatic stenting is indicated in patients with severe hilar or extrahepatic stricturing, persistent jaundice and/or recurrent cholangitis, and no evidence of cirrhosis. Hepatic transplantation should be reserved for patients with PSC who have well-established cirrhosis and in whom other therapeutic options have failed.


MAPK inhibitors, particularly the JNK inhibitor, increase cell death effects in H2O2-treated lung cancer cells via increased superoxide anion and glutathione depletion.
Reactive oxygen species (ROS), especially hydrogen peroxide (H2O2), induce apoptosis in cancer cells by regulating mitogen-activated protein kinase (MAPK) signaling pathways. The present study investigated the effects of MAPK inhibitors on cell growth and death as well as changes in ROS and glutathione (GSH) levels in H2O2-treated Calu-6 and A549 lung cancer cells. H2O2 inhibited growth and induced death of Calu-6 and A549 lung cancer cells. All MAPK inhibitors appeared to enhance growth inhibition in H2O2-treated Calu-6 and A549 lung cancer cells and increased the percentage of Annexin V-FITC-positive cells in these cancer cells. Among the MAPK inhibitors, a JNK inhibitor significantly augmented the loss of mitochondrial membrane potential (MMP; ΔΨm) in H2O2-treated Calu-6 and A549 lung cancer cells. Intracellular ROS levels were significantly increased in the H2O2-treated cells at 1 and 24 h. Only the JNK inhibitor increased ROS levels in the H2O2-treated cells at 1 h and all MAPK inhibitors raised superoxide anion levels in these cells at 24 h. In addition, H2O2 induced GSH depletion in Calu-6 and A549 cells and the JNK inhibitor significantly enhanced GSH depletion in H2O2‑treated cells. Each of the MAPK inhibitors altered ROS and GSH levels differently in the Calu-6 and A549 control cells. In conclusion, H2O2 induced growth inhibition and death in lung cancer cells through oxidative stress and depletion of GSH. The enhanced effect of MAPK inhibitors, especially the JNK inhibitor, on cell death in H2O2-treated lung cancer cells was correlated with increased O2•- levels and GSH depletion.


Impact of Complications After Cardiac Operation on One-Year Patient-Reported Outcomes.
Current reporting on cardiac surgical outcomes focuses on a patient's status at 30 days and lacks long-term meaningful data. The purpose of this study was to determine the impact of complications after cardiac operation on patient-reported outcomes (PROs) at 1 year after surgery. All patients undergoing cardiac operation at an academic institution (2014-2015) were contacted 1 year after surgery to obtain vital status, location, and PROs using the validated National Institutes of Health Patient-Reported Outcomes Measurement Information System (NIH-PROMIS). Records were merged with Society of Thoracic Surgeons (STS) data, and multivariate linear regression evaluated the risk-adjusted effects of complications on 1-year PROs. A total of 782 eligible patients underwent cardiac operation, with PROs data available for 91% of patients alive at 1 year (648 of 716). Mean NIH-PROMIS scores were global physical health (GPH), 48.8 ± 10.2; global mental health (GMH), 51.3 ± 9.5; and physical functioning (PF), 45.5 ± 10.2 (reference score for general adult population, 50 ± 10). Occurrence of an STS Major Morbidity (prolonged ventilation, renal failure, reoperation, stroke, or deep sternal wound infection) significantly reduced 1-year PROs (GPH, 45.4 ± 8.9 [P < .001]; GMH, 48.6 ± 9.5 [P = .01]; PF, 40.9 ± 10.2 [P < .001]). After risk adjustment, incidence of a STS Major Morbidity, prolonged ventilation, or renal failure had a significant adverse effect on 1 or more PRO domains. Although cardiac surgical patients have PROs scores similar to the general population, complications after cardiac operation continue to negatively influence patient quality of life 1 year after surgery. Use of NIH-PROMIS shows that prolonged ventilation and renal failure have the largest impact on 1-year patient-reported outcomes.


[Change in acetylation activity in 7,12-dimethylbenz(alpha)-anthracene induction].
In mice, injected DMBA subcutaneously 12 weeks prior to sarcomas detection, an increased activity of N-acetyltransferase was noted. As a result of DMBA application into mice skin the increased activity of this enzyme was noted 16 weeks prior to the appearance of papillomas and cancer of skin. Initial increase of the enzyme activity was followed by its considerable decrease and terminated by a new increase in the detection of tumors. The causes of the changes in the activity of N-acetyl-transferase are discussed, as well as the possibility to consider these changes as a sign indicating that tumor is likely to appear in the nearest future.


