Protein Oxidation Products as Biomarkers.
Oxidative stress is associated with aging and most degenerative diseases: it contributes to clinical complications, organ failure and mortality. Furthermore, oxidative damage accumulation in macromolecules has been considered as a cause of cellular damage and pathology. Interestingly, it is unknown whether and to what extent oxidative stress contributes to the clinical worsening and most importantly, no common strategy exists about its measurement. This is partially due to the fact that many methods of measuring oxidative stress have proven unreliable and no single method exists enabling objective determination and characterization of oxidative stress in clinical settings whether in aging or in chronic disease. Some methods basing on the measurement of lipid peroxidation, as the determination of F2-isoprostanes or malondialdehyde, or on the measurement of DNA/RNA damage, as 8-hydroxydesoxyguanosine or 8-hydroxydesoxyguanine, are widely used to determine oxidative stress and gain more and more acceptance or are reliable supportive parameters. A set of methods exists for clinical set-ups based on the measurement of protein oxidation or oxidative protein modification. Some of these methods are gaining more and more acceptance due to the development of easy to use and stable methods. This includes the long known method of protein carbonyl determination in various methodological variations, but also the use of the determination of protein-based nitrotyrosine or HNE-modified proteins. All these methods can be used in clinical set-ups, but special care has to be taken on chemical and biological sample stability. It should be mentioned, that no single method, however, is yet alone able to characterize oxidative stress under clinical conditions and, therefore, various combinations of damage parameters are the most promising tools.


The scope of using pragmatic language tests for early detection of dementia: A systematic review of investigations using figurative language.
Dementia cases are expected to rise to 81.1 million in 2040. Efforts are underway to develop diagnostic methods to facilitate early detection of the disease. Herein we review research findings focusing on pragmatic dysfunction in patients with dementia and evaluate the usefulness of assessing dementia and its progress with a battery of tests assessing figurative language skills. A total of 74,778 article titles were identified from EMBASE, PubMed, and Google Scholar databases. After systematic screening, 51 journal articles were selected for the final review. The review suggests that impaired figurative language might be a marker for early cognitive decline. Different forms of figurative language may be impaired at different stages of the disease and in different types of dementia involving different neuropathologies. The use of pragmatic tests in combination with the existing diagnostic protocols might increase the probability of early diagnosis. HIGHLIGHTS Pragmatic impairment could be a marker of early cognitive impairment. Figurative language-an important pragmatic aspect-is disrupted in mild cognitive impairment (MCI) and early Alzheimer's disease (AD). Figurative language impairment might precede literal language impairment. Pragmatic tests could be more sensitive than standard neuropsychological tests. Inclusion of pragmatic tests in diagnostic guidelines might bolster early detection.


Dictyocaulus species: cross infection between cattle and red deer.
To discover whether cross infection between red deer (Cervus elaphus) and cattle is possible with either a bovine isolate of the cattle lungworm, Dictyocaulus viviparus, or with a cervine isolate of the lungworm, Dictyocaulus eckerti which is thought to be maintained primarily in deer. Twelve cattle and 12 red deer were reared parasite-free from birth. At 3-4 months of age, half of each species (n=6) were experimentally infected with D. viviparus and the other half with D. eckerti. The course of infection was monitored for 34 days, after which the animals were slaughtered and the lungs removed to assess levels of infection. Faecal larval counts demonstrated that patent Dictyocaulus infections occurred in all groups. At necropsy, adult worms were found in the lungs in all groups except the cattle that were infected with D. eckerti. The largest numbers of adult worms were found in the red deer infected with D. eckerti. It was demonstrated that both cattle and red deer could be infected with either D. viviparus or D. eckerti. However, D. eckerti larvae that originated from deer established more successfully in deer and D. viviparus larvae that originated from cattle established more successfully in cattle.


Substance P, injected intrathecally, antagonizes the spinal antinociceptive effect of morphine, baclofen and noradrenaline.
The effect of substance P on the antinociceptive effect of morphine, baclofen and noradrenaline in the spinal cord was examined in the tail-flick and hot plate tests, after intrathecal administration. Substance P (5-20 micrograms) produced a dose-related antagonism of the effect of all three agents, which persisted for the entire time-course of the antinociceptive effect in each case. The rank order of potency of substance P and related peptides in antagonizing the antinociceptive effect of morphine, was substance P greater than physalaemin greater than eledoisin greater than eledoisin-related peptide. A similar order of potency was observed against noradrenaline, except that physalaemin appeared to be the most potent. The intrathecal administration of these peptides did not alter reaction latencies in the tail-flick test when baseline values were 2-3 sec, but produced a significant decrease in latency (hyperalgesia) when baseline values were 6-8 sec. There was a slight increase in reaction latency in the hot plate test. The specificity of the antagonism was examined by determining the effect of phentolamine on the antinociceptive effect of morphine and baclofen. Although phentolamine (30 micrograms) produced comparable hyperalgesia to substance P, it did not significantly alter the antinociceptive effect of morphine or baclofen. These results suggest that alterations in the function of substance P in the spinal cord may contribute to the spinal antinociceptive effects of morphine, baclofen and noradrenaline. The effects of substance P on nociception in the spinal cord appear to be mediated by substance P type receptors.


Implementation of Siemens USS protocol into LabVIEW.
This article gives basic overview of the USS protocol as a communication interface to drive Siemens frequency inverters. It presents our implementation of this protocol into LabVIEW, as there was permanent demand from the community of the users to have native LabVIEW implementation of the USS protocol. It also states encountered problems and their solutions.


[Diagnostic image (72). An adult woman with coarsening of the face. Acromegaly].
A 45-year-old woman with acromegaly went into remission after pituitary surgery.


Strength and fracture pattern of monolithic CAD/CAM-generated posterior crowns.
This study evaluated the strength and fracture pattern of monolithic posterior CAD/CAM crowns hypothesizing that zinc-phosphate cemented lithium disilicate crowns might show the same fracture strength as adhesively cemented crowns. Two sets of monolithic posterior crowns each with uniform occlusal and lateral wall thickness of 1.5mm were fabricated from three types of block ceramic (1) lithium disilicate glass, (2) leucite glass and (3) feldspathic ceramic using CEREC 3 CAD/CAM. Crowns (n = 15) of ceramics (1), (2) and (3) each were (A) zinc-phosphate cemented, (B) adhesively cemented on resin-based composite dies and loaded until fracture. Load data was analyzed using ANOVA and Scheffé tests. Crack pattern was evaluated on an additional three sample cross-sections for each group at start of fracture. Radial cracks originated early at the cementation interfaces and cone cracks were observed finally at the loading sites. Mean load values (SD) of A-crowns at fracture start/end (1) 807 (91) N/2082 (192) N; (2) 915 (193) N/1130 (166) N; (3) 985 (199) N/1270 (301) N were all significantly (P < 0.001) lower when compared to their B-crown analogs (1) 1456 (205) N/2389 (84) N; (2) 1684 (395) N/2469 (171) N; (3) 1548 (304) N/2392 (75) N, rejecting the authors hypothesis. A-1 crowns had significantly (P < 0.001) higher fracture load than A-2 and A-3 crowns. The A-1 crown fracture load data, even if significantly (P < 0.001) lower, came close to the B-1 values. Adhesive cementation balanced the strength of weak ceramics with that of strong ceramic and recommended itself for leucite glass ceramic and feldspathic ceramic crowns. Zinc-phosphate cementation appeared feasible for lithium disilicate crowns.


The nitric oxide donor, diethylamine NONOate, enhances preservation of the donor rat heart.
Ischemia/reperfusion injury to transplanted organs may be associated with loss of endothelial release of nitric oxide. The aim of this study was to determine whether supplementation of an extracellular-based cardioplegic solution in routine clinical use at our institution with nitric oxide (as diethylamine NONOate) enhanced poststorage functionality of an isolated working heart model. Excised hearts were ligated to an aortic cannula and immediately perfused retrogradely with oxygenated Krebs solution at a hydrostatic pressure of 100 cm H2O at 37 degrees C. This preparation was then converted to a working system by switching the supply of perfusate from the aorta to a left atrial cannula at a filling pressure of 15 cm H2O. After a 1-minute stabilization period, baseline measurements of heart rate, aortic flow, coronary artery flow, and cardiac output were performed. Oxygenated cardioplegic solution (0.1 micromol/L), with or without NONOate, was then infused into the coronary circulation. Hearts were then stored in the same solutions for 6 or 12 hours at 2 degrees to 3 degrees C. The hearts were then remounted on the perfusion apparatus and reperfused as before, and hemodynamic measurements were repeated. Water content of the hearts were then determined. Addition of the nitric oxide donor significantly improved all hemodynamic parameters measured after 12 hours storage and aortic flow at 6 hours storage compared with the untreated control groups. There was no significant difference between the water contents of the NONOate-treated and control groups. The presence of the nitric oxide donor diethylamine NONOate was associated with significantly better preservation of coronary artery flow and cardiac function in the isolated rat heart after a 12-hour period of hypothermic storage and suggests a novel use for this family of compounds in the transplantation context.


Activity-based selection of a proteolytic species using ribosome display.
We have examined the potential of displaying a protease species in vitro using ribosome display and demonstrate specific capture on the basis of its catalytic activity. Using a model bacterial cysteine protease, sortase A (SrtA), we show that this enzyme can be functionally expressed in vitro. By overlap PCR we constructed ribosome display templates with the SrtA open reading frame fused to a C terminal glycine-serine rich flexible linker and a tether derived from eGFP. Using the broad range cysteine protease irreversible inhibitor E-64 linked to acrylic beads, we show that we can isolate SrtA ribosome display ternary complexes, and recover their encoding mRNA by RT-PCR. This recovery was lost when applied to a SrtA catalytically inactive mutant, or could be alleviated by competition with free inhibitor. This sensitive technique could be further developed to allow the screening of proteases against putative inhibitors and/or the identification of novel proteolytic species.


Enhancement of the permeability and activities of epigallocatechin gallate by quaternary ammonium chitosan/fucoidan nanoparticles.
Epigallocatechin gallate (EGCG) has many biological functions; however, the use of EGCG in biomedical and food industries was limited due to its poor oral absorption and high susceptibility to degradation. In this study, a mucoadhesive quaternary chitosan was synthesized and combined with fucoidan (FD) (or depolymerized lower molecular weight fucoidan, LMWF) to prepare EGCG-loaded nanoparticles, which extended EGCG release over 300 min and enhanced the transepithelial permeation of EGCG using Caco-2 cells as a model for intestinal absorption. The nanoparticls protected EGCG against degradation in phosphate buffer (pH 6.8) and the remaining EGCG was 1.7-folds higher than the control (EGCG alone). The additive effects of EGCG combined with FD or LMWF in the nanoparticles increased the DPPH radical scavenging activity and the enzyme inhibitory activity against α-amylase (2.82-4.92 fold increase) and α-glucosidase (1.35-1.67 fold increase), while quaternary chitosan helped to enhance the antibacterial effect of EGCG.


Modeling families of particle distributions with conditional GAN for Monte Carlo SPECT simulations.
Objective.We propose a method to model families of distributions of particles exiting a phantom with a conditional generative adversarial network (condGAN) during Monte Carlo simulation of single photon emission computed tomography imaging devices.Approach.The proposed condGAN is trained on a low statistics dataset containing the energy, the time, the position and the direction of exiting particles. In addition, it also contains a vector of conditions composed of four dimensions: the initial energy and the position of emitted particles within the phantom (a total of 12 dimensions). The information related to the gammas absorbed within the phantom is also added in the dataset. At the end of the training process, one component of the condGAN, the generator (G), is obtained.Main results.Particles with specific energies and positions of emission within the phantom can then be generated withGto replace the tracking of particle within the phantom, allowing reduced computation time compared to conventional Monte Carlo simulation.Significance.The condGAN generator is trained only once for a given phantom but can generate particles from various activity source distributions.


Optical resolution of enantiomeric amino acid derivatives on a naphthylethylurea multiple-bonded chiral stationary phase prepared via an activated carbamate intermediate.
A new chiral stationary phase (CSP) was developed for the direct optical resolution of enantiomeric amino acid derivatives. The CSP was readily prepared by a three-step reaction carried out in a pre-packed aminopropylsilyl silica gel column. In the first step, a solution of disuccinimido carbonate (DSC) was delivered through the pre-packed column to give a succinimido carbamyl aminopropylsilyl-bonded, activated-carbamate type silica gel (ACsil) column. Through the column was then delivered a solution of pentaethylenehexamine to afford a polyamine-bonded column. Finally, a solution of optically active succinimido (S)- or (R)-naphthylethyl carbamate was delivered through the polyamine column, to give a naphthylethylurea multiple-bonded CSP. p-Bromophenylcarbamyl derivatives of enantiomeric protein amino acids were resolved on these CSPs by elution with an aqueous mobile phase. Simultaneous analysis of these amino acid enantiomers by means of gradient elution was also accomplished.


Retraction Note to: Excessive mitochondrial fragmentation triggered by erlotinib promotes pancreatic cancer PANC‑1 cell apoptosis via activating the mROS‑HtrA2/Omi pathways.
[This retracts the article DOI: 10.1186/s12935-018-0665-1.].


The effects of external cations and ouabain on the intracellular sodium activity of sheep heart Purkinje fibres.
1. The intracellular Na activity of sheep heart Purkinje fibres has been measured using recessed-tip Na(+)-sensitive glass micro-electrodes.2. The internal Na activity was 7.2 +/- 2.0 mM (mean +/- S.D., n = 32) at the normal external Na concentration, [Na](o), in these experiments of 140 mM (equivalent to an external Na activity of 105 mM). The equilibrium potential for Na across the fibre membrane was therefore approximately + 70 mV.3. When the [K](o) was altered the internal Na activity changed, reaching a new level within about 20 min. Increasing the [K](o) from 4 to 25 mM decreased the internal Na by approximately 30%, while decreasing the [K](o) from 4 to 1 mM increased internal Na by 20%.4. The removal of external K produced an easily reversible increase in the internal Na with an initial rate equivalent to a concentration change of 0.24 +/- 0.07 m-mole/min (mean +/- S.D., n = 8).5. Ouabain produced increases in the internal Na activity that were only very slowly reversible. The threshold concentration for producing an increase was approximately 10(-7)M.6. When [Na](o) was reduced the internal Na activity fell rapidly with a single exponential time course (time constant 3.3 +/- 0.8 min, mean +/- S.D., n = 16) to a new, relatively stable level. The recovery of internal Na on return to the normal [Na](o) did not have a simple time course. It was normally complete within 10-30 min.7. The relationship of the stabilized level of the internal Na activity to the [Na](o) was approximately linear over the range 140-14 mM-[Na](o). When [Na](o) was reduced from 140 to 14 mM the internal Na activity fell by 72 +/- 5% (mean +/- S.D., n = 21).8. When the [Na](o) was reduced, the decrease in the internal Na activity was partially inhibited by Mn or by removal external Ca.9. When the [Ca](o) was altered over the range 0.2-16 mM the internal Na activity was reduced by approximately 50% for a tenfold increase in the [Ca](o).10. The relationship between internal Na and contractility is discussed.


Anti-depressant therapy and cancer risk: a nested case-control study.
Previous studies demonstrated a possible association between anti-depressant therapy with selective serotonin reuptake inhibitors (SSRI) and tricyclic anti-depressants (TCA), several genetic and hormonal pathways and cancer risk, with inconsistent results. Exposure to serotonin-norepinephrine reuptake inhibitors (SNRI) was not studied extensively. We sought to evaluate the association between exposure to SSRIs, TCAs and SNRIs and the five most common solid tumors. We conducted nested case-control studies using a large UK population-representative database. Cases were those with any medical code for the specific malignancy. For every case, four controls matched on age, sex, practice site, and duration of follow-up before index date were selected using incidence-density sampling. Exposure of interest was SSRI, SNRI or TCA therapy before index date. Odds ratios (ORs) and 95% CIs were estimated for each anti-depressant class using conditional logistic-regression analysis, adjusted for potential confounders, such as obesity, smoking history and alcohol consumption. 109,096 cancer patients and 426,402 matched controls were included. Current SSRI users with treatment initiation>one year before index date had modestly higher risk for lung and breast cancers with ORs of 1.27 (95% CI 1.16-1.38) and 1.12 (95% CI 1.06-1.18), respectively. Among current TCA users, there was a higher risk only for lung cancers with OR of 1.45 (95% CI 1.31-1.6). There was no statistically significant association between current SNRI therapy and cancer risk. Treatment with SSRI and TCA might be associated with increased lung cancer risk. SSRI therapy might be associated with modest increase in breast cancer risk.


Genetic differences among North African Berber and Arab-speaking populations revealed by Y-STR diversity.
Y-chromosome STR polymorphisms are inherited in a haploid state which makes them a powerful tool for easy tracing of paternal lineage and for use in human population evolutionary studies. North-African Y chromosomal diversity has traditionally been studied in order to find genetic and geographic associations as well as to test how natural and cultural barriers have affected the degree of genetic flow not only within North Africa but also in a wider Mediterranean context. The degree of Berber/Arab genetic differentiation in the Moroccan population has been tested for a complete set of forensic markers as sixteen Y-chromosomal short tandem repeats (STRs) (DYS19, DYS385, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635 and GATA H4.1). The results suggest considerable population heterogeneity in North Africa.


Evaluation of periodontitis in hospital outpatients with major depressive disorder. A focus on gingival and circulating cytokines.
An imbalance in stimulated cytokine production is associated with the etiopathogenesis of numerous diseases such as major depressive disorder (MDD) and periodontal disease. Increased cytokine levels have been reported in the gingival crevicular fluid (GCF) of patients with MDD. Thirty-six outpatients with MDD participated in this study. Each outpatient was age-matched (± 3 years) with a healthy control (n=36). The patients were controlled for race and smoking habits. Unstimulated and stimulated interleukin 6 (IL-6), interleukin 1β (IL-1β), and interferon-γ (INF-γ) production in whole blood culture (WBC) and IL-6 and IL-1β levels in the GCF were evaluated. Circulating levels of IL-6 and IL-1β (unstimulated) as well as GCF IL-1β were modestly lower in MDD patients, compared to the levels in age-matched controls (Mann-Whitney, p=0.002, 0.0075, ANCOVA, p=0.025, respectively). In the unstimulated group, there was no correlation between the levels of circulating IL-6 and GCF IL-6 (r=0.07, p=0.67), and between the levels of circulating IL-1β and the IL-1β level in the CGF (r=-0.08, p=0.63). In the LPS stimulation group, there was no correlation between the levels of circulating levels of IL-6 and GCF IL-6 (r=0. 02, p=0.91) or between the circulating IL-1β and GCF IL-1β (r=0.13, p=0.42). We observed modest immunosuppression in MDD patients (evaluated by no stimulation whole blood culture [WBC]), especially in patients with melancholic depression, chronic depression, and severe depression.


Tuning of interfacial HGO@CLS nanohybrid S-scheme heterojunction with improved carrier separation and photocatalytic activity towards RhB degradation.
Herein, we premeditated and invented the innovative hybrid photocatalyst 2D/2D CuLa2S4 on holey graphene oxide (HGO) (HGO@CLS) via the hydrothermal method. Electrochemical techniques demonstrate the action of HGO in the HGO@CLS photocatalyst as an effective medium for electron transfer. Combining bimetallic sulfides on porous HGO synergistically provides a higher negative conduction band edge (-0.141 V), greater photo response (10.8 mA/cm2), smaller charge transfer resistance (Rct = 1.79Ω), and lower photoluminescence (PL) spectral intensity. According to our research, the catalytic recitals are sped up when HGO is assimilated into CLS photocatalyst hetero-junction. Additionally, it lowers the reassimilation rate due to the combined mesh nanostructures and functionality of CLS and HGO. UV-Vis DRS, Mott-Schottky, PL, and Electrochemical impedance spectra (EIS) results manifested that the CuLa2S4/HGO makes the spatial separation competent and transference of charge carriers due to the photon irradiation and exhibits superior photocatalytic ability. Electron spin resonance (ESR) analysis confirmed that •OH and h+ were the predominant radical species responsible for Rhodamine B(RhB) degradation. Moreover, conceivable degradation ways of RhB were deduced according to the identified intermediates which are responsible for the degradation of recalcitrant products. To check the stability of the photocatalyst, revival tests were also carried out. Similarly, the oxidative byproducts created in the deprivation courses were looked at, and a thorough explanation for the mechanism of degradation was given.


Phase 2 Clinical Trial of Separation Surgery Followed by Stereotactic Body Radiation Therapy for Metastatic Epidural Spinal Cord Compression.
Stereotactic body radiation therapy (SBRT) is a postoperative treatment option for spinal metastases. Because data on surgery with SBRT are limited to retrospective studies, this single-center, single-arm, phase 2 study aimed to prospectively evaluate the outcomes of separation surgery and SBRT for metastatic epidural spinal cord compression (MESCC). Patients with symptomatic MESCC due to a solid carcinoma were enrolled. The protocol for treatments comprised preoperative embolization, separation surgery, and spine SBRT. Surgical procedures were performed via the posterior approach, with decompression and a fixation procedure. The prescribed dose for spine SBRT was 24 Gy in 2 fractions. The primary endpoint was the 12-month local failure rate. The secondary endpoints were ambulatory functions and adverse effects. A total of 33 patients were registered between November 2017 and October 2019. All patients met the inclusion criteria, and all but 1 completed the protocol treatment. Of the included patients, 23 (70%) had radioresistant lesions. The Bilsky grade at registration was 1c in 3 patients, 2 in 8 patients, and 3 in 21 patients. The median follow-up duration after registration was 15 months (range, 3-35 months). Three months after the administration of treatments according to the protocol, 90% of patients (26 of 29) had disease of Bilsky grade ≤1. The 12-month local failure rate was 13%. Twenty patients could walk normally or with a cane 12 months after registration. Radiation-induced myelopathy, radiculopathy, and vertebral compression fracture were observed in 0, 1, and 6 patients, respectively. Separation surgery with SBRT for MESCC was effective in decompression and long-term local control. These findings suggest that larger randomized controlled trials are warranted to compare SBRT with conventional radiation therapy.


Major depression, parental mental disorder and early family relationships.
Sixty middle-aged urban women with a major depressive episode diagnosed in a community survey were compared with those 400 participants of the study who had no history of major depression. The study design is retrospective. The depressed women's parents had been in contact with psychiatric services twice as often as those of never depressed women. The rate of paternal alcoholism was however the same in both groups. As compared with the controls, women with major depression reported significantly more often frequent corporal punishment, poor relationship with mother, having been misunderstood by parents, and unhappy childhood.


Characterization and identification of a pyrazole-inducible form of cytochrome P-450.
In vivo administration of the alcohol dehydrogenase inhibitor pyrazole induces a cytochrome P-450 isozyme. The pyrazole-inducible cytochrome P-450 has been purified from rat livers to electrophoretic homogeneity and its biochemical, spectral, and immunological properties characterized. The final preparation had a specific content of 11 nmol of cytochrome P-450/mg of protein. A single band with an apparent molecular weight of 52,000 was observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The absolute spectrum of the isolated pyrazole cytochrome P-450 displayed peaks at 648 and 396 nm, suggestive of a high spin cytochrome. The ethylisocyanide difference spectrum exhibited two maxima, one at 457 nm, the other at 428 nm. Pyrazole and dimethyl sulfoxide produced binding spectra with the purified P-450, with peaks at 425 or 419 nm and troughs at 390 or 386 nm, respectively. K8 values for dimethyl sulfoxide and pyrazole were 21 and 0.04 mM, respectively. The catalytic activity of the pyrazole cytochrome P-450 was elevated with aniline and dimethylnitrosamine (low Km) but not with aminopyrine, benzphetamine, ethoxycoumarin, or ethoxyresorufin as substrates. An antibody against pyrazole cytochrome P-450 recognized a 52,000 molecular weight protein upon reaction with saline microsomes. The intensity of the immunoblot was increased when microsomes isolated from pyrazole, 4-methylpyrazole-, acetone-, or chronic ethanol-treated rats were utilized, but not after phenobarbital or 3-methylcholanthrene treatment. Homology at the amino terminus of 19 amino acids was observed between pyrazole P-450 and the isoniazid-inducible P-450j. Based upon the above catalytic, spectral, and immunological properties, it appears that pyrazole induces a form of cytochrome P-450 which is identical to that induced by ethanol and isoniazid.


ATPase and GTPase activities associated with the 5-S RNA-protein complex of Escherichia coli ribosomes.
Specific 5-S RNA-protein complexes were reconstituted from Escherichia coli 5-S RNA and 50-S ribosomal proteins. These complexes consist of 5-S RNA and two major proteins, namely E-L18 and E-L25. Analysis for enzymatic activities shows that ATP and GTP are hydrolyzed and that this hydrolysis is independent of elongation factors.


Faculty prefer continuity with medical students in the emergency department.
The aim of this investigation was to better understand emergency medicine (EM) faculty opinions as they relate to continuity with students. This was a prospective cohort study of faculty supervising students completing an EM clerkship. Student schedules were aligned to maximise continuity with faculty. Faculty completed surveys prior to the start of the study and again at the end of the study period. Faculty generally indicated a favourable opinion regarding continuity with students. Significant change was noted in two survey questions from pre- to post-intervention: faculty reported higher motivation to teach and felt the students' learning experience was better with improved continuity. EM faculty express theoretical optimism regarding the value of improved continuity between teacher and learner. This positive sentiment persisted after actual experience with students on a shift allocation model that aligns faculty and student schedules.


The Use of the Overstitch to Close Endoscopic Resection Defects.
Endoscopic resection of luminal gastrointestinal neoplasia offers a minimally invasive, lower risk alternative that can be successful in the appropriate setting. Bleeding and perforation can occur with endoscopic mucosal resection and endoscopic submucosal dissection. Defect closure with conventional endoclips or modified technique using endoloops can decrease the risk of adverse events. The Overstitch (Apollo Endosurgery, Austin, TX) endoscopic suturing device is designed for tissue apposition and thus can effectively close a large resection defect. Herein we describe our technique. Our and other groups' initial experience with suturing for closure of the resection defect demonstrates high procedural success rates and safety.


Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy.
Clinical presentation of spinal muscular atrophy (SMA) ranges from a neonatal-onset, very severe disease to an adult-onset, milder form. SMA is caused by the mutation of the Survival Motor Neuron 1 (SMN1) gene, and prognosis inversely correlates with the number of copies of the SMN2 gene, a human-specific homolog of SMN1. Despite progress in identifying potential therapies for the treatment of SMA, many questions remain including how late after onset treatments can still be effective and what the target tissues should be. These questions can be addressed in part with preclinical animal models; however, modeling the array of SMA severities in the mouse, which lacks SMN2, has proven challenging. We created a new mouse model for the intermediate forms of SMA presenting with a delay in neuromuscular junction maturation and a decrease in the number of functional motor units, all relevant to the clinical presentation of the disease. Using this new model, in combination with clinical electrophysiology methods, we found that administering systemically SMN-restoring antisense oligonucleotides (ASOs) at the age of onset can extend survival and rescue the neurological phenotypes. Furthermore, these effects were also achieved by administration of the ASOs late after onset, independent of the restoration of SMN in the spinal cord. Thus, by adding to the limited repertoire of existing mouse models for type II/III SMA, we demonstrate that ASO therapy can be effective even when administered after onset of the neurological symptoms, in young adult mice, and without being delivered into the central nervous system.


Identification of the major polyadenylylated transcription products and the genes active in their synthesis in a rat insulinoma.
Three RNA fractions with molecular weights of 200,000, 280,000, and 360,000, have been identified as the major polyadenylylated transcription products in a transplantable rat pancreatic islet cell tumor that synthesizes insulin. These three RNAs share sequence homology as demonstrated by comparisons of both partial and complete RNase T1 digestion products. The 200,000 and 280,000 molecular weight species hybridize primarily with three EcoRI restriction fragments of the rat genome having molecular weights of 1.4 X 10(6), 1.6 X 10(6), and 6.0 X 10(6). The 360,000 molecular weight species hybridizes preferentially with the 6.0 X 10(6) molecular weight DNA fragment.


H2S-RhoA/ROCK Pathway and Glial Cells in Axonal Remyelination After Ischemic Stroke.
Ischemic stroke is one of the main reasons of disability and death. Stroke-induced functional deficits are mainly due to the secondary degeneration of the white matter characterized by axonal demyelination and injury of axon-glial integrity. Enhancement of the axonal regeneration and remyelination could promote the neural functional recovery. However, cerebral ischemia-induced activation of RhoA/Rho kinase (ROCK) pathway plays a crucial and harmful role in the process of axonal recovery and regeneration. Inhibition of this pathway could promote the axonal regeneration and remyelination. In addition, hydrogen sulfide (H2S) has the significant neuroprotective role during the recovery of ischemic stroke via inhibiting the inflammatory response and oxidative stress, regulating astrocyte function, promoting the differentiation of endogenous oligodendrocyte precursor cells (OPCs) to mature oligodendrocyte. Among all of these effects, promoting the formation of mature oligodendrocyte is a crucial part of axonal regeneration and remyelination. Furthermore, numerous studies have uncovered the crosstalk between astrocytes and oligodendrocyte, microglial cells and oligodendrocyte in the axonal remyelination following ischemic stroke. The purpose of this review was to discuss the relationship among H2S, RhoA/ROCK pathway, astrocytes, and microglial cells in the axonal remyelination following ischemic stroke to reveal new strategies for preventing and treating this devastating disease.


Irritable bowel syndrome: I. A practical approach. ACG Committee of FDA-Related Matters. American College of Gastroenterology.
An overview of current concepts of the irritable bowel syndrome has been presented. The definition, symptomatology, epidemiology, diagnosis, physical examination, and appropriate evaluation have been discussed. The role of emotional factors as triggering mechanisms has been analyzed. Succeeding papers will deal with clinical and experimental findings related to motor dysfunction in this disorder, nutritional factors related to the irritable syndrome, and a final paper discussing appropriate therapeutic approaches in IBS.


Efficacy of knee joint aspiration in patients with acute ACL injury in the emergency department.
To evaluate the influence of joint aspiration on the sensitivity of physical examination for diagnosing acute anterior cruciate ligament (ACL) lesion in the second outpatient-department (OPD) follow-up referred from emergency department (ED). This retrospective study included sixty patients underwent ACL reconstruction with initial visit at ED. They were divided into two groups based on the presence or absence of joint aspiration at ED. All participants were referred to second OPD follow-up within 7-14days after the injury. Clinical manifestation (including visual analogue scale (VAS) for pain, range of motion (ROM), and severity of knee effusion) and physical examination (Lachman test and pivot shift test) were checked in ED and the second OPD follow-up. The group of patients with joint aspiration (G1) showed substantial decreases in mean values of VAS for pain (p=0.005), ROM (p=0.001), and effusion level (p<0.001), even higher VAS and effusion level and lower ROM at the initial visit of ED than the other group (G2). The sensitivity of positive Lachman and pivot shift test was significantly (p<0.05) increased following knee joint aspiration. Positive Lachman test was recorded at 76.5% in the second follow-up in G1, which was significantly (p=0.047) higher than that (47.6%) in G2. The percentage of positive pivot shift test was recorded at 76.5% in the second follow-up in G1, which as significantly (p<0.001) higher than that (31.0%) in G2. Knee joint aspiration in acute ACL injury with suspected hemarthrosis could be considered as a diagnostic procedure. Joint aspiration in early medical attendance might be able to lower pain scores or raise the sensitivity of physical examination for diagnosing acute ACL injury at follow up visit in orthopedic outpatient department. Retrospective cohort study III.


Implementation of the American Diabetes Association's Standards of Medical Care post-Medicare Part D: The case of statin utilization in the elderly with diabetes.
The American Diabetes Association's (ADA's) Standards of Medical Care in Diabetes for statin use have changed to be driven by risk status rather than low-density lipoprotein cholesterol level. The objectives of this study were to 1) examine how statins were used by risk status in elderly diabetics for whom they are recommended by the ADA's Standards with high levels of evidence, and 2) identify potential predictors of statin non-use using data containing Medicare Part D information in understanding how to further align patient care with the ADA's Standards. This study was a pooled cross-sectional study of the Medicare Current Beneficiaries Survey from 2006 to 2010. Sampling weights were applied to generate national estimates. Weighted logistic regression was performed to identify potential predicators of statin non-use. Between 2006 and 2010, 53.96%, 52.14%, 52.28%, 57.74%, and 59.81% of eligible diabetics used statins, respectively. About 70% of the patients with overt cardiovascular disease (CVD) took statins while only about 50% of those with CVD risk factors used statins in 2010. Compared to those with overt CVD, patients with CVD risk factors were less likely to take statins (OR: 0.56; 95% CI: 0.48-0.64). Other non-use predictors included: non-Hispanic Black, non-metropolitan areas, and comorbidities. Implementation of the ADA's statin recommendations increased over the study period. Statin use differed significantly by patients' risk status. Future ADA's Standards focusing on how to improve utilization of statins for individuals with different risk status, particularly those with CVD risk factors but without overt CVD, are warranted.


Molecular analysis of the TMPRSS3 gene in Moroccan families with non-syndromic hearing loss.
Autosomal recessive non-syndromic hearing impairment (ARNSHI) is the most common type of inherited hearing impairment, accounting for approximately 80% of inherited prelingual hearing impairment. Hearing loss is noted to be both phenotypically and genetically heterogeneous. Mutations in the TMPRSS3 gene, which encodes a transmembrane serine protease, are known to cause autosomal recessive non-syndromic hearing impairment DFNB8/10. In order to elucidate if the TMPRSS3 gene is responsible for ARNSHI in 80 Moroccan families with non-syndromic hearing impairment, the gene was sequenced using DNA samples from these families. Nineteen TMPRSS3 variants were found, nine are located in the exons among which six are missense and three are synonymous. The 10 remaining variations are located in non-coding regions. Missense variants analysis show that they do not have a significant pathogenic effect on protein while pathogenicity of some variant remains under discussion. Thus we show that the TMPRSS3 gene is not a major contributor to non-syndromic deafness in the Moroccan population.


Gel-based Microemulsion Design and Evaluation for Topical Application of Rivastigmine.
The aim of the present study was to design nanocarriers for the topical application of rivastigmine. The effect of cosurfactants, hydrophilic gel and loading amount on the permeability of rivastigmine through rat skin was evaluated. Skin irritation tests and stability tests were performed to evaluate the utility of tested formulations. The results showed that the microemulsion formation and characteristics of drug-loaded formulations were related to many parameters of the components. When using microemulsion systems as a vehicle, the permeation rate remarkably increased about 13.2~24.3-fold and the lag time was significantly shortened from 24 h to 4.7 h. Formulations containing a cosurfactant of Diethylene Glycol Monobutyl Ether (DEGBE) showed higher enhancement effect, while increasing the loading dose from 0.5% to 5% further increased the flux about 2.1-fold and shortened the lag time. The drug-loaded experimental formulation did not cause skin irritation and had good stability at 20ºC and 40ºC storage for at least 3 months. The result showed that gel-based microemulsion formulation could be a promising approach for topical administration.


Clinical and psychological characteristics of propofol abusers in Korea: a survey of propofol abuse in 38, non-healthcare professionals.
The aim of this study is to investigate the characteristics of propofol abuse based on the results of a survey analysis of abusers among non-healthcare professionals in Korea. Thirty-eight propofol abusers were questioned between October and December 2010, and were enrolled and voluntarily participated in a structured survey consisting of an interview and completing a previously prepared questionnaire. The questionnaire was divided into three distinct parts: part 1 dealt with the history of propofol abuse; part 2 highlighted the problems caused by propofol abuse; and part 3 enquired regarding demographics of abusers. Thirty-one (81.6%) of the 38 interviewees abused propofol for more than one year. During the last 12 months, 34 (89.0%) received propofol at two or three times a week. The minimum and maximum amounts of propofol (median, range) administered each time were 500 (100, 1000) and 2000 (500, 4000) mg, respectively. Stress relief and the maintenance of a sense of well-being were quoted the most important reasons for the first-time administration of propofol and its subsequent abuse, respectively. The majority of abusers (36.0, 97.3%) reported a sense of pleasure or euphoria at the time of their propofol injection. Withdrawal symptoms occurred in five abusers (13.2%). Thirteen (36.1%) reported disruptions in their work life. None of the respondents had previously admitted to and or reported abuse of any other controlled substances. These results provided reference data for the regulation of propofol in Korea as a controlled substance and may also be of interest to international agencies in other countries.


Holmium laser enucleation of prostate in patients with prostate size </=60 cm3.
To evaluate the safety and efficacy of holmium laser enucleation of the prostate in patients with small to moderate size prostate. We retrospectively reviewed the data of 224 patients with a preoperative prostate size </=60 cm(3), who had undergone holmium laser enucleation of the prostate at our institution from March 1998 to February 2005. The patient characteristics, indications for surgery, preoperative and postoperative International Prostate Symptom Score, including quality-of-life score, peak urinary flow rate, postvoid residual urine volume, enucleation time, morcellation time, total energy used, enucleated tissue weight, catheterization time, hospital stay, pathologic examination findings, and complications were recorded. The mean prostate size was 43 +/- 11.1 cm(3), the mean operative time was 80 minutes, and the enucleated tissue weight was 24 g. The mean catheterization time and hospital stay was 1.2 and 1.4 days, respectively. No major intraoperative complications were encountered. Only 2 patients (0.9%), who were receiving anticoagulation therapy, required a postoperative blood transfusion. At 1 year postoperatively, the International Prostate Symptom Score had improved from 17.6 +/- 6.7 to 4.9 +/- 4.4 (72%), the quality-of-life score had improved from 3.5 +/- 1.3 to 1.2 +/- 1.3 (66%), the peak urinary flow rate had increased from 7.5 +/- 3.1 to 21.2 +/- 9.5 mL/s (183%), and the postvoid residual urine volume had decreased from 155 +/- 170 to 27 +/- 48 mL (83%). Holmium laser enucleation of the prostate is safe and effective treatment in patients with small to moderate size prostate as well as those with larger prostates, with low morbidity and a short catheterization time and hospital stay.


circPARD3 drives malignant progression and chemoresistance of laryngeal squamous cell carcinoma by inhibiting autophagy through the PRKCI-Akt-mTOR pathway.
Laryngeal squamous cell carcinoma (LSCC) is the second most common malignant tumor in head and neck. Autophagy and circular RNAs (circRNAs) play critical roles in cancer progression and chemoresistance. However, the function and mechanism of circRNA in autophagy regulation of LSCC remain unclear. The autophagy-suppressive circRNA circPARD3 was identified via RNA sequencing of 107 LSCC tissues and paired adjacent normal mucosal (ANM) tissues and high-content screening. RT-PCR, Sanger sequencing, qPCR and fluorescence in situ hybridization were performed to detect circPARD3 expression and subcellular localization. Biological functions of circPARD3 were assessed by proliferation, migration, invasion, autophagic flux, and chemoresistance assays using in vitro and in vivo models. The mechanism of circPARD3 was investigated by RNA immunoprecipitation, RNA pulldown, luciferase reporter assays, western blotting and immunohistochemical staining. Autophagy was inhibited in LSCC, and circPARD3 was upregulated in the LSCC tissues (n = 100, p < 0.001). High circPARD3 level was associated with advanced T stages (p < 0.05), N stages (p = 0.001), clinical stages (p < 0.001), poor differentiation degree (p = 0.025), and poor prognosis (p = 0.002) of LSCC patients (n = 100). Functionally, circPARD3 inhibited autophagy and promoted LSCC cell proliferation, migration, invasion and chemoresistance. We further revealed that activation of the PRKCI-Akt-mTOR pathway through sponging miR-145-5p was the main mechanism of circPARD3 inhibited autophagy, promoting LSCC progression and chemoresistance. Our study reveals that the novel autophagy-suppressive circPARD3 promotes LSCC progression and chemoresistance through the PRKCI-Akt-mTOR pathway, providing new insights into circRNA-mediated autophagy regulation and potential biomarker and target for LSCC treatment.


Mueller-Weiss syndrome: an uncommon cause of midfoot pain.
There are various osseous pathologies that afflict the tarsal navicular. These range from stress fractures and coalitions to overt fractures. In certain instances there is an interruption of its vascular supply. If this occurs in childhood, it is called Koehler's disease. Spontaneous osteonecrosis of the navicular in the adult is a rare entity and is known as Mueller-Weiss syndrome. There is little English literature available on the latter. A review of the literature and a case report are presented here.


Impact of radiographic honeycombing on transplant free survival and efficacy of immunosuppression in fibrotic hypersensitivity pneumonitis.
The distinction between hypersensitivity pneumonitis (HP) and idiopathic pulmonary fibrosis (IPF) was thought to be important due to the difference in mortality between the conditions as well as the response to treatment. However, recent work suggests that the clinical diagnosis may matter less than certain radiographic features, namely usual interstitial pneumonia (UIP) pattern. The purpose of this study is to evaluate whether radiographic honeycombing is more predictive of transplant-free survival (TFS) than other clinical, radiographic, or histologic findings that distinguish HP from IPF in the current guidelines and to evaluate the impact of radiographic honeycombing on the efficacy of immunosuppression in fibrotic HP. We retrospectively identified IPF and fibrotic HP patients evaluated between 2003 and 2019. Univariable and multivariable logistic regression was performed for patients with fibrotic HP and IPF to evaluate TFS. To assess the impact of treatment with immunosuppression on TFS in fibrotic HP, a cox proportional hazard model adjusted for known predictors of survival in HP including age, gender, and baseline pulmonary function testing results was constructed, and p-interaction for the presence of honeycombing on high resolution computed tomography and use of immunosuppression was calculated. Our cohort included 178 with IPF and 198 with fibrotic HP. In a multivariable analysis, the presence of honeycombing had a greater impact on the TFS than the diagnosis of HP vs. IPF. Among the criteria used in the HP diagnostic guidelines, only typical HP scan impacted survival in a multivariable model, while identification of antigen and surgical lung biopsy findings had no impact on survival. We identified a trend toward worse survival on immunosuppression in those with HP with radiographic honeycombing. Our data suggests that honeycombing and baseline pulmonary function testing have a greater impact on TFS than the clinical diagnosis of IPF vs. fibrotic HP and that radiographic honeycombing is a predictor of poor TFS in fibrotic HP. We suggest that invasive diagnostic testing including surgical lung biopsy may not be useful in predicting mortality in HP patients with honeycombing and may potentially increase risk of immunosuppression.


Teaching medical students diagnostic sonography.
The purpose of this pilot project was to train medical students in sonography. Thirty-three medical students participated in a pilot sonography course, which included exposure to ultrasound physics, knobology of a compact ultrasound scanner, training in scanning and anatomy of the aorta and right kidney, and reading assignments in these areas. Pretraining and posttraining examinations were given in these areas to analyze the degree of knowledge gained by these methods. Nearly all of the medical students increased their basic knowledge of sonography and improved their scanning skills. The improvement was statistically significant in all areas. Training in sonography for medical students could be used as a foundation for later, more specialty-specific training to improve the overall medical sonography skills for all physicians.


Overexpression of cathepsin Z contributes to tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma.
The aim of this study was to characterize the oncogenic function and mechanism of Cathepsin Z (CTSZ) at 20q13.3, a frequently amplified region in hepatocellular carcinoma (HCC). Real-time PCR were used to compare CTSZ expression between paired HCC tumor and non-tumor specimens. CTSZ gene was stably transfected into HCC line QGY-7703 cells and its role in tumorigenicity and cell motility was characterized by soft agar, wound-healing, transwell invasion and cell adhesion assay, and tumor xenograft mouse model. Western blot analysis was used to study expression of proteins associated with epithelial-mesenchymal transition (EMT).Upregulation of CTSZ was detected in 59/137 (43%) of primary HCCs, which was significantly associated with advanced clinical stage (P = 0.000). Functional study found that CTSZ could increase colony formation in soft agar and promote cell motility. Further study found that the metastatic effect of CTSZ was associated with its role in inducing epithelial-mesenchymal transition (EMT) by upregulating mesenchymal markers (fibronectin and vimentin) and downregulating epithelial markers (E-cadherin and α-catenin). In addition, CTSZ could also upregulate proteins associated with extracellular matrix remodeling such as MMP2, MMP3 and MMP9. Taken together, our data suggested that CTSZ was a candidate oncogene within the 20q13 amplicon and it played an important role in HCC metastasis.


E-cadherin promotes proliferation of human ovarian cancer cells in vitro via activating MEK/ERK pathway.
E-cadherin is unusually highly expressed in most ovarian cancers. This study was designed to investigate the roles of E-cadherin in the carcinogenesis and progression of ovarian cancers. Human ovarian adenocarcinoma cell line SKOV-3 was examined. E-cadherin gene CDH1 in SKOV-3 cells was knocked down via RNA interference (RNAi), and the resultant variation of biological behavior was observed using CCK-8 and colony formation experiment. E-cadherin-mediated Ca(2+)-dependent cell-cell adhesion was used to study the mechanisms underlying the effects of E-cadherin on the proliferation and survival of SKOV-3 cells. The expression levels of E-cadherin, extracellular signal-related kinase (ERK), phosphorylated ERK (P-ERK) were measured using Western blot assays. Transfection with CDH1-siRNA for 24-96 h significantly suppressed the growth and proliferation of SKOV-3 cells. E-cadherin-mediated calcium-dependent cell-cell adhesion of SKOV-3 cells resulted in a rapid increase of P-ERK, but did not modify the expression of ERK protein. The phosphorylation of ERK in the cells was blocked by pretreatment with the MEK1 specific inhibitor PD98059 (50 μmol/L), but not by the PI3K inhibitor wortmannin (1 μmol/L) or PKA inhibitor H89 (10 μmol/L). E-cadherin may function as a tumor proliferation enhancer via activating the MEK/ERK pathway in development of ovarian epithelial cancers.


Congenital Anomalies of the Ear Canal.
Congenital anomalies of the external auditory canal (EAC) are classically divided into congenital aural atresia (CAA) and congenital aural stenosis (CAS). CAA can present as an isolated anomaly, unilateral or bilateral, or in the setting of a craniofacial syndrome. Hearing testing (ABR with air and bone conduction thresholds for both ears) early in the perinatal period is important to document hearing thresholds. Hearing status thus informs parent counseling on options for hearing habilitation: Bone conducting technology is a must for children with bilateral CAA to support normal speech and language development. Bone conducting technology should be considered for children with unilateral CAA; benefits are unclear. In select candidates, atresia repair can provide improved hearing with a clean, dry, epithelialized ear canal. First branchial cleft cyst or sinus is rare; high index of suspicion is needed to diagnose along with high-resolution CT. Congenital aural stenosis (CAS) is a rare condition, and hearing testing should be similar to that in children with CAA. Early (age 4-5) CT imaging is recommended in the setting of a canal <2 mm or pinpoint canal to evaluate for trapped skin/ear canal cholesteatoma.


Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling.
The Wnt signaling pathway is involved in normal embryonic development and controls the homeostatic self-renewal of stem cells in adult tissues. Constitutive activation of Wnt signaling contributes to cancer development and progression. We identified a CXXC4 homozygous deletion at 4q24 in an aggressive renal cell carcinoma (RCC) using single-nucleotide polymorphism (SNP) arrays. CXXC4 encodes Idax, which negatively regulates Wnt signaling by binding to the PDZ domain of Dishevelled. CXXC4 mRNA levels in tumor samples were significantly lower in patients with metastases compared with those without (P=0.0016). Patients whose tumors had lower CXXC4 expression than normal kidney showed a poorer cause-specific survival outcome than those with higher expression (P=0.0095). Decreased expression of CXXC4 also correlated with cytoplasmic staining of beta-catenin. Knockdown of CXXC4 induced the nuclear translocation of beta-catenin and altered expression of a set of genes involved in cell proliferation, invasion and survival. Furthermore, reduced expression of CXXC4 by small interfering RNAs promoted cell proliferation and inhibited apoptosis after 5-FU and doxorubicin treatment in RCC cells. These data suggest that CXXC4 plays a critical role in tumor progression of RCC through Wnt signaling. Wnt signaling could thus be a potential molecular target in RCC indicating decreased CXXC4 expression.


TElewoRk-RelAted Stress (TERRA), Psychological and Physical Strain of Working From Home During the COVID-19 Pandemic: A Systematic Review.
Many workers shifted to working from home due to the COVID-19 pandemic. This review aims to investigate if this sudden change caused an increase in TElewoRk-RelAted stress (TERRA) which is defined as physical and mental stress caused by telework. A systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was performed of three scientific databases (PubMed, ISI Web of Knowledge, and Scopus), which also included a quality assessment. Articles measuring stress, psychological or physical, in remote workers, published from December 2019 through August 2021 were included in the review. Results were extracted by reporting: authors, country, study design, type of workers, sample, questionnaires and measurements, and outcomes. Data were synthesized quantitatively for country, type of workers, and outcomes. Out of the 518 articles found in the three databases, 19 articles were included in the systematic review (10,012 participants overall), and 78.9% of these highlighted an increase in TERRA levels in remote workers. Among 85.7% of the studies considering gender as a variable, TERRA levels were higher in female workers. Twelve (63.2%) of the studies investigated psychological well-being, two (10.5%) focused on the physical well-being of remote workers, three (15.8%) investigated both, and two studies had other outcomes (10.5%). Considering the redefinition of workplaces dictated by the COVID-19 pandemic, this review highlights the emerging issue of remote work and the use of technology in working from home, emphasizing a rapidly growing occupational health problem. Remote workers need to be provided with emotional and technical support to prevent TERRA in remote workers.


Angiographic profile and outcomes in persistent non-valvular atrial fibrillation: A study from tertiary care center in North India.
The relationship of atrial fibrillation (AF) with coronary artery disease (CAD) is well established, yet it is often missed. There is evidence of myocardial ischemia on stress imaging in AF patients in the absence of obstructive CAD. In this prospective cohort, we studied the angiographic profiles of non-valvular AF patients. The study was a nonrandomized, prospective, single-center observational study of consecutive patients of persistent non-valvular AF. Patients symptomatic for AF despite optimal medical therapy for 3 months were recruited and all underwent coronary angiograms (CAG). Patients with prior history of CAD were excluded. A total of 70 patients were followed for a mean duration of 12 ± 1.4 months. The mean age of the study group was 66.07 (±11.49) years. Hypertension was the commonest comorbidity seen in 74% patients. Obstructive CAD was present in 32 (46%) patients, non-obstructive (<50% stenosis) CAD in 17 (24%) patients and normal coronaries in 21 (30%) patients. Overall 49 (70%) patients had evidence of CAD. Amongst patients without obstructive CAD, slow flow was seen in 16 (42%) patients. Lower baseline ejection fraction, lower haemoglobin & albumin levels and higher creatinine levels was associated with increased mortality. In patients without obstructive CAD, hospitalizations for fast ventricular rate were significantly increased in those having slow flow on CAG (p = 0.005). Majority (70%) of our patients had evidence of atherosclerotic CAD on CAG. A large proportion of patients without obstructive CAD had slow flow on CAG.


Generalist predator dynamics under kolmogorov versus non-Kolmogorov models.
Ecosystems often contain multiple species across two or more trophic levels, with a variety of interactions possible. In this paper we study two classes of models for generalist predators that utilize more than one food source. These models fall into two categories: predator - two prey and predator - prey - subsidy models. For the former, we consider a generalist predator which utilizes two distinct prey species, modelled via a Kolmogorov system of equations with Type II response functions. For the latter, we consider a generalist predator which exploits both a prey population and an allochthonous resource which is provided as a subsidy to the system exogenously, again with Type II response functions. This latter class of model is no longer Kolmogorov in form, due to an exogenous forcing term modelling the input of the allochthonous resource into the system. We non-dimensionalize both models, so that their respective parameter spaces may be more easily compared, and study the dynamics possible from each type of model, which will then indicate - for specific parameter regimes - which generalist predator's preferences are more favorable to survival, including the prevalence of coexistence states. We also consider the various non-equilibrium dynamics emergent from such models, and show that the non-Kolmogorov predator - prey - subsidy model of 10 admits more regular dynamics (including steady states and one type of limit cycle), whereas the predator - two prey Kolmogorov model can feature multiple types of limit cycles, as well as multistability resulting in strong sensitivity to initial conditions (with stable limit cycles and steady states both coexisting for the same model parameters). Our results highlight several interesting differences and similarities between Kolmogorov and non-Kolmogorov models for generalist predators.


Anticholinergic side effects of tricyclic antidepressants and their management.
Side effects associated with tricyclic antidepressant (TCA) therapy often leads to premature drug discontinuation. The most common side effects associated with TCA's are those related to the anticholinergic activity of these medicines. The peripheral anticholinergic complaints of dry mouth, constipation, ocular side effects and urinary hesitancy are described and specific clinical guidelines for their effective management are provided.


Partnerships as an Avenue to Translate Emerging Disease Ecology of SARS-CoV-2 to Agricultural Groups.
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and associated coronavirus disease 19 (COVID-19) has brought farmers and farmworkers the designation of "essential", while placing them into heightened vulnerability for the disease. Many factors diminish access to education and prevention technologies emerging to combat COVID-19. For farmers, advanced age and rural location play a part. Farmworkers encounter numerous additional barriers including language and cultural differences, socioeconomic pressures, and immigration status. The unusual persistence and multiple transmission pathways of SARS-CoV-2 emerging from ongoing scientific study require customization of otherwise standard prevention messaging to farmers and farmworkers to prevent infection and disease exacerbation. AgriSafe Network and Migrant Clinicians Network, both national organizations and major stakeholders in agricultural health, are on the front lines of translating science into practical prevention strategies for those providing health services to farmworkers and farmers. The partnerships pursued provide a blueprint for quickly translating emerging disease ecology to support the health of agricultural populations during the COVID-19 pandemic.


Effect of dietary lipids on renal function in rats with subtotal nephrectomy.
Female rats with 1-3/4 nephrectomy were divided in two groups and pair fed for five weeks diets differing in their linoleic acid content. Five weeks after subtotal nephrectomy, values for glomerular filtration rate and renal plasma flow were significantly higher and the values of blood pressure significantly lower in rats fed a diet rich in linoleic acid. Systolic blood pressure averaged 156 +/- 5.6 mm Hg in high and 215 +/- 8.1 mm Hg in low linoleic acid-fed rats. Differences in the values of blood pressure between the two groups were observed three weeks after subtotal renal ablation and persisted throughout the period of observation. Inulin clearance averaged 0.89 +/- 0.07 ml/min in the high and 0.44 +/- 0.05 ml/min in the low linoleic acid group. Protein excretion in the urine was significantly less in rats fed the high linoleic acid diet (36.9 +/- 4.4 mg/24 hr) than in those fed the low linoleic acid diet (90.1 +/- 12.5 mg/24 hr). The weight of the remnant kidney five weeks after subtotal renal ablation was greater in rats fed a low linoleic acid diet as compared to those fed a high linoleic acid diet (P less than 0.05). Glomerular lesions were more severe in rats fed a low linoleic acid diet than in those fed a high linoleic acid diet. Feeding high linoleic acid diets to normal and subtotally nephrectomized rats increased the content of linoleic and arachidonic acid in renal cortex and medulla.(ABSTRACT TRUNCATED AT 250 WORDS)


Development of babesial vaccines.
The most widely used vaccine against cattle babesiosis was blood from a carrier animal. The development of a calf passage attenuated strain in Australia was a great improvement in vaccine safety and efficacy. The degree of immunity generated by this vaccine remains a standard against which to compare other vaccines. Vaccines derived from culture supernatants have also been developed. These have considerable value. To date no efficacious recombinant vaccine exists. A variety of antigens will probably be required in any synthetic vaccine. Study of clones derived from calf passage attenuated vaccines indicate that the vaccine contains a variety of parasites of differing virulence. The attenuation process enriches for the less virulent clones. The clones may also vary in their antigenic characteristics. To date no single clone gives immunity equal to the original uncloned preparation. An ideal vaccine should not be a living agent. It will probably contain a variety of antigens and may induce less strong immunity than the living vaccine but its greater safety, stability and ease of handling will more than compensate for this.


Bt maize can provide non-chemical pest control and enhance food safety in China.
China is the world's second-largest maize producer and consumer. In recent years, the invasive fall armyworm Spodoptera frugiperda (J.E. Smith) has adversely affected maize productivity and compromised food security. To mitigate pest-inflicted food shortages, China's Government issued biosafety certificates for two genetically modified (GM) Bt maize hybrids, Bt-Cry1Ab DBN9936 and Bt-Cry1Ab/Cry2Aj Ruifeng 125, in 2019. Here, we quantitatively assess the impact of both Bt maize hybrids on pest feeding damage, crop yield and food safety throughout China's maize belt. Without a need to resort to synthetic insecticides, Bt maize could mitigate lepidopteran pest pressure by 61.9-97.3%, avoid yield loss by 16.4-21.3% (range -11.9-99.2%) and lower mycotoxin contamination by 85.5-95.5% as compared to the prevailing non-Bt hybrids. Yield loss avoidance varied considerably between experimental sites and years, as mediated by on-site infestation pressure and pest identity. For either seed mixtures or block refuge arrangements, pest pressure was kept below established thresholds at 90% Bt maize coverage in Yunnan (where S. frugiperda was the dominant species) and 70% Bt maize coverage in other sites dominated by Helicoverpa armigera (Hübner) and Ostrinia furnacalis (Guenée). Drawing on experiences from other crop/pest systems, Bt maize in se can provide area-wide pest management and thus, contribute to a progressive phase-down of chemical pesticide use. Hence, when consciously paired with agroecological and biodiversity-based measures, GM insecticidal crops can ensure food and nutrition security, contribute to the sustainable intensification of China's agriculture and reduce food systems' environmental footprint.


[Follow-up results of 258 navicular fractures of the hand (author's transl)].
258 fresh and old navicular fractures and pseudarthroses are analysed with regard to conservative and operative treatment. Fracture healing occurred in 97.2% of conservatively treated cases. The method described by Matti-Russe using an iliac graft has given good results in old fractures and pseudarthroses, causing 95% fracture healing in old fractures and 76% in pseudarthroses.


A role for the insular cortex in long-term memory for context-evoked drug craving in rats.
Drug craving critically depends on the function of the interoceptive insular cortex, and may be triggered by contextual cues. However, the role of the insula in the long-term memory linking context with drug craving remains unknown. Such a memory trace probably resides in some neocortical region, much like other declarative memories. Studies in humans and rats suggest that the insula may include such a region. Rats chronically implanted with bilateral injection cannulae into the high-order rostral agranular insular cortex (RAIC) or the primary interoceptive posterior insula (pIC) were conditioned to prefer the initially aversive compartment of a 2-compartment place preference apparatus by repeatedly pairing it to amphetamine. We found a reversible but long-lasting loss (ca. 24 days) of amphetamine-conditioned place preference (CPP) and a decreased expression in the insula of zif268, a crucial protein in memory reconsolidation, when anisomycin (ANI) was microinjected into the RAIC immediately after the reactivation of the conditioned amphetamine/context memory. ANI infusion into the RAIC without reactivation did not change CPP, whereas ANI infusion into pIC plus caused a 15 days loss of CPP. We also found a 24 days loss of CPP when we reversibly inactivated pIC during extinction trials. We interpret these findings as evidence that the insular cortex, including the RAIC, is involved in a context/drug effect association. These results add a drug-related memory function to the insular cortex to the previously found role of the pIC in the perception of craving or malaise.


Organocatalytic diastereo- and enantioselective conjugate addition of pyrazol-3-ones to 3-trifluoroethylidene oxindoles with a newly developed squaramide catalyst.
An efficient organocatalytic conjugated addition reaction of pyrazol-3-ones with 3-trifluoroethylidene oxindoles has been developed for the synthesis of enantioenriched triflouromethylated indolin-2-ones bearing adjacent tertiary chiral centers in good yields and good to excellent diastereo- and enantioselectivities. The use of a newly developed chiral spirobiindane-derived squaramide catalyst is essential in achieving high diastereo- and enantioselectivities.


The vesicular transporter STX11 governs ATGL-mediated hepatic lipolysis and lipophagy.
Hepatic lipid accumulation is closely associated with nonalcoholic fatty liver disease (NAFLD). Adipose-triglyceride-lipase (ATGL) regulates triglyceride hydrolysis and maintains energy homeostasis in hepatocytes. Identifying key factors in the regulation of ATGL will help tackle hepatic lipid accumulation and related metabolic diseases. Herein, we demonstrate that syntaxin11 (STX11), a member of the SNARE family, generally expressed in immune cells, mediates lipid metabolism by binding to ATGL and inhibiting lipid droplet degradation and lipid autophagy in hepatocytes. Our data show that the C-terminal of STX11 and the patatin domain-containing segment of ATGL have direct physical interactions. Thus, STX11 overexpression prevents spatial translocation of ATGL onto LDs by recruitment of ATGL to the ER. Conversely, STX11 deficiency in hepatocytes promotes lipid hydrolysis, and the ATGL-SIRT1 signaling pathway enhances lipophagy. Overall, this study uncovered that the regulation of lipolysis and lipophagy is achieved by STX11 through the attenuation of ATGL action in hepatocytes.


Inhibition of prostate carcinoma establishment and metastatic growth in mice by an antiangiogenin monoclonal antibody.
A neutralizing monoclonal antibody (MAb) 26-2F to human angiogenin, a potent inducer of neovascularization, has been shown previously to prevent or delay the appearance of angiogenin-secreting human colon, fibrosarcoma and lung tumor cell xenografts implanted subcutaneously (s.c.) into athymic mice. In an analogous model system, we report here that the antibody also prevents the establishment of PC-3 androgen-independent human prostate cancer tumors in, on average, 40% of treated mice (p < 0.0001, survivor analysis). Intriguingly, combining MAb 26-2F together with cisplatin and suramin, 2 therapeutic agents that together showed little antitumor activity in the aforementioned model, resulted in an even greater degree of protection (71% protected, p = 0.009 compared to antibody treatment alone). This protective effect persisted several weeks after cessation of treatment. Additionally, prophylactic systemic administration of MAb 26-2F dramatically reduced by 50% the formation of spontaneous regional metastasis originating from primary growth in the prostate gland of PC-3M cells, highly metastatic variants of PC-3. Protection from metastasis was still significant when treatment with MAb 26-2F was delayed until after the primary tumor was well established. The antibody is not directly cytotoxic to either cell type, both of which secrete angiogenin in vitro and when growing as tumors in vivo, but changes the pattern of vascularity in primary tumors growing orthotopically. These findings, together with the observation that angiogenin protein and mRNA are apparently overexpressed in cancerous vs. normal human prostate tissues, demonstrate that angiogenin antagonism represents a promising new approach for preventing progression and metastasis of clinical prostate cancer.


Do maternal characteristics and past pregnancy experiences