Platelet functions and coagulation changes in Indian children with nephrotic syndrome.
Only little is known on the effect of the platelet function in the paediatric nephrotic syndrome. The earlier studies which had been done on hypercoagulability have mainly featured the secondary forms of the nephrotic syndrome and the data on the minimal change type of disease is limited. We therefore, made an effort to study the platelet functions and the coagulation profile in children with the nephrotic syndrome,to find the relationship between the steroid response and the coagulation profile, and to look for the correlation between thromboembolism and the hypercoagulable states. Twenty nine children with the steroid responsive nephrotic syndromewere studied to see the platelet aggregation and the coagulation parameters and their response to the steroid therapy. Doppler studies were done for the renal vein and the inferior vena cava (IVC) thrombus. It was seen that an increased aggregability of the platelets occurred with Adenosine diphosphate (ADP) and collagen (out of the four agonists, ADP, Collagen, Ristocetin and Arachidonic acid) which were used as agonists for the assay. We also observed that the Partial thromboplastin time (PTT) had become prolonged and a significant decline in the high values of the procoagulant proteins (Protein C and Protein S) was seen after the steroid therapy and when the children went into remission. These findings were suggestive of a reversibility of the changes in the steroid responsive nephrotic syndrome with the steroid therapy. One child was found to have thrombosis of the inferior vena cava (IVC) on Doppler studies, which resolved with treatment subsequently. An increased platelet aggregability contributes to the hypercoagulable states, that may increase the incidence of thrombosis in such patients. Although the incidence of such complications is very low, in a given child with the hypercoagulable states, Doppler may be used to look for any evidence of a latent thrombus and, an early intervention could be instituted. A change in the coagulation parameters points to the reversibility of the changes which are produced in a diseased state.


Role of peroxiredoxin 1 and peroxiredoxin 4 in protection of respiratory syncytial virus-induced cysteinyl oxidation of nuclear cytoskeletal proteins.
The respiratory epithelium plays a central role in innate immunity by secreting networks of inflammatory mediators in response to respiratory syncytial virus (RSV) infection. Previous proteomic studies focusing on the host cellular response to RSV indicated the existence of a nuclear heat shock response and cytoplasmic depletion of antioxidant proteins in model type II-like airway epithelial cells. Here, we increased the depth of nuclear proteomic interrogation by using fluorescence difference labeling followed by liquid isoelectric focusing prefractionation/two-dimensional gel electrophoresis (2-DE) to identify an additional 41 proteins affected by RSV infection. Surprisingly, we found inducible oligomers and shifts in isoelectric points for peroxiredoxin 1 (Prdx-1), Prdx-3, and Prdx-4 isoforms without changes in their total abundance, indicating that Prdxs were being oxidized in response to RSV. To address the role of Prdx-1 and Prdx-4 in RSV infection, isoforms were selectively knocked down by small interfering RNA (siRNA) transfection. Cells lacking Prdx-1, Prdx-4, or both showed increased levels of reactive oxygen species formation and a higher level of protein carbonylation in response to RSV infection. Using a novel saturation fluorescence labeling 2-DE analysis, we showed that 15 unique proteins had enhanced oxidative modifications of at least >1.2-fold in the Prdx knockdowns in response to RSV, including annexin A2 and desmoplakin. Our results suggest that Prdx-1 and Prdx-4 are essential for preventing RSV-induced oxidative damage in a subset of nuclear intermediate filament and actin binding proteins in epithelial cells.


Studies on the induction and turnover of citrate-oxidizing capacity in Klebsiella aerogenes using chemostat culture.
Steady-state chemostat cultures of Klebsiella aerogenes growing on a carbon-limited medium were challenged with pulse of carbon sources, and the resultant changes in dissolved oxygen tension were shown to reflect changes in respiration rate. These changes were used to study the kinetics of induction of citrate-oxidizing capacity, which is most probably limited by citrate permease, and the return to the preinduced state. Previously unexposed cells showed a lag phase, the duration of which decreased with increasing growth rate, with a minimum of 10 min, followed by an induction phase of linear increase of citrate oxidation rate which continued as long as citrate was present. The rate of increase in activity, which can be equated to the rate of induction of citrate permease, was independent of citrate concentration but increased with growth rate. Previously exposed cells showed no lag and some residual activity before further induction. The kinetics of return to the preinduced state were unusual in that activity was short-lived with a half-life of 16 to 23 min while the lag took over 8 h to re-establish. The rate of decay of activity decreased with increasing growth rate.


Different Glycoconjugate Content in Mucus Secreting Cells of the Rat Fundic Gastric Glands.
The fundic glands of the stomach contain two types of mucous cells: surface mucous cells (SMCs) located at the surface of the stomach and the pits, and mucous neck cells (MNCs) situated in the neck of the glands. They produce mucins, highly glycosylated proteins. Very little is known about the glycan composition of these mucins and of gastric secretion in general. We used several lectins combined with deglycosylation pretreatments to analyze the glycan composition of SMCs and MNCs. The results showed the presence of terminal sialic acid and subterminal Gal and GalNAc, which is consistent with previous knowledge about glycosylation in mucins. Our results also support previous reports that showed a different expression of mucins in the SMCs, depending on their superficial or deep location in the pit. Some lectins labeled only the perinuclear region of the SMCs, but not the apical region, where the secretory granules are stored. This suggests that the lectins are labeling sugar residues that are accessible to lectins during the first steps of glycan synthesis, which occurs in the endoplasmic reticulum and Golgi apparatus. Our results indicate that SMCs and MNCs produce a mucus secretion with a different glycoconjugate composition. The secretion is more varied in SMCs. As our results coincide with what we know about glycosylation of mucins, we can conclude that most of the glycans detected belong to mucins, and the differences in glycosylation observed in each cell type may be due, mainly, to the different secreted mucins. Anat Rec, 301:2128-2144, 2018. © 2018 Wiley Periodicals, Inc.


[The effect of mutagenic environmental factors on recombination in Drosophila melanogaster].
We studied recombination in Drosophila melanogaster males exposed in a thermoelectric power station in Moscow for six years and, for comparison, in another thermoelectric power station during 1994. The frequency of recombination in the experimental males was two to three times that in the control. The annual differences in the frequency of recombination in the experimental males were not statistically significant. The differences between the data obtained for two different thermoelectric power stations were not statistically significant as well. A marked increase in the frequency of recombination in the D. melanogaster males exposed at thermoelectric power stations may be considered as an adequate reaction to the presence of a sufficient amount of effective mutagens in discharges of thermoelectric power stations.


A new strategy for exploiting ion exchange in sequential injection analysis: in-line phytic acid separation/determination in foods as an example.
A novel strategy for exploiting ion exchange in sequential injection systems is proposed. The procedure is based on the selection of a defined volume of a resin suspension, which is introduced and packed in the analytical path, establishing a resin mini-column in the system. The passage of a selected sample volume through the resin mini-column leads to the retention of the analyte, while the sample matrix is discarded. The analyte is eluted during the passage of the eluant/reagent by the packed beads, being the analytical signal monitored (absorbance) in the liquid phase. The beads are then aspirated back to the holding coil and directed to a recovery flask, linked at the selection valve; then the system is ready to begin a new cycle. With the proposed strategy, the main characteristics of the sequential injection system are kept as any new artifact is added to the manifold and system reconfiguration is not required. The feasibility of the approach is demonstrated by the phytic acid determination in food samples. For this specific application, AG1-X8 was selected as ion exchanger, and a solution containing Cl- and Fe(III)-salicylate complex was used as eluant and spectrophotometric reagent.


Mechanism of activation of the human cysteine desulfurase complex by frataxin.
The function of frataxin (FXN) has garnered great scientific interest since its depletion was linked to the incurable neurodegenerative disease Friedreich's ataxia (FRDA). FXN has been shown to be necessary for iron-sulfur (Fe-S) cluster biosynthesis and proper mitochondrial function. The structural and functional core of the Fe-S cluster assembly complex is a low-activity pyridoxal 5'-phosphate (PLP)-dependent cysteine desulfurase enzyme that consists of catalytic (NFS1), LYRM protein (ISD11), and acyl carrier protein (ACP) subunits. Although previous studies show that FXN stimulates the activity of this assembly complex, the mechanism of FXN activation is poorly understood. Here, we develop a radiolabeling assay and use stopped-flow kinetics to establish that FXN is functionally linked to the mobile S-transfer loop cysteine of NFS1. Our results support key roles for this essential cysteine residue in substrate binding, as a general acid to advance the Cys-quinonoid PLP intermediate, as a nucleophile to form an NFS1 persulfide, and as a sulfur delivery agent to generate a persulfide species on the Fe-S scaffold protein ISCU2. FXN specifically accelerates each of these individual steps in the mechanism. Our resulting architectural switch model explains why the human Fe-S assembly system has low inherent activity and requires activation, the connection between the functional mobile S-transfer loop cysteine and FXN binding, and why the prokaryotic system does not require a similar FXN-based activation. Together, these results provide mechanistic insights into the allosteric-activator role of FXN and suggest new strategies to replace FXN function in the treatment of FRDA.


Nonspecific ulcerative colitis as a sequel to amebic dysentery.
In two patients, treatment of amebic dysentery was followed (despite the disappearance of the infecting organism) by an illness with the clinical, pathological, and radiological characteristics of nonspecific ulcerative colitis. Their case histories indicate that in addition to persistent or recurrent amebic infection, the irritable colon syndrome, and ulcerative postdysenteric colitis, nonspecific ulcerative colitis should be kept in mind in the evaluation and therapy of continuing symptoms in patients with treated amebic dysentery.


[Instrumental diagnostics of pulmonary hypertension in patients with chronic pulmonary heart].
64 patients aged 30-49 with chronic cor pulmonale underwent the following diagnostic evaluation: electromyography of the heart and vessels, electrocardiography, lung rheography to diagnose the presence of pulmonary hypertension. Electromyography was shown to play a key role in diagnosing pulmonary hypertension. Attention should be paid to electrocardiography (with the help of L. Burstin's nomogram) and electrocardiography (after S. A. Dushanin) methods of quantitative evaluation of pulmonary hypertension. Electrocardiography (after R. Bernar and al) was noted to have a low sensitivity, especially at early stages of the development of chronic cor pulmonale. It was established that lung rheography suggested by A. M. Novikov is to be used for diagnosing pulmonary hypertension even though it doesn't allow estimating exactly an absolute value of mean blood pressure in pulmonary arteries.


Comparison between NRT-based MAPs and behaviourally measured MAPs at different stimulation rates--a multicentre investigation.
Seventeen adult subjects participated in a multicentre trial to compare the performance between an NRT-based MAP and their behavioural MAP. The NRT-based MAP was made using a correction factor to predict T/C levels, calculated from the difference between the ECAP threshold ('T-NRT') and the measured T/C levels at electrode 10, as described by Brown et al. (2000). A secondary aim was to compare T/C levels in behavioural MAPs at different stimulation rates with the predicted T/C levels in NRT-based MAPs. Performance with both MAPs was evaluated using CNC words and sentences. Variations in the T/C levels between all MAPs were found, although results of the speech discrimination tests demonstrated no statistically significant difference between behavioural and NRT-based MAPs.


Design may be counterproductive for optimizing flexion after TKR.
Pain-free flexion of as much as 155 degrees with stability is the ultimate goal of total knee replacement (TKR). Achieving this amount of flexion depends on implant design, surgical technique, preoperative range of motion (ROM), and patient cooperation. Current design trends are focusing on shortening the radii of curvature; such shortening, in turn, thickens the posterior femoral condyle, and increases the height of the posterior-stabilized box, both of which require removal of more bone. The end results may be excessive wear, increased patellofemoral complications, and difficult revisions. Several studies have indicated preoperative ROM is more predictive of postoperative ROM than any other criteria, including implant design. Based on currently available information, if full or almost full preoperative ROM is required for the high flex total knee design, few patients would qualify for the high flex TKA.


Endothelins produced by endothelial cells promote collagen gel contraction by fibroblasts.
Endothelial 1 (E1) is identified as an endothelial cell secreted factor that stimulates collagen gel contraction by fibroblasts. This identification is based on (a) co-localization of stimulatory activity in endothelial cell conditioned media with synthetic E1 in reversed phase analysis; (b) removal of the activity from conditioned media with antiserum directed against E1; and (c) the activity of synthetic E1. Treatment of endothelial cell conditioned media with immobilized anti-E1 antibodies removed 59% of the activity from the pool suggesting that E1 is the major contraction promoter in endothelial cell conditioned medium. The mechanism of action of E1 is shown to be different from serum in that E1-promoted contraction is dependent upon the synthesis of an unknown effector protein. Synthetic E1 is shown to be a potent promoter of gel contraction with half-maximal activity occurring at 32 pM. Two other endothelins, E2 and VIC, are slightly less active than E1. A fourth endothelin species, E3, is substantially less active. A comparison of E1 with other contraction promoting peptides revealed that E1 and platelet-derived growth factor are essentially equal in specific activity, whereas TGF beta is approximately 50-fold more potent.


Multiple mechanisms are responsible for altered expression of ornithine decarboxylase in overproducing variant cells.
We selected and characterized a series of mouse S49 cell variants that overproduce ornithine decarboxylase (ODC). Previously, we described variants that have an amplified ODC gene and produce about 500-fold more ODC than the wild-type cells of origin (L. McConlogue and P. Coffino, J. Biol. Chem. 258:12083-12086, 1983). We examined a series of independent variants that overproduce ODC to a lesser degree and found that a number of mechanisms other than gene amplification are responsible for the increased ODC activity. Variants were selected for resistance to 0.1 mM difluoromethylornithine, an inhibitor of ODC, by either a single or a multistep process. All showed increased ODC activity and increased ODC mRNA steady-state levels. The half-life of the enzyme was not increased in any of the variants. In one class of variant the increase of ODC mRNA was sufficient to account for ODC overproduction. In a second class, the rate of synthesis of ODC polypeptide per ODC mRNA was at least four- to eightfold higher than that in wild-type cells. Therefore, these variants were altered in the translatability of ODC mRNA. Southern analysis showed that gene amplification does not account for the increased ODC mRNA levels in any of the variants. In both variant and wild-type cells, ODC activity was responsive to changes in polyamine pools; activity was reduced following augmentation of pool size. This change in activity was associated with modification of the rate of synthesis and degradation of ODC but no change in the level of ODC mRNA.


Non-neoplastic pineal cysts.
We identified 53 patients with non-neoplastic cysts of the pineal gland. In contrast to patients with pineal neoplasms, pineal cysts are usually asymptomatic. They infrequently obstruct the aqueduct to cause hydrocephalus or compress the tectum to produce the neuro-ophthalmologic signs of dorsal midbrain dysfunction. Obstructive hydrocephalus was present in only five patients (9.4%); three of them showed clinical signs of Parinaud's syndrome. CT and MRI typically reveal a cystic mass that averages 1.6 cm in anteroposterior (A-P) diameter with calcification at the periphery and faint rim-like contrast enhancement. Sagittal MRI is the most useful diagnostic test because it shows the anatomic relationship of the cyst to the aqueduct. The mass may compress the tectum and distort the proximal aqueduct; occasionally a large cyst may occlude the aqueduct. All patients with obstructive hydrocephalus had cysts greater than 2.0 cm in A-P diameter. Nine patients had suboccipital craniotomy. In all of them, the cysts contained clear fluid and were easily removed. We advocate conservative management with clinical observation of these benign lesions that may be developmental variants of normal pineal gland.


[Variability of the levorin producer, Actinomyces levoris Krass].
Natural variation of the levorin-producing organism Act. levoris, strain 28 was studied with respect to the colony morphology and production of levorin and levoristatin. The population of strain 28 consisted of 3 morphological colony types, the main type amounting to 99.7 percent. The strain variation with respect to production of levorin and levoristatin ranged from 20 to 180 and from 0 to 300 percent respectively as compared to the control. Mutant M-28 differing from the initial strain by the colony morphology, moderate phage titer and preferable production of levoristatin was isolated as a result of repeated passages of strain 28 onto agarized Chapek media with starch without maintaining selection. Variants differing from the population of strains 28 and M-28 by the ratio of levorin and levoristatin in the culture fluid were selected. No correlation in production of the above antibiotics by strain 28 was noted. Preparations obtained with strain M-28 differed from those obtained with strain 28 in a significant content of levoristatin.


Donor-acceptor preassociation, excited state solvation threshold, and optical energy cost as challenges in chemical applications of photobases.
Photobases are molecules with increased pKa in the excited state that can serve to transduce light energy into proton removal capability. They can be used to control chemical reactions using light, such as removing protons from a catalytic site in reactions that are rate-limited by proton transfer. We identify and explore several major challenges toward their practical applications. Two important challenges are the need for pre-association (or ground state hydrogen bonding) between the proton donor and the photobase, and the need for excited state solvation of the photogenerated products. We investigate these two challenges with the photobase 5-methoxyquinoline as the proton acceptor and a low-pKa alcohol, 2,2,2-trifluoroethanol, as the proton donor. We vary the concentration of the donor in a background non-hydrogen-bonding solvent. Using absorption spectroscopy, we have identified that the donor-acceptor concentration ratio must exceed 100 : 1 to achieve appreciable ground state hydrogen bonding. Interestingly, emission spectroscopy reveals that the onset of ground state hydrogen bonding does not guarantee successful excited state proton transfer. It takes an additional order of magnitude increase in donor-acceptor ratio to achieve that goal, revealing that it is necessary to have excess donor molecules to reach the solvation threshold for the photogenerated products. The next challenge is reducing the large ground-excited state energy gap, which often requires UV photons to drive proton transfer. We show experimental and computational data comparing the photobasicity and optical energy gap for a few N-aromatic heterocyclic photobases. In general, we find that reducing the energy gap by increasing the conjugation size necessarily reduces photobasicity, while adding substituents of varying electron-withdrawing strength allows some fine-tuning of this effect. The combination of these two factors provide a preliminary design space for creating new photobasic molecules.


Thioredoxin system modulation by plant and fungal secondary metabolites.
Thioredoxin (Trx) is the major cellular protein disulfide reductase in a broad range of organisms, including humans. Trx, together with glutaredoxin (Grx), plays critical roles in the regulation of cellular protein redox homeostasis. Reduced thioredoxin transfers reducing equivalents to disulphides in target proteins, leading to reversible oxidation of its active centre dithiol to a disulphide. The resulting disulphide bridge is, in turn, reduced to a dithiol by thioredoxin reductase (TrxR). Increasing attention has been paid to the role of Trx, as it has been shown to be a signalling intermediate beyond its intrinsic antioxidant activity. Indeed, this protein acts as a growth factor, activates a number of transcription factors regulating cell growth and survival, acts as cofactor for ribonucleotide reductase, and promotes angiogenesis. In addition, Trx have been demonstrated to cooperatively inhibit programmed cell death. Because of the multiple roles of Trx system in tumorigenesis, this protein represents an emerging target for anti-cancer drugs. Several Trx system modulators have been identified: a semi-synthetic Trx inhibitor, PX-12 (1-methylpropyl 2-imidazolyl disulfide), has been placed in a clinical trial. However, there is a growing interest in finding new selective ones. Natural products continue to provide structurally complex, but highly original lead structures for drug discovery programs: polyphenols, quinones, and terpenoids showed to affect the Trx/TrxR system at different levels. The purpose of this review is to provide an overview of the plant and fungal secondary metabolites interfering with Trx and TrxR activities, paying particularly attention on their mechanism of action. Among polyphenols, curcumin and some flavonoids such as myricetin and quercetin, have been identified as potential anticancer agents with a mechanism of action that may be mediated by the Trx system.


Manic psychosis induced by long term alpha-interferon treatment for hepatitis C.
There is increasing evidence of psychiatric side-effects following long-term alpha-interferon treatment, but no previous reports of psychosis as a side-effect. There is little evidence to suggest the best treatment of interferonrelated psychiatric illness. A case of manic psychosis developing after longterm alpha-interferon treatment is reported in a woman with no previous psychiatric history. The patient did not respond to termination of alphainterferon therapy. She responded partially to olanzapine but completely recovered after sodium valproate was added, with no deleterious effects. Psychiatric side-effects, including psychosis, are appreciable problems of alpha-interferon. This is the first case report of psychosis developing after long-term treatment. It supports suggestions that the pathological mechanisms of the early and late side-effects are different. Sodium valproate proved to be a safe and effective treatment. (Int J Psych Clin Pract 2000; 4:161-162).


Electron Beam Induced Circularly Polarized Light Emission of Chiral Gold Nanohelices.
Chiral plasmonic nanostructures possess a chiroptical response orders of magnitude stronger than that of natural biomolecular systems, making them highly promising for a wide range of biochemical, medical, and physical applications. Despite extensive efforts to artificially create and tune the chiroptical properties of chiral nanostructures through compositional and geometrical modifications, a fundamental understanding of their underlying mechanisms remains limited. In this study, we present a comprehensive investigation of individual gold nanohelices by using advanced analytical electron microscopy techniques. Our results, as determined by angle-resolved cathodoluminescence polarimetry measurements, reveal a strong correlation between the circular polarization state of the emitted far-field radiation and the handedness of the chiral nanostructure in terms of both its dominant circularity and directional intensity distribution. Further analyses, including electron energy-loss measurements and numerical simulations, demonstrate that this correlation is driven by longitudinal plasmonic modes that oscillate along the helical windings, much like straight nanorods of equal strength and length. However, due to the three-dimensional shape of the structures, these longitudinal modes induce dipolar transverse modes with charge oscillations along the short axis of the helices for certain resonance energies. Their radiative decay leads to observed emission in the visible range. Our findings provide insight into the radiative properties and underlying mechanisms of chiral plasmonic nanostructures and enable their future development and application in a wide range of fields, such as nano-optics, metamaterials, molecular physics, biochemistry, and, most promising, chiral sensing via plasmonically enhanced chiral optical spectroscopy techniques.


Inflammatory bowel disease patients undergoing total hip arthroplasty have higher odds of implant-related complications.
This study evaluates whether IBD patients are at increased risk of implant-related complications after THA. A retrospective study from 01 January 2010 to 31 October 31 2020 using an administrative claims database was performed. IBD patients undergoing THA (n = 11,025), without corticosteroid treatment, were propensity score matched to controls in a 1:5 ratio (n = 55,121) based on age, sex, and the Charlson Comorbidity Index (CCI). Outcomes evaluated included periprosthetic fracture, aseptic loosening, prosthetic joint infection, and THA revision within 2 years of index procedure. Chi-square analyses were used to compare the matched cohorts. The association of IBD and implant-related complications was evaluated using logistical regression to calculate odds ratios (ORs), 95% confidence intervals (95% CIs), and p-values. A p-value < 0.001 was used as the significance threshold. Patients with IBD had a greater incidence and odds of total implant complications (7.03% vs. 3.98%; OR 1.76; p < 0.001) compared with matched controls. IBD patients had significantly higher incidence and odds of developing periprosthetic fracture (0.50% vs. 0.20%; OR 2.46; p < 0.001), THA revisions (2.21% vs. 1.17%; OR 1.91; p < 0.001), aseptic loosening (1.45% vs. 0.84%; OR 1.75; p < 0.001), and prosthetic joint infection (2.87% vs. 1.77%; OR 1.64; p < 0.001). Patients with IBD who underwent primary THA had a significantly higher risk of implant-related complications compared to matched controls. Providers should use this study to appropriately assess post-complication risk factors for their patients with IBD.


Rats anticipate and discriminate between two daily feeding times.
Intact rats and rats bearing lesions of the suprachiasmatic nuclei (SCNX rats) were trained to obtain food by pressing either of two levers located on opposite sides of a cylindrical cage. Intact rats were maintained in constant light (LL) and under daily light-dark (LD) cycles, SCNX rats in LL only. A restricted daily feeding schedule was next imposed, such that pressing one lever provided food for a limited duration (1 or 2 hr) at one time of day while pressing the second lever provided food for the same duration at another time of day. Most rats generally showed anticipatory lever-pressing preceding both daily feeding times, and several discriminated between the two, pressing the lever appropriate for each feeding time more than the inappropriate lever. Discrimination performance was better in intact rats in LD than in intact or SCNX rats in LL. These results indicate that rats can associate different food locations with different times of day, an ability previously known only in honeybees and birds.


Dietary Sugar Intake and Its Association with Obesity in Children and Adolescents.
Sugar intake has been associated with increased prevalence of childhood overweight/obesity; however, results remain controversial. The aim of this study was to examine the probability of overweight/obesity with higher sugar intakes, accounting for other dietary intakes. Data from 1165 children and adolescents aged ≥2-18 years (66.8% males) enrolled in the Hellenic National Nutrition and Health Survey (HNNHS) were used; specifically, 781 children aged 2-11 years and 384 adolescents 12-18 years. Total and added sugar intake were assessed using two 24 h recalls (24 hR). Foods were categorized into specific food groups to evaluate the main foods contributing to intakes. A significant proportion of children (18.7%) and adolescents (24.5%) exceeded the recommended cut-off of 10% of total energy intake from added sugars. Sweets (29.8%) and processed/refined grains and cereals (19.1%) were the main sources of added sugars in both age groups, while in adolescents, the third main contributor was sugar-sweetened beverages (20.6%). Being overweight or obese was 2.57 (p = 0.002) and 1.77 (p = 0.047) times more likely for intakes ≥10% of total energy from added sugars compared to less <10%, when accounting for food groups and macronutrient intakes, respectively. The predicted probability of becoming obese was also significant with higher total and added-sugar consumption. We conclude that high consumption of added sugars increased the probability for overweight/obesity among youth, irrespectively of other dietary or macronutrient intakes.


Low concentration of LatB dramatically changes the microtubule organization and the timing of vegetative nucleus/generative cell entrance in tobacco pollen tubes.
Low concentration of LatB inhibits not only the actin polymerization, but also induces profound alteration of MT distribution in pollen tubes of Nicotiana tabacum. The short randomly oriented MTs in the apical and subapical regions, became organized as bundles forming subapical rings or basket-like structures, surrounding the apex. Moreover, the depolymerization of AFs in the cortical regions of the apex and subapical region affects the timing of entrance of the vegetative nucleus and generative cell into the pollen tube.


Central cardiovascular hemodynamic response to unilateral handgrip exercise with blood flow restriction.
Exercise training with blood flow restriction (BFR) increases muscle size and strength. However, there is limited investigation into the effects of BFR on cardiovascular health, particularly central hemodynamic load. To determine the effects of BFR exercise on central hemodynamic load (heart rate-HR, central pressures, arterial wave reflection, and aortic stiffness). Fifteen males (age = 25 ± 2 years; BMI = 27 ± 2 kg/m2, handgrip max voluntary contraction-MVC = 50 ± 2 kg) underwent 5-min bouts (counter-balanced, 10 min rest between) of rhythmic unilateral handgrip (1 s squeeze, 2 s relax) performed with a moderate-load (60% MVC) with and without BFR (i.e., 71 ± 5% arterial inflow flow reduction, assessed via Doppler ultrasound), and also with a low-load (40% MVC) with BFR. Outcomes included HR, central mean arterial pressure (cMAP), arterial wave reflection (augmentation index, AIx; wave reflection magnitude, RM%), aortic arterial stiffness (pulse wave velocity, aPWV), and peripheral (vastus lateralis) microcirculatory response (tissue saturation index, TSI%). HR increased above baseline and time control for all handgrip bouts, but was similar between the moderate load with and without BFR conditions (moderate-load with BFR = + 9 ± 2; moderate-load without BFR = + 8 ± 2 bpm, p < 0.001). A similar finding was noted for central pressure (e.g., moderate load with BFR, cMAP = + 14 ± 1 mmHg, p < 0.001). No change occurred for RM% or AIx (p > 0.05) for any testing stage. TSI% increased during the moderate-load conditions (p = 0.01), and aPWV increased above baseline following moderate-load handgrip with BFR only (p = 0.012). Combined with BFR, moderate load handgrip training with BFR does not significantly augment central hemodynamic load during handgrip exercise in young healthy men.


Insect immunity: early events in the encapsulation process of parasitoid (Leptopilina boulardi) eggs in resistant and susceptible strains of Drosophila.
Eggs of an immune suppressive strain (= virulent) of the parasitoid Leptopilina boulardi are encapsulated neither in resistant nor in susceptible strains of Drosophila melanogaster but are encapsulated in Drosophila yakuba. Eggs of a nonimmune suppressive strain (= avirulent) of the same parasitoid are encapsulated in a resistant strain of D. melanogaster and in D. yakuba but are not encapsulated in a susceptible strain of D. melanogaster. Egg chorion in the 2 parasitoid strains showed the same morphology and the same modifications after egg laying whatever the host strain. When a capsule is built, a small dotted dense layer was first spread on the chorion, followed by accumulation layers of cells (plasmatocytes and lamellocytes) and lastly necrosis of the inner haemocytes. The encapsulated eggs darken only at the time of necrosis of haemocytes. In susceptible hosts, neither the tiny dense layer nor haemocyte accumulation occurred. We concluded that (1) this tiny dense layer was present before the deposition of the first haemocytes, (2) inhibition of deposition of this dense layer was the initial event of the induced immunosuppression, (3) haemocytes other than lamellocytes were engaged in capsule formation, (4) the immunosuppressive factors did not target only the lamellocytes but also the plasmatocytes, (5) darkening of the encapsulated eggs was due to cell necrosis rather than to extracellular melanin deposition.


Temporal and spatial assessment of river surface water quality using multivariate statistical techniques: a study in Can Tho City, a Mekong Delta area, Vietnam.
The present study is an evaluation of temporal/spatial variations of surface water quality using multivariate statistical techniques, comprising cluster analysis (CA), principal component analysis (PCA), factor analysis (FA) and discriminant analysis (DA). Eleven water quality parameters were monitored at 38 different sites in Can Tho City, a Mekong Delta area of Vietnam from 2008 to 2012. Hierarchical cluster analysis grouped the 38 sampling sites into three clusters, representing mixed urban-rural areas, agricultural areas and industrial zone. FA/PCA resulted in three latent factors for the entire research location, three for cluster 1, four for cluster 2, and four for cluster 3 explaining 60, 60.2, 80.9, and 70% of the total variance in the respective water quality. The varifactors from FA indicated that the parameters responsible for water quality variations are related to erosion from disturbed land or inflow of effluent from sewage plants and industry, discharges from wastewater treatment plants and domestic wastewater, agricultural activities and industrial effluents, and contamination by sewage waste with faecal coliform bacteria through sewer and septic systems. Discriminant analysis (DA) revealed that nephelometric turbidity units (NTU), chemical oxygen demand (COD) and NH₃ are the discriminating parameters in space, affording 67% correct assignation in spatial analysis; pH and NO₂ are the discriminating parameters according to season, assigning approximately 60% of cases correctly. The findings suggest a possible revised sampling strategy that can reduce the number of sampling sites and the indicator parameters responsible for large variations in water quality. This study demonstrates the usefulness of multivariate statistical techniques for evaluation of temporal/spatial variations in water quality assessment and management.


The expression of biologically active cholera toxin in Escherichia coli.
Chromosomal DNA from Vibrio cholerae El Tor strain 1621 was digested with Hind III and the products fractionated by centrifugation through a sucrose gradient. A 15kb fragment containing the toxin gene of V. cholerae was identified by its homology with the heat labile toxin (LT) gene of toxigenic E. coli. This fragment was cloned in E. coli using pAT153 and subsequently characterised by digestion with different restriction endonucleases. Sequences homologous to the LT gene were identified by hybridisation and then sub-cloned using either pAT153 or pACYC184. Expression of the cloned CT gene in E. coli was detected using both cell culture and ELISA assays. One recombinant plasmid coded for the synthesis of an immunologically active but biologically inactive derivative of CT.


How Do We Grow Our Next Generation of Nurse Leaders?
A plus sign can mean many things depending on the context-math for a school-aged child, a positive balance for an accountant, or, for us (the authors), new beginnings and new additions to our families. We were thrilled with the news that we were both expecting at the same time and that our children would be growing up together. As reality set in, however, we realized that this timing would have an incredible impact on our clinical oncology care teams because the two of us would be on leave at the same time.


Variables Related to Victimization and Perpetration of Dating Violence in Adolescents in Residential Care Settings.
Violence in dating relationships constitutes a serious problem, thus, the study of related factors could help to better understand this violence and intervene in it. This study had three goals: (1) To analyze the prevalence of dating violence in adolescents under residential care settings according to sex and age; (2) to explore the relationships between victimization and perpetration in adolescents' dating violence, sexist attitudes and clinical variables; and (3) to identify variables associated to adolescents' dating violence (victimization and perpetration). The sample comprised 271 adolescents (54.6% boys and 45.4% girls), aged between 12 and 17 years (M = 15.23, SD = 1.60). The victimization (R2 = .17, p <.001) and perpetration (R2 = .20. p < .001) results showed prevalence rates higher than those of previous studies. Sex was not a differentiating factor for perpetration of dating violence, but age was: the older they were, the higher the perpetration rate. In the case of victimization, an interaction between sex and age was found. Results showed that age, sex, hostile sexism and depression were variables associated to victimization whereas age, hostile sexism and depression were associated to perpetration of dating violence.


Anxiety on Primigravid Women Attending Antenatal Care: A Hospital Based Cross-sectional Study.
Background High levels of anxiety during pregnancy have adverse effects on mother and baby. Objective To assess anxiety on primigravid women attending Antenatal Care. Method Analytical cross-sectional study was carried out on the primigravid women attending Antenatal Care out-patient department of Dhulikhel Hospital. Perinatal Anxiety Screening Scale (PASS) was used to assess anxiety on 502 women. Data were collected through face-to-face interview using Systematic Random Sampling Technique from May 2017 to December 2017. Chi-square test was applied to test the association between selected variables. All p- values less than 0.05 were considered statistically significant. Result The mean (± Standard deviation [SD]) age of the participants was 23.17±3.9 years. More than half (57.6%) of the women were from the age group 20-25 years. Just above two-fifth (41.4%) of the participants were in the third trimester of pregnancy. Out of 502 pregnant women, nearly half (46.4%) of them were at high risk of anxiety. High risk of anxiety was significantly associated with age and type of family. However significant associations were not seen between high risk of anxiety during pregnancy and residence, educational status, occupation, husband's occupation and gestational period of women. Conclusion The high risk of anxiety on primigravid women was quite up. Anxiety during pregnancy was more likely to fall on younger women (age < 20 years) and joint families in comparison to those women from age twenty and above and nuclear families respectively.


[In Vitro Degradation Behavior of Absorbable Interface Screws].
The composite material PLGA compounded with β-tricalcium phosphate (β-TCP) was prepared by melt blending method, and the absorbable interface screw was prepared by injection molding process. Prepare PBS buffer that simulates human body, conduct in vitro degradation experiments on interface screws according to relevant national and industry standards, then test and characterize interface screws at different time points for degradation of intrinsic viscosity, average molecular weight distribution, mass loss, mechanical properties and thermal properties. According to the degradation performance-time curve, determine the time node at which the interface screw loses the mechanical properties. In this paper, the in vitro degradation behavior of interfacial screws prepared from PLGA and β-TCP composites was studied in detail, providing a reference and basis for the degradation behavior of absorbable products prepared from PLGA and β-TCP composites.


Repair of Retinal Degeneration by Human Amniotic Epithelial Stem Cell-Derived Photoreceptor-like Cells.
The loss of photoreceptors is a major event of retinal degeneration that accounts for most cases of untreatable blindness globally. To date, there are no efficient therapeutic approaches to treat this condition. In the present study, we aimed to investigate whether human amniotic epithelial stem cells (hAESCs) could serve as a novel seed cell source of photoreceptors for therapy. Here, a two-step treatment with combined Wnt, Nodal, and BMP inhibitors, followed by another cocktail of retinoic acid, taurine, and noggin induced photoreceptor-like cell differentiation of hAESCs. The differentiated cells demonstrated the morphology and signature marker expression of native photoreceptor cells and, intriguingly, bore very low levels of major histocompatibility complex (MHC) class II molecules and a high level of non-classical MHC class I molecule HLA-G. Importantly, subretinal transplantation of the hAESCs-derived PR-like cells leads to partial restoration of visual function and retinal structure in Royal College of Surgeon (RCS) rats, the classic preclinical model of retinal degeneration. Together, our results reveal hAESCs as a potential source of functional photoreceptor cells; the hAESCs-derived photoreceptor-like cells could be a promising cell-replacement candidate for therapy of retinal degeneration diseases.


Relation of handedness with season of birth of professional baseball players revisited.
We reexamined the relationship between month and season of birth and handedness in male professional baseball players listed in Lahman's Baseball Archive Vol. 4.5 database. The sample of 8,016 individuals (left-handed = 1,658; right-handed = 6,358) played major league baseball between 1900-2001. A slightly higher, but statistically significant, percentage of left-handed players were born in June compared to other months, and in the winter-spring months, but we were unable to corroborate Rogerson's spring and early summer categorization of handedness as related to birth season. The data did not support the hypothesis that the prevalence of left-handedness is related to season of birth.


RAAS and adrenergic genes in heart failure: Function, predisposition and survival implications.
It is well appreciated that several neurohormones and signaling cascades are activated that promote long-term deterioration of cardiac function and structure. Activation of the renin-angiotensin-aldosterone system (RAAS) and the adrenergic system is closely related to heart failure. Common gene variants that encode neurohormonal, adrenergic and intracellular proteins have been demonstrated to modulate the course and consequences of heart failure. However, the literature is replete with conflicting results and it remains uncertain as to whether particular gene variants predispose heart failure. Therefore, the main purpose of this review was to discuss the effects of single nucleotide polymorphisms (SNPs) that are located in genes encoding elements of the RAAS and the adrenergic system on the predisposition to and survival from heart failure. Most studies indicate that common SNPs encoding elements of the RAAS and the adrenergic system do not predispose individuals to heart failure. Conversely, it has been demonstrated that ARB1 Arg389Gly, GRK5 Gln41Leu, ACE I/D, CYP11B2 C-344T and AGTR1 A+1166C modulate pharmacological responses and have a considerable impact on cardiac-related survival. It should not be expected, however, that a single polymorphism determines survival, given that multiple gene products and environmental factors contribute to the pathogenesis of heart failure. Therefore, future studies should consider the interaction effects of multiple genes in populations that are as homogeneous as possible with respect to environmental characteristics.


Lacticaseibacillus rhamnosus CRL1505 Peptidoglycan Modulates the Inflammation-Coagulation Response Triggered by Poly(I:C) in the Respiratory Tract.
Lacticaseibacillus rhamnosus CRL1505 beneficially modulates the inflammation-coagulation response during respiratory viral infections. This study evaluated the capacity of the peptidoglycan obtained from the CRL1505 strain (PG-Lr1505) to modulate the immuno-coagulative response triggered by the viral pathogen-associated molecular pattern poly(I:C) in the respiratory tract. Adult BALB/c mice were nasally treated with PG-Lr1505 for two days. Treated and untreated control mice were then nasally challenged with poly(I:C). Mice received three doses of poly(I:C) with a 24 h rest period between each administration. The immuno-coagulative response was studied after the last administration of poly(I:C). The challenge with poly(I:C) significantly increased blood and respiratory pro-inflammatory mediators, decreased prothrombin activity (PT), and increased von Willebrand factor (vWF) levels in plasma. Furthermore, tissue factor (TF), tissue factor pathway inhibitor (TFPI), and thrombomodulin (TM) expressions were increased in the lungs. PG-Lr1505-treated mice showed significant modulation of hemostatic parameters in plasma (PT in %, Control = 71.3 ± 3.8, PG-Lr1505 = 94.0 ± 4.0, p < 0.01) and lungs. Moreover, PG-Lr1505-treated mice demonstrated reduced TF in F4/80 cells from lungs, higher pro-inflammatory mediators, and increased IL-10 compared to poly(I:C) control mice (IL-10 in pg/mL, Control = 379.1 ± 12.1, PG-Lr1505 = 483.9 ± 11.3, p < 0.0001). These changes induced by PG-Lr1505 correlated with a significant reduction in lung tissue damage. Complementary in vitro studies using Raw 264.7 cells confirmed the beneficial effect of PG-Lr1505 on poly(I:C)-induced inflammation, since increased IL-10 expression, as well as reduced damage, production of inflammatory mediators, and hemostatic parameter expressions were observed. In addition, protease-activated receptor-1 (PAR1) activation in lungs and Raw 264.7 cells was observed after TLR3 stimulation, which was differentially modulated by PG-Lr1505. The peptidoglycan from L. rhamnosus CRL1505 is able to regulate inflammation, the procoagulant state, and PAR1 activation in mice and macrophages in the context of the activation of TLR3 signaling pathways, contributing to a beneficial modulation of inflammation-hemostasis crosstalk.


Comparison of Thoracic Radiography and Computed Tomography in Calves with Naturally Occurring Respiratory Disease.
To evaluate the severity and extent of lung disease using thoracic computed radiography (CR) compared to contrast-enhanced multi-detector computed tomography (MDCT) of the thorax in calves with naturally occurring respiratory disease and to evaluate the feasibility and safety of performing contrast-enhanced thoracic multi-detector MDCT examinations in sedated calves. Furthermore, to evaluate if combining CR or MDCT with respiratory scoring factors will improve prediction of the chronicity of pulmonary disease in calves. Thirty Jersey heifer calves ranging in age between 25 and 89 days with naturally occurring respiratory disease. All calves were evaluated via thoracic CR and contrast-enhanced MDCT. All calves were euthanized immediately following thoracic MDCT and submitted for necropsy. Imaging and histopathology results were compared with each other. Thoracic MDCT was superior for evaluation of pneumonia in calves due to the lack of summation in all areas of the lungs. Intravenously administered sedation provided an adequate plane of sedation for acquiring MDCT images of diagnostic quality, without the need for re-scanning. A diagnosis of pneumonia was made with equal rate on both thoracic CR and MDCT. Although mild differences in classification of lung pattern and extent of lung disease were seen when comparing an experienced and a less experienced evaluator, the overall differences were not statistically significant. The best intra- and inter-observer agreement was noted when evaluating the cranioventral aspects of the lungs in either modality. Clinical respiratory scoring is inadequate for diagnosing chronicity of pneumonia in calves with naturally occurring pneumonia. Both imaging modalities allowed diagnosis of pneumonia in calves. The cranial ventral aspects of the lungs were most commonly affected. Thoracic CR and MDCT provided similar diagnostic effectiveness in diagnosing pneumonia. However, MDCT provided better assessment of subtle details, which may be otherwise obscured due to summation artifact.


Aucula magnifica (Schaus, 1904) (Lepidoptera: Noctuidae: Agaristinae): morphology of egg and last instar larvae.
Aiming to contribute to knowledge of the immature instars of Neotropical Lepidoptera, this study details the morphology of the egg and last instar larvae of Aucula magnifica (Schaus, 1904) (Lepidoptera: Noctuidae: Agaristinae), emphasising the structures of the corium and the chaetotaxy. There is also a report of the occurrence of entomopathogenic action of Nomuraea rileyi (Farlow) Samson fungi on the larva.


Psychosocial impact and effectiveness of tadalafil among treatment-naïve and previously-treated men with erectile dysfunction in Saudi Arabia and other Gulf-region countries.
This observational, comparative study, conducted in Saudi Arabia, Kuwait, and the United Arab Emirates, assessed psychosocial and efficacy outcomes of tadalafil 20 mg on demand, over a period of 20 weeks, in men with erectile dysfunction (ED) who were treatment-naïve versus pretreated with an ED treatment other than tadalafil. The short form of the Psychological and Interpersonal Relationship Scales (SF-PAIRS) was used to assess psychosocial outcomes (Time Concerns, Spontaneity, and Sexual Self-Confidence). Change from baseline in the International Index of Erectile Function (IIEF) erectile function (EF) domain score was used to assess effectiveness, and Global Assessment Question (GAQ) was asked to determine improvement in erections. Of 1080 patients analyzed, 557 (51.6%) were treatment-naïve and 523 (48.4%) were pretreated. In all, 500 (89.8%) treatment-naïve men and 473 (90.4%) pretreated men completed the study. Some statistically significant differences were observed in baseline characteristics between treatment-naïve and pretreated groups, including ED etiology, ED severity, duration of ED, and the presence of cormorbid cardiovascular disease, other vascular disease, and neurological disease. Adjusted mean SF-PAIRS Time Concerns domain score was significantly more improved, while the Sexual Self-Confidence domain score was significantly less improved, for the pretreated group compared with the treatment-naive group (both p<0.0001). No significant difference was observed for the Spontaneity domain. The mean change in IIEF-ED domain score for the treatment-naïve group was 13.26 compared with 9.28 for the pretreated group (p<0.0001). Positive responses to GAQ at the last assessment were observed in 97.3% of treatment-naïve men and 94.4% of pretreated men (p<0.0263). This large, observational study in the Gulf region demonstrates that ED patients treated with tadalafil in a naturalistic setting, report improvements in both psychosocial outcomes and erectile function, with some differences between the treatment-naïve and pretreated groups. The results of this study may assist physicians in tailoring tadalafil therapy and setting realistic treatment expectations.


Atypical Genetic Basis of Pyrazinamide Resistance in Monoresistant Mycobacterium tuberculosis.
Pyrazinamide (PZA) is a widely used antitubercular chemotherapeutic. Typically, PZA resistance (PZA-R) emerges in Mycobacterium tuberculosis strains with existing resistance to isoniazid and rifampin (i.e., multidrug resistance [MDR]) and is conferred by loss-of-function pncA mutations that inhibit conversion to its active form, pyrazinoic acid (POA). PZA-R departing from this canonical scenario is poorly understood. Here, we genotyped pncA and purported alternative PZA-R genes (panD, rpsA, and clpC1) with long-read sequencing of 19 phenotypically PZA-monoresistant isolates collected in Sweden and compared their phylogenetic and genomic characteristics to a large set of MDR PZA-R (MDRPZA-R) isolates. We report the first association of ClpC1 mutations with PZA-R in clinical isolates, in the ClpC1 promoter (clpC1p-138) and the N terminus of ClpC1 (ClpC1Val63Ala). Mutations have emerged in both these regions under POA selection in vitro, and the N-terminal region of ClpC1 has been implicated further, through its POA-dependent efficacy in PanD proteolysis. ClpC1Val63Ala mutants spanned 4 Indo-Oceanic sublineages. Indo-Oceanic isolates invariably harbored ClpC1Val63Ala and were starkly overrepresented (odds ratio [OR] = 22.2, P < 0.00001) among PZA-monoresistant isolates (11/19) compared to MDRPZA-R isolates (5/80). The genetic basis of Indo-Oceanic isolates' overrepresentation in PZA-monoresistant tuberculosis (TB) remains undetermined, but substantial circumstantial evidence suggests that ClpC1Val63Ala confers low-level PZA resistance. Our findings highlight ClpC1 as potentially clinically relevant for PZA-R and reinforce the importance of genetic background in the trajectory of resistance development.


Study of Norwalk virus and Mexico virus infections at Ga-Rankuwa Hospital, Ga-Rankuwa, South Africa.
Small round-structured viruses (SRSVs) or Norwalk-like viruses have been implicated as an important causative agent of gastroenteritis outbreaks. We used the relatively newly developed recombinant enzyme immunoassays (EIAs) to determine the seroprevalence of Norwalk virus (NV) and Mexico virus (MxV) in a family-based cohort and an antenatal clinic cohort at Ga-Rankuwa Hospital, Ga-Rankuwa, South Africa. High prevalences (96 to 99%) of anti-NV and anti-MxV antibodies were detected in both cohorts. We also investigated the pattern of antibody acquisition in a cohort of infants and young children without gastroenteritis and found that by 48 months of age all children had acquired adult antibody levels to both these viruses. Lastly, we tested 276 stool specimens collected from infants and young children with gastroenteritis for the presence of NV or MxV antigen by recombinant EIAs to each virus, by electron microscopy (EM), and by reverse transcription (RT)-PCR. NV and MxV antigens were present in 1.8 and 4.3% of the stool specimens, respectively, by the recombinant EIAs; 9.2% were positive for SRSVs by EM, and 25% of these SRSVs gave a positive result by RT-PCR for primer pair 35-36 directed to a region of the RNA-dependent RNA polymerase gene. The seroprevalence studies indicate a high level of exposure to these viruses in both children and adults. Although the viral antigens are not highly prevalent in diarrheal stools, it was determined by the two assays for NV and MxV that children are, nevertheless, infected early in life.


Pulmonary embolism in a patient with neuroleptic malignant syndrome.
Venous thromboembolism is one of the complications in patients prescribed antipsychotic medications. Neuroleptic malignant syndrome (NMS) is a rare side effect of antipsychotic medications in this population. In this case, a young patient, who presented with NMS after a recent start of antipsychotic medications, had developed a pulmonary embolism despite standard of care measures of venous thromboprophylaxis and early mobilization. A low threshold of VTE suspicion and effective preventive measures are both required in order to avoid this preventable complication in this population.


Dermatofibrosarcoma protuberans in children: an update on the diagnosis and treatment.
Dermatofibrosarcoma protuberans (DFSP) is a fibrohistiocytic tumor of low grade malignant potential. Although rare, pediatric cases pose a particular challenge in diagnosis and management. In children, the clinical appearance may be heterogeneous and a high index of suspicion is necessary to avoid delays in diagnosis which can lead to further morbidity. Histologic examination, often with the use of appropriate immunostains, is necessary for diagnosis. Advances in the understanding of the molecular genetics of DFSP have led to further diagnostic and therapeutic modalities. DFSP is thought to result from a translocation between platelet-derived growth factor beta (PDGFB, 22q13.1) and type 1 collagen (COL1A1, 17q21≈22) leading to a fusion protein (PDGFB) which stimulates the PDGF receptor. Detection of this translocation in tissue via PCR or fluorescence in situ hybridization (FISH) can be helpful in difficult cases. While surgery with wide local excision or Mohs micrographic surgery is the mainstay of treatment, the use of targeted therapy with imatanib mesylate shows promise in large or unresectable tumors. Knowledge of the clinical features, histology, genetics, and treatment options is important for successful management of these tumors.


Bis(tert-butylimido)bis(N,O-chelate)tungsten(VI) Complexes: Probing Amidate and Pyridonate Hemilability.
Four new bis(tert-butylimido)bis(N,O-chelate)tungsten(VI) complexes (3-6), in which the N,O-chelate is an amidate or pyridonate ligand, have been synthesized and characterized. Computational analysis has been used to calculate the relative energies of different stereoisomers and shown how the steric demand of each ligand influences coordination and bonding modes. The electronically saturated complexes have been employed to evaluate 1,3-N,O-chelated metal-ligand interactions. Complexes 3-6 were treated with electrophilic reagents, which resulted in strikingly different reactivity patterns between the amidate and the pyridonate ligated complexes. The observed reactivity differences are accompanied by direct observation of different trends in the hemilability of these two different classes of 1,3-N,O-chelates.


Heart Failure is Highly Prevalent and Difficult to Diagnose in Severe Exacerbations of COPD Presenting to the Emergency Department.
Some 20% of patients with stable Chronic Obstructive Pulmonary Disease (COPD) might have heart failure (HF). HF contribution to acute exacerbations of COPD (AECOPD) presenting to the emergency department (ED) is not well established. To assess (1) the HF incidence in patients presenting to the ED with AECOPD; (2) the concordance between ED and respiratory ward (RW) diagnosis; (3) the factors associated with risk of death after hospital discharge. Retrospective chart review of 119 COPD patients presenting to ED for acute exacerbation of respiratory symptoms and then admitted to RW where a final diagnosis of AECOPD, AECOPD and HF and AECOPD and OD (other diagnosis), was obtained. ED and RW diagnosis were then compared. Factors affecting survival at follow-up were investigated. At RW, 40.3% of cases were diagnosed of AECOPD, 40.3% of AECOPD and HF and 19.4% of AECOPD and OD, with ED diagnosis coinciding with RW's in 67%, 23%, and 57% of cases respectively. At RW, 60% of patients in GOLD1 had HF, of which 43% were diagnosed at ED, while 40% in GOLD4 had HF that was never diagnosed at ED. Lack of inclusion in a COPD care program, HF, and early readmission for AECOPD were associated with mortality. HF is highly prevalent and difficult to diagnose in patients in all GOLD stages presenting to the ED with severe AECOPD, and along with lack of inclusion in a COPD care program, confers a high risk for mortality.


[Bradykinin and asthma].
Bradykinin and related kinins formed in tissues and fluids during inflammation, exert many physiological effects mediated by two receptor subtypes: B1 and B2. The involvement of kinins in bronchial asthma has been speculated in numerous clinicals reports. The effects of bradykinin on airways have been studied in vivo and in vitro in animals and humans, but its mode of action remains uncertain. The recent availability of selective B2 antagonists could be of help in defining more precisely kinins in the various aspects of asthma.


The effects of acute beta-adrenergic blockade on aortic wave reflection in postmenopausal women.
BACKGROUND Acute beta-adrenergic blockade increases aortic-wave reflection in young women. However, it is not known whether this effect extends to postmenopausal women. We therefore examined the effect of systemic beta-adrenergic blockade on aortic wave reflection in 14 postmenopausal women with a mean age of 58±2 years. METHODS Aortic pressure waveforms were synthesized noninvasively from high-fidelity radial pressure waveforms obtained through applanation tonometry before and during systemic beta-blockade with propranolol given in a bolus dose of 0.25mg/kg, followed by a continuous infusion at 0.004mg/kg/min. To further examine the effects of acute beta-blockade on aortic-wave reflection in postmenopausal women, we compared the changes in hemodynamics and indices of aortic-wave reflection with published data from a previous study with a protocol identical to that in the present study but which involved young women. RESULTS Acute beta-blockade increased the aortic augmentation index (AIx) in postmenopausal women (32±2% vs. 35±2%, P < 0.01). However, AIx adjusted for a heart rate of 75 bpm (AIx75) was unchanged (25±2% vs. 24±2%, P > 0.05). The changes in AIx, AIx75, and the amplitude of reflected waves (augmented aortic pressure) during beta-blockade were all substantially smaller in postmenopausal women than in their younger counterparts (P < 0.05). Conclusions As compared with those in our previously published study involving young women, indices of aortic-wave reflection were significantly less affected by acute systemic beta-adrenergic blockade in the postmenopausal women in the present study. Taken together, our data suggest that the negative effects (i.e. increased aortic wave reflection) of nonselective beta-adrenergic blockade are less pronounced in postmenopausal than in young women.


Detection of latent tuberculosis in immunosuppressed patients with autoimmune diseases: performance of a Mycobacterium tuberculosis antigen-specific interferon gamma assay.
To analyse the performance of a new M. tuberculosis-specific interferon gamma (IFNgamma) assay in patients with chronic inflammatory diseases who receive immunosuppressive drugs, including tumour necrosis factor alpha (TNFalpha) inhibitors. Cellular immune responses to the M. tuberculosis-specific antigens ESAT-6, CFP-10, TB7.7 were prospectively studied in 142 consecutive patients treated for inflammatory rheumatic conditions. Results were compared with tuberculin skin tests (TSTs). Association of both tests with risk factors for latent M. tuberculosis infection (LTBI) and BCG vaccination were determined and the influence of TNFalpha inhibitors, corticosteroids, and disease modifying antirheumatic drugs (DMARDs) on antigen-specific and mitogen-induced IFNgamma secretion was analysed. 126/142 (89%) patients received immunosuppressive therapy. The IFNgamma assay was more closely associated with the presence of risk factors (odds ratio (OR) = 23.8 (95% CI 5.14 to 110) vs OR = 2.77 (1.22 to 6.27), respectively; p = 0.009), but less associated with BCG vaccination than the TST (OR = 0.47 (95% CI 0.15 to 1.47) vs OR = 2.44 (0.74 to (8.01), respectively; p = 0.025). Agreement between the IFNgamma assay and TST results was low (kappa = 0.17; 95% CI 0.02 to 0.32). The odds for a positive IFNgamma assay strongly increased with increasing prognostic relevance of LTBI risk factors. Neither corticosteroids nor conventional DMARDs significantly affected IFNgamma responses, but the odds for a positive IFNgamma assay were decreased in patients treated with TNFalpha inhibitors (OR = 0.21 (95% CI 0.07 to 0.63), respectively; p = 0.006). These results demonstrate that the performance of the M. tuberculosis antigen-specific IFNgamma ELISA is better than the classic TST for detection of LTBI in patients receiving immunosuppressive therapy for treatment of systemic autoimmune disorders.


Study of autonomic modulation by non-linear analysis of heart rate variability in different age groups and analysis of health status, disease and risk of death in dogs.
The symbolic analysis of heart rate variability (biomarker of cardiac autonomic homeostasis) is a nonlinear and effective tool for pattern extraction and classification in a series analysis, which implies the transformation of an original time series into symbols, represented by numbers. Autonomic heart rate control is influenced by different factors, and better indicators of heart rate variability are found in healthy young individuals than in older and sicker individuals. The aim of this study was to compare the indicators of heart rate variability among healthy dogs in different age groups and in health status using the nonlinear method of symbolic analysis to evaluate the diagnostic accuracy of this method for the risk of death in dogs. An increase in cardiac sympathetic modulation was observed in puppies and dogs at risk of death, which was evidenced by a marked increase of 0 V% (without variation - associated with sympathetic modulation) and a decrease in patterns of 2 V% (two variations - associated with parasympathetic modulation), while the opposite was observed in young adult dogs with increased parasympathetic modulation. Elderly dogs showed a gradual decrease in parasympathetic activity, which tended to worsen with loss of health. It is concluded that the variables of symbolic analysis may be useful to evaluate autonomic modulation in dogs and assist in the differentiation between health states, advanced disease and death throughout the life cycle and have been shown to be indices with high specificity, sensitivity and diagnostic accuracy to help identify dogs at risk of death.


Biochemical and localization analyses of putative type III secretion translocator proteins CopB and CopB2 of Chlamydia trachomatis reveal significant distinctions.
Chlamydia spp. are among the many pathogenic Gram-negative bacteria that employ a type III secretion system (T3SS) to overcome host defenses and exploit available resources. Significant progress has been made in elucidating contributions of T3S to the pathogenesis of these medically important, obligate intracellular parasites, yet important questions remain. Chief among these is how secreted effector proteins traverse eukaryotic membranes to gain access to the host cytosol. Due to a complex developmental cycle, it is possible that chlamydiae utilize a different complement of proteins to accomplish translocation at different stages of development. We investigated this possibility by extending the characterization of C. trachomatis CopB and CopB2. CopB is detected early during infection but is depleted and not detected again until about 20 h postinfection. In contrast, CopB2 was detectible throughout development. CopB is associated with the inclusion membrane. Biochemical and ectopic expression analyses were consistent with peripheral association of CopB2 with inclusion membranes. This interaction correlated with development and required both chlamydial de novo protein synthesis and T3SS activity. Collectively, our data indicate that it is unlikely that CopB serves as the sole chlamydial translocation pore and that CopB2 is capable of association with the inclusion membrane.


Haemodynamic and echocardiographic characteristics of a stentless allograft mitral prosthesis: an in vitro study.
Poor long-term durability and impaired haemodynamic performance are known disadvantages of bioprosthetic heart valves when compared to valve replacement using aortic allografts. A new stentless allograft mitral implant was developed and tested in vitro in a left ventricular model and pulsatile flow system to evaluate hydrodynamic function. Mitral valves were excised from sheep hearts and the mitral annulus reinforced by a strip of ovine pericardium. A patch of expanded polytetrafluoroethylene (ePTFE) was placed above the tips of the remaining papillary muscles. For in vitro evaluation of a total of five valves were investigated in a pulse duplicator. Transvalvular pressure gradients (delta P) were measured over a flow range corresponding to a cardiac output of 5l/min, at a heart rate of 70 beats/min, with a systole accounting for approximately 35% of the cardiac cycle. The systolic ejection period and diastolic filling period in this model were 350 and 510 ms, respectively, and aortic pressure was 120/80 mmHg. The effective orifice area was calculated from measurements of mean pressure drop and root mean square flow. Additionally, valve performance was evaluated by Doppler echocardiography. Results of in vitro studies of a 25 mm stentless allograft mitral implant, which is similar to the valves implanted in a chronic weaning sheep model, revealed a mean(s.d.) delta P of 2.0(1.6) mmHg (range 1.0-4.9 mmHg). The mean calculated effective orifice area was 3.38(0.52) cm(2) (range 2.5-3.8 cm(2)). Doppler echocardiography showed excellent performance of the mitral valve components and valve competence could be achieved. During the in vitro studies no failure caused by tissue rupture was detected. The results of the in vitro studies revealed data for delta P and effective orifice area superior to data obtained for standard 25 mm porcine bioprostheses.


Protective effects of apigenin against 3-MCPD-induced renal injury in rat.
Apigenin (API) is a kind of important flavonoid present in temperate and tropical fruit and vegetables, especially the celery. It exerts anticancer, anti-bacterial, anti-viral, anti-inflammatory, anti-oxidation properties. In the present study, the mechanism of protective action of apigenin on 3-chloro-1, 2-propanediol (3-MCPD)-induced renal injury was investigated in rat. Sprague-Dawley (SD) rats were divided into five groups: control group (ultrapure water treated), CMC group (sodium carboxymethylcellulose treated), 3-MCPD treatment group (30 mg/kg body weight/day), 3-MCPD plus API co-treatment group (20, 40 mg/kg body weight/day). The results showed that API significantly reduced renal function markers, serum creatinine and urea nitrogen content. Besides, the renal tissue lesion in 3-MCPD treatment group was restored by API to some extent. We indicated that API exerted renoprotective effect by modulating oxidative phosphorylation especially up-regulated the expressions of ATP6 and ATP8, re-establishing mitochondrial membrane potential (MMP), relieving the increase of Bax/Bcl2 ratio, reducing cytochrome c release, thus inhibiting the activation of Caspase 9 and Caspase 3. In conclusion, apigenin possesses excellent protective effect against 3-MCPD-induced renal injury by modulating mitochondria dependent Caspase cascade pathway.


Photoclickable dendritic molecular glue: noncovalent-to-covalent photochemical transformation of protein hybrids.
A water-soluble dendron with a fluorescein isothiocyanate (FITC) fluorescent label and bearing nine pendant guanidinium ion (Gu(+))/benzophenone (BP) pairs at its periphery (Glue(BP)-FITC) serves as a "photoclickable molecular glue". By multivalent salt-bridge formation between Gu(+) ions and oxyanions, Glue(BP)-FITC temporarily adheres to a kinesin/microtubule hybrid. Upon subsequent exposure to UV light, this noncovalent binding is made permanent via a cross-linking reaction mediated by carbon radicals derived from the photoexcited BP units. This temporal-to-permanent transformation by light occurs quickly and efficiently in this preorganized state, allowing the movements of microtubules on a kinesin-coated glass plate to be photochemically controlled. A fundamental difference between such temporal and permanent bindings was visualized by the use of "optical tweezers".


Shifting of puncture site in the fossa ovalis during radiofrequency catheter ablation: intracardiac echocardiography-guided transseptal left heart catheterization.
Intracardiac echocardiography (ICE) serves as an adjunct to fluoroscopy for electrophysiological procedures by identifying critical anatomic landmarks and confirming catheter-endocardial contact. In the present study, we investigated the usefulness of ICE for radiofrequency catheter ablation. ICE was utilized to guide transseptal puncture in 19 patients undergoing radiofrequency catheter ablation. The fossa ovalis, which was one critical anatomic landmark, had an average vertical diameter of 18.5 +/- 6.9 mm and an average horizontal diameter of 10.0 +/- 2.4 mm, as measured by ICE and fluoroscopy. Although there was only a small shift of the puncture site in the horizontal direction, the puncture site shifted towards the upper edge of the fossa ovalis for 17 patients (89%). Furthermore, we could verify that the distance between the apex of the tent-shape formed by the pressure of the puncture needle in the fossa ovalis and the left atrial wall opposing it was sufficient to carry out the procedure safely. Confirming the puncture site using ICE is useful in carrying out transseptal left heart catheterization safely.


Frequent associations between CTL and T-Helper epitopes in HIV-1 genomes and implications for multi-epitope vaccine designs.
Epitope vaccines have been suggested as a strategy to counteract viral escape and development of drug resistance. Multiple studies have shown that Cytotoxic T-Lymphocyte (CTL) and T-Helper (Th) epitopes can generate strong immune responses in Human Immunodeficiency Virus (HIV-1). However, not much is known about the relationship among different types of HIV epitopes, particularly those epitopes that can be considered potential candidates for inclusion in the multi-epitope vaccines. In this study we used association rule mining to examine relationship between different types of epitopes (CTL, Th and antibody epitopes) from nine protein-coding HIV-1 genes to identify strong associations as potent multi-epitope vaccine candidates. Our results revealed 137 association rules that were consistently present in the majority of reference and non-reference HIV-1 genomes and included epitopes of two different types (CTL and Th) from three different genes (Gag, Pol and Nef). These rules involved 14 non-overlapping epitope regions that frequently co-occurred despite high mutation and recombination rates, including in genomes of circulating recombinant forms. These epitope regions were also highly conserved at both the amino acid and nucleotide levels indicating strong purifying selection driven by functional and/or structural constraints and hence, the diminished likelihood of successful escape mutations. Our results provide a comprehensive systematic survey of CTL, Th and Ab epitopes that are both highly conserved and co-occur together among all subtypes of HIV-1, including circulating recombinant forms. Several co-occurring epitope combinations were identified as potent candidates for inclusion in multi-epitope vaccines, including epitopes that are immuno-responsive to different arms of the host immune machinery and can enable stronger and more efficient immune responses, similar to responses achieved with adjuvant therapies. Signature of strong purifying selection acting at the nucleotide level of the associated epitopes indicates that these regions are functionally critical, although the exact reasons behind such sequence conservation remain to be elucidated.


Behavioral medicine approaches to somatoform disorders.
This article reviews the research evidence for the efficacy of cognitive-behavioral therapy (CBT) for somatoform disorders. Randomized controlled studies support the efficacy of individual CBT for the treatment of hypochondriasis, body dysmorphic disorder (BDD), and undifferentiated somatoform disorders including medically unexplained symptoms, chronic fatigue syndrome, and noncardiac chest pain, and group CBT for the treatment of BDD and somatization disorder. On the basis of this review of the existing research and a theoretical model of the processes involved in somatoform disorders, the authors offer suggestions for future research and effective treatment.


Microarray expression profiling in melanoma reveals a BRAF mutation signature.
We have used microarray gene expression profiling and machine learning to predict the presence of BRAF mutations in a panel of 61 melanoma cell lines. The BRAF gene was found to be mutated in 42 samples (69%) and intragenic mutations of the NRAS gene were detected in seven samples (11%). No cell line carried mutations of both genes. Using support vector machines, we have built a classifier that differentiates between melanoma cell lines based on BRAF mutation status. As few as 83 genes are able to discriminate between BRAF mutant and BRAF wild-type samples with clear separation observed using hierarchical clustering. Multidimensional scaling was used to visualize the relationship between a BRAF mutation signature and that of a generalized mitogen-activated protein kinase (MAPK) activation (either BRAF or NRAS mutation) in the context of the discriminating gene list. We observed that samples carrying NRAS mutations lie somewhere between those with or without BRAF mutations. These observations suggest that there are gene-specific mutation signals in addition to a common MAPK activation that result from the pleiotropic effects of either BRAF or NRAS on other signaling pathways, leading to measurably different transcriptional changes.


The role of immunophilins in mutant superoxide dismutase-1linked familial amyotrophic lateral sclerosis.
It has been reported that expression of familial amyotrophic lateral sclerosis (FALS)-associated mutant Cu/Zn superoxide dismutase-1 (SOD) induces apoptosis of neuronal cells in culture associated with an increase in reactive oxygen species. SOD recently has been shown to prevent calcineurin inactivation, initiating the present investigations examining the role of calcineurin in mutant SOD-induced cell death. Wild-type or mutant SOD was expressed in neuronal cells by infection with replication-deficient adenoviruses. PC12 cells overexpressing human wild-type SOD exhibited higher calcineurin activity than cells expressing FALS-related mutant SOD (SODV148G); however, cells expressing SODV148G had calcineurin activity equal to mock-infected cells, suggesting that cell death induced by mutant SOD was not related to a decrease in calcineurin activity. Calcineurin antagonists such as cyclosporin A and FK506, as well as nonimmunosuppressant analogs of cyclosporin A, significantly enhanced SODV148G- and SODA4V-induced cell death. Because both groups of drugs inhibit the rotamase activity of cyclophilins (CyP), but only the immunosuppressant analogs inhibit calcineurin activity, these data suggest that rotamase inhibition underlies the enhanced cell death after SODV148G expression. The importance of rotamase activity in mutant SOD-mediated apoptosis was supported by experiments showing that overexpressed wild-type cyclophilin A (CyPA), but not CyPA with a rotamase active site point mutation, protected cells from death after SODV148G expression. These data suggest that mutant SOD produces a greater need for rotamase and, also, highlights possible new therapeutic strategies in FALS.


Quinalizarin, a specific CK2 inhibitor, reduces cell viability and suppresses migration and accelerates apoptosis in different human lung cancer cell lines.
Protein kinase CK2 is widely expressed in eukaryotic cells, and plays an important role in cell proliferation, migration, apoptosis, etc. The aim of the current study is to explore how Quinalizarin, a specific CK2 inhibitor, affects the cell proliferation, migration, and apoptosis of different pathological and genetic types of human lung cancer cell lines. MTT assays were performed to evaluate the cell viability after being treated by Quinalizarin. Transwell migration assays were used to assess whether Quinalizarin could suppress cell migration. Flow cytometry was employed to test the apoptosis rate of different cells. After being treated by Quinalizarin, the viability of different pathological types of lung cancer cells (H446, H460, A549) were significantly suppressed in a time and dose-dependent manner. More interestingly, in a serial of human lung adenocarcinoma cell lines with different epidermal growth factor receptor (EGFR) mutation status, Quinalizarin was shown to have a much better ability to reduce the viability of cells with EGFR sensitive mutation than those with resistance mutations. Meanwhile, we also found that the cell migration of different pathological types of lung cancer cells (H446, H460, A549) was significantly decreased by Quinalizarin dose-dependently. In addition, the apoptosis rates in those cells were proved to be increased after exposed to Quinalizarin. Quinalizarin, the specific CK2 inhibitor, could reduce cell viability with emphasis on adenocarcinoma cells harboring EGFR sensitive mutation, suppresses migration, and accelerates apoptosis in different human lung cancer cell lines.


Different sensitivity and threshold in response to nitrogen addition in four alpine grasslands along a precipitation transect on the Northern Tibetan Plateau.
The increase in atmospheric nitrogen (N) deposition has resulted in some terrestrial ecological changes. In order to identify the response of sensitive indicators to N input and estimate the sensitivity and saturation thresholds in alpine grasslands, we set up a series of multilevel N addition experiments in four types of alpine grasslands (alpine meadow [AM], alpine meadow-steppe [AMS], alpine steppe [AS], and alpine desert-steppe [ADS]) along with a decreasing precipitation gradient from east to west on the Northern Tibetan Plateau. N addition only had significant effects on species diversity in AMS, while had no effects on the other three alpine grasslands. Aboveground biomass of grasses and overall community in ADS were enhanced with increasing N addition, but such effects did not occur in AS. Legume biomass in ADS and AS showed similar unimodal patterns and exhibited a decreasing tend in AM. Regression fitting showed that the most sensitive functional groups were grasses, and the N saturation thresholds were 103, 115, 136, and 156 kg N hm-2 year-1 in AM, AMS, AS, and ADS, respectively. This suggests that alpine grasslands become more and more insensitive to N input with precipitation decrease. N saturation thresholds also negatively correlated with soil N availability. N sensitivity differences caused by precipitation and nutrient availability suggest that alpine grasslands along the precipitation gradient will respond differently to atmospheric N deposition in the future global change scenario. This different sensitivity should also be taken into consideration when using N fertilization to restore degraded grasslands.


The Idea of Precaution: Ethical Requirements for the Regulation of New Biotechnologies in the Environmental Field.
The rapid emergence of new biotechnologies for selectively altering genetic material-so-called genome editing-has sparked public controversy about how their development and application in the environmental fields are to be regulated. Since the use of these new technologies harbors not only considerable potential but also risks of serious damage whose occurrence is uncertain due to their application in complex environmental systems, many national and international legal authorities are currently adhering to policies of precaution. According to critics, however, precautionary measures and the legal principle of precaution on which they are based are unduly restrictive in the case of the new biotechnologies, hindering advancements in both research and various fields of application. At the same time, legal notions of precaution are highly ambiguous within and across different national and international formulations, thereby further complicating the controversy about their implications. This paper goes beyond the concept of precaution as found in environmental law by examining the ethical significance and the ethical justification of precautionary measures in the environmental field. In particular, it clarifies the criterion of potential damage, disambiguates different types of epistemic bases in precaution decisions, and considers the relevance and implications of different ethical risk theories as to their response to epistemic uncertainty and vagueness. The two main conclusions are that, first, irrespective of the ethical risk theory embraced, there is an ethical obligation to take precautionary measures whenever serious damage is possible and the probability of damage occurring epistemically uncertain or vague. Regarding the risk assessment, it is argued that the burden of proof lies not with those who fear the occurrence of serious environmental damage. Rather, it is up to those whose actions give rise to such fears to demonstrate that serious damage is extremely improbable or scientifically absurd. Second, the moral responsibility to determine precaution situations and to specify appropriate precautionary measures is attributed not only to state authorities but also to industrial players as well as research communities. Based on these two conclusions, recommendations are given as to how the precautionary principle should be incorporated in political and legal decision-making.


Immunohistochemical expression of types I and III collagen antibodies in the temporomandibular joint disc of human foetuses.
The objective was to study the morphology of the articular disc and analyse the immunohistochemical expression of types I and III collagen markers in the temporomandibular joint (TMJ) disc of human foetuses of different gestational ages. Twenty TMJ from human foetuses supplied by Universidade Federal de Uberaba with gestational ages from 17 to 24 weeks were studied. The gestational age of the foetuses was determined by measuring the crown-rump (CR) length. Macroscopically, the foetuses were fixed in 10% formalin solution and dissected by removing the skin and subcutaneous tissue and exposing the deep structures. Immunohistochemical markers of type I and III were used to characterize the existence of collagen fibres. Analysis of the immunohistochemical markers of types I and III collagen revealed the presence of heterotypical fibril networks.


The credibility crisis in research: Can economics tools help?
The issue of nonreplicable evidence has attracted considerable attention across biomedical and other sciences. This concern is accompanied by an increasing interest in reforming research incentives and practices. How to optimally perform these reforms is a scientific problem in itself, and economics has several scientific methods that can help evaluate research reforms. Here, we review these methods and show their potential. Prominent among them are mathematical modeling and laboratory experiments that constitute affordable ways to approximate the effects of policies with wide-ranging implications.


Improved behavior, motor, and cognition assessments in neonatal piglets.
The alterations of animal behavior after traumatic brain injury (TBI) can be subtle, and their quantitative characterization can present significant methodological challenges. Meeting these challenges is a critical need, because quantitative measures are required in studies that compare the efficacy of different clinical interventions. We developed a battery of assessments to quantify behavioral, motor, and cognitive changes in neonatal piglets with good sensitivity and specificity to the detection of persistent deficits that correlate with axonal injury severity after a rapid non-impact head rotation with a diffuse pattern of axonal injury. The battery of measures developed included open field behaviors of sniffing and moving a toy, locomotion measures of Lempel-Ziv complexity and the probability of remaining in the current location, and a novel metric for evaluating motor performance. Our composite porcine disability score was able to detect brain injury with a sensitivity of 100% and specificity of 85.7% at day +4 post-injury for n=8 injured and n=7 sham piglets and significantly correlated with the percent axonal injury in these animals (day +4: ρ=0.76, p=0.0011). A significant improvement over our previous assessments, this new porcine disability score has potential use in a wide variety of porcine disease and injury models.


Diamine oxidase induces neurite outgrowth in chick dorsal root ganglia by a nonenzymatic mechanism.
The enzyme diamine oxidase (DAO) catalyzes the oxidative deamination of histamine, diamines, and polyamines. DAO has been localized to several tissues, including thymus, kidney, intestine, seminal vesicles, placenta, and pregnancy plasma. DAO is not constitutively expressed in the mammalian brain, but it becomes detectable following focal injury. Although the physiologic role of DAO remains unknown, the observation that it is present at the interface between rapidly dividing and quiescent cells in several tissues suggests that it might be involved in regulating cell division or differentiation at tissue boundaries. In addition, the observation that DAO is expressed in the brain following injury suggests that the protein might play a role in the CNS response to focal neuronal damage. To test that hypothesis, we assessed the ability of purified DAO to alter the pattern of neuronal differentiation and nerve growth in vitro. In chick dorsal root ganglion explant cultures, purified porcine DAO induced neurite outgrowth in the low nanomolar range. Addition of aminoguanidine, which inhibits DAO enzyme activity, did not inhibit the protein's neurotrophic activity. These findings suggest that DAO can function as a neurotrophic ligand independent of its enzymatic activity.


A Low-Vision Navigation Platform for Economies in Transition Countries.
An ability to move freely, when wanted, is an essential activity for healthy living. Visually impaired and completely blinded persons encounter many disadvantages in their day-to-day activities, including performing work-related tasks. They are at risk of mobility losses, illness, debility, social isolation, and premature mortality. A novel wearable device and computing platform called VIS4ION is reducing the disadvantage gaps and raising living standards for the visually challenged. It provides personal mobility navigational services that serves as a customizable, human-in-the-loop, sensing-to-feedback platform to deliver functional assistance. The platform is configured as a wearable that provides on-board microcomputers, human-machine interfaces, and sensory augmentation. Mobile edge computing enhances functionality as more services are unleashed with the computational gains. The meta-level goal is to support spatial cognition, personal freedom, and activities, and to promoting health and wellbeing. VIS4ION can be conceptualized as the dovetailing of two thrusts: an on-person navigational and computing device and a multimodal functional aid providing microservices through the cloud. The device has on-board wireless capabilities connected through Wi-Fi or 4/5G. The cloud-based microservices reduce hardware and power requirements while allowing existing and new services to be enhanced and added such as loading new map and real-time communication via haptic or audio signals. This technology can be made available and affordable in the economies of transition countries.


N- to C-terminal SNARE complex assembly promotes rapid membrane fusion.
Assembly of the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) syntaxin 1, SNAP-25, and synaptobrevin 2 is thought to be the driving force for the exocytosis of synaptic vesicles. However, whereas exocytosis is triggered at a millisecond time scale, the SNARE-mediated fusion of liposomes requires hours for completion, which challenges the idea of a key role for SNAREs in the final steps of exocytosis. We found that liposome fusion was dramatically accelerated when a stabilized syntaxin/SNAP-25 acceptor complex was used. Thus, SNAREs do have the capacity to execute fusion at a speed required for neuronal secretion, demonstrating that the maintenance of acceptor complexes is a critical step in biological fusion reactions.


Inhibition of Rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection.
Endothelium-derived nitric oxide (NO) plays a pivotal role in vascular protection. The Rho kinase (ROCK) inhibitor, hydroxyfasudil, prevents the downregulation of endothelial NO synthase (eNOS) under hypoxic conditions. However, it is unknown whether inhibition of ROCK can attenuate ischemia-induced endothelial dysfunction and tissue damage in vivo. Human vascular endothelial cells were treated with increasing concentrations of hydroxyfasudil (0.1 to 100 micromol/L) and eNOS expression and activity were measured. To determine the physiological relevance of eNOS regulation by ROCK, we administered fasudil, which is metabolized to hydroxyfasudil in vivo, to mice for 2 days before subjecting them to middle cerebral artery occlusion. Cerebral blood flow, cerebral infarct size, and neurologic deficit were measured. In a concentration-dependent manner, hydroxyfasudil increased eNOS mRNA and protein expression, resulting in a 1.9- and 1.6-fold increase, respectively, at 10 micromol/L (P<0.05 for both). This correlated with a 1.5- and 2.3-fold increase in eNOS activity and NO production, respectively (P<0.05 for both). Fasudil increased cerebral blood flow to both ischemic and nonischemic brain areas, reduced cerebral infarct size by 33%, and improved neurologic deficit score by 37% (P<0.05). This correlated with inhibition of brain and vascular ROCK activity and increased eNOS expression and activity. Another ROCK inhibitor, Y-27632, also showed similar effects. The neuroprotective effects of fasudil were absent in eNOS-deficient mice. These findings indicate that the neuroprotective effect of ROCK inhibition is mediated by endothelium-derived NO and suggest that ROCK may be an important therapeutic target for ischemic stroke.


An Exceedingly Rare Case of Antithrombin III Deficiency and Catastrophic Antiphospholipid-Like Disease.
Antithrombin III (AT III) is a critical component of the coagulation cascade that functions primarily to inhibit activated coagulation factors IIa and Xa. AT III deficiency is a disorder that predisposes patients to thromboemboli. Antiphospholipid syndrome (APS) is an autoimmune disorder that predisposes patients to vascular and microvascular thrombosis, which can often be devastating and lead to multiorgan involvement. The mainstay of treatment for both conditions involves the use of lifetime vitamin K antagonists. Recent studies suggest that patients with APS refractory to warfarin therapy may benefit from the addition of aspirin, statin, or hydroxychloroquine; low weight molecular heparin; or a combination regimen. Studies have also suggested that patients with AT III deficiency refractory to warfarin therapy may see improvement with use of a novel oral anticoagulant. This case report describes the recurrent hospitalizations of a 45-year-old patient who presented with multiorgan thrombosis involving the descending aorta, deep lower extremity veins, superior mesenteric artery and artery of the brain. This led to mesenteric ischemia, limb necrosis and a subacute frontal cortex infarct. Initial anticoagulation therapy was refractory to the use of warfarin. Enoxaparin therapy was initiated, resulting in no further thrombotic events. Clinicians should consider poor gastrointestinal absorption of warfarin in patients who fail to reach therapeutic anticoagulation goals. In addition, a thorough workup for hereditary and acquired thrombophilias should be performed in patients who present with recurrent thromboemboli, as these disorders increase the risk of poor patient outcomes if left untreated.