Paracoccidioidomycosis vaccine.
Paracoccidioidomycosis is a granulomatous pulmonary infection that is generally controlled by chemotherapy. The efficacy of treatment, however, is limited by the status of the host immune response. The inhibition of a Th-2 immunity or the stimulation of Th-1 cytokines generally increases the efficacy of antifungal drugs. ( 1) This has been achieved by immunization with an internal peptide of the major diagnostic antigen gp43 of Paracoccidioides brasiliensis. Peptide 10 (QTLIAIHTLAIRYAN) elicits an IFN-γ rich Th-1 immune response that protects against experimental intratracheal infection by this fungus. The combination of chemotherapy with P10 immunization showed additive protective effect even after 30 d of infection or in anergic mice, rendering in general, increased production of IL-12 and IFN-γ and reduction of IL-4 and IL-10. Immunotherapy with P10 even in the absence of simultaneous chemotherapy has been effective using various protocols, adjuvants, nanoparticles, P10-primed dendritic cells, and especially a combination of plasmids encoding the P10 minigene and IL-12. Gene therapy, in a long-term infection protocol succeeded in the virtual elimination of the fungus, preserving the lung structure, free from immunopathological side effects.


Acid stimulation reduces bactericidal activity of surface liquid in cultured human airway epithelial cells.
To examine the effects of acid exposure with moderate acidity (pH 3.0-5.0) on bactericidal activity of airway surface liquid (ASL), ASL was collected by washing the surface of primary cultures of human tracheal epithelial cells 24 h after treatment with phosphate-buffered saline (PBS) adjusted to a pH of 3.0, 4.0, or 5.0. In all ASL, bactericidal activity was sensitive to sodium concentration. Escherichia coli (500 colony forming units [CFU]) was incubated in ASL, and the number of surviving bacteria was examined. The number of surviving bacteria in ASL from cultured cells with acid exposure at pH 3.0-5.0 was significantly higher than that in control ASL. The minimum inhibitory dilution ratio of ASL against 500 CFU of E. coli was also examined by microdilution assays. According to this assay, the bactericidal activity in ASL with acid challenge at a pH of 3.0 was less than half of that in control ASL. Reverse transcription-polymerase chain reaction and Western blot analysis showed that the production of mRNA and protein of human beta-defensin (HBD)-1 were significantly decreased by acid exposure at pH 3.0-5.0. In contrast, acid exposure did not change the production of mRNA and protein of HBD-2 and beta-actin mRNA. These results indicate that acid exposure, even with moderate acidity, may inhibit the production of bactericidal molecules, including HBD-1, in airway epithelial cells. Acid exposure may reduce bactericidal activity of ASL in human airway epithelial cells and may increase susceptibility of the airway to bacterial infection.


Food, water, and sanitation insecurities: Complex linkages and implications for achieving WASH security.
Food, water and sanitation insecurities are complex, multi-dimensional phenomena that entail more than availability and access; food, water, and sanitation resources must be safe and culturally appropriate. Researchers and implementers concerned with these insecurities have demonstrated that there are notable interactions between them resulting in significant psychological and biological outcomes. Recent randomised controlled trials (RCTs) in Bangladesh, Kenya (WASH Benefits) and Zimbabwe (SHINE) demonstrated no effect from water, sanitation and hygiene (WASH) interventions on linear growth, and mixed evidence on enteropathogen burden and risk of diarrhoea in young children. These data suggest a need for a more comprehensive understanding of WASH security. The risks posed by multiple resource insecurities shift depending on the individual, their movement throughout their day, their economically and socially prescribed roles, and ecological features such as seasonality and precipitation. By more fully integrating food, water and sanitation security in interventions and subsequent impact evaluations, we can achieve WASH security-one that addresses myriad transmission pathways and co-occurring diseases-that ultimately would improve health outcomes throughout the world. In this critical review, we outline the complexity of combined resource insecurities as a step towards transformative WASH.


Understanding the association between admission source and in-hospital delirium: A cross-sectional study.
Patients admitted via interhospital transfer (IHT) experience increased risk-adjusted mortality, adverse events, length of stay, and discharge to facility; however, the etiology is not well understood. We hypothesize that IHTs are more likely to experience in-hospital delirium as compared with admissions to the hospital via the emergency department (ED) and clinic. This is a cross-sectional study of all adult admissions to medical, surgical, neurological, and obstetrics and gynecology services at an academic medical center who were screened for delirium between August 2018 and January 2020. Unit of analysis was admission source (IHT vs ED vs clinic) as the independent variable and the primary outcome was in-hospital delirium, assessed with initial brief confusion assessment method (bCAM) screening. 30,100 hospitalizations were included in this study with 3925 admissions (13.0%) screening positive for delirium at the initial bCAM assessment. The prevalence of delirium was much higher in IHTs at 22.3% (1334/5971) when compared with clinic at 5.8% (244/4214) and ED at 11.8% (2347/19,915) admissions. Multivariable logistic regression adjusting for demographics and comorbidities showed that IHT admissions had higher odds (OR 1.91, 95% CI 1.74 to 2.10) and clinic admissions had lower odds (OR 0.56, 95% CI 0.48 to 0.64) of in-hospital delirium compared with ED admissions. Increased odds of delirium in IHT admissions may contribute to the observed increased length of stay, discharge to facility, and mortality. These results emphasize the importance of routine screening and possible intervention prior to patient transfer.


Carrier dynamics of a visible-light-responsive Ta3N5 photoanode for water oxidation.
The physicochemical properties of a tantalum nitride (Ta3N5) photoanode were investigated in detail to understand the fundamental aspects associated with the photoelectrochemical (PEC) water oxidation. The Ta3N5 thin films were synthesized using DC magnetron sputtering followed by annealing in air and nitridation under ammonia (NH3). A polycrystalline structure with a dense morphology of the monoclinic Ta3N5 films was obtained. A relatively low absorption coefficient (10(4) to 10(5) cm(-1)) in the visible light range was measured for Ta3N5, consistent with the nature of the indirect band-gap. Ultra-fast spectroscopic measurements revealed that the Ta3N5 with different thicknesses films possess low transport properties and fast carrier recombination (<10 ps). These critical kinetic properties of Ta3N5 as a photoanode may necessitate high overpotentials to achieve appreciable photocurrents for water oxidation (onset ∼0.6 V vs. RHE).


Acremostrictin, a highly oxygenated metabolite from the marine fungus Acremonium strictum.
The novel natural product acremostrictin was isolated from the culture broth of Acremonium strictum, a marine fungus collected from a Choristida sponge off the coast of Korea. Structurally, acremostrictin is a tricyclic lactone of an unprecedented skeletal class based on combined spectroscopic and X-ray crystallographic analyses. The new compound exhibited weak antibacterial and moderate antioxidant activities.


Processing bulk natural wood into a high-performance structural material.
Synthetic structural materials with exceptional mechanical performance suffer from either large weight and adverse environmental impact (for example, steels and alloys) or complex manufacturing processes and thus high cost (for example, polymer-based and biomimetic composites). Natural wood is a low-cost and abundant material and has been used for millennia as a structural material for building and furniture construction. However, the mechanical performance of natural wood (its strength and toughness) is unsatisfactory for many advanced engineering structures and applications. Pre-treatment with steam, heat, ammonia or cold rolling followed by densification has led to the enhanced mechanical performance of natural wood. However, the existing methods result in incomplete densification and lack dimensional stability, particularly in response to humid environments, and wood treated in these ways can expand and weaken. Here we report a simple and effective strategy to transform bulk natural wood directly into a high-performance structural material with a more than tenfold increase in strength, toughness and ballistic resistance and with greater dimensional stability. Our two-step process involves the partial removal of lignin and hemicellulose from the natural wood via a boiling process in an aqueous mixture of NaOH and Na2SO3 followed by hot-pressing, leading to the total collapse of cell walls and the complete densification of the natural wood with highly aligned cellulose nanofibres. This strategy is shown to be universally effective for various species of wood. Our processed wood has a specific strength higher than that of most structural metals and alloys, making it a low-cost, high-performance, lightweight alternative.


Pharmacist-lead screening for diabetic peripheral neuropathy using Michigan Neuropathy Screening Instrument (MNSI).
Diabetic peripheral neuropathy (DPN) is highly prevalent among Jordanian patients, mostly are asymptomatic. Early recognition and appropriate management of neuropathy is important to improve symptoms, reduce sequelae, and improve quality of life. This study aims at exploring the role of pharmacists in the early recognition of DPN and providing quick screening for the presence of it among diabetic patients. A cross-sectional study was conducted at multi-pharmacy settings, in Irbid, Jordan. Twenty trained pharmacists who had bachelor's degrees in pharmacy participated in data collection. A total of 400 patients with confirmed diagnosis of type 2 diabetes mellitus (DM) according to the World Health Organization diagnostic criteria were recruited. DPN was assessed using the translated Arabic version of Michigan Neuropathy Screening Instrument (MNSI) history version. The mean MNSI questionnaire score for all participants was 4.40 ± 3.00. Mean age of the patients was 62.6 ± 10.7 years old and duration of diabetes was 8.25 ± 6.9. DN was present in 23.7% of the population. Diabetic patients with neuropathy were older than patients without neuropathy (p < 0.05) and had had diabetes longer (p < 0.05). Poor glycemic control, hypertension and gender, were significantly risk factors for DN (p < 0.05). In addition to delivering medications, this study suggests that pharmacists can have a role in screening and counseling about diabetic peripheral neuropathy using a simple objective, and non-invasive tool and also can determine level of damage and risk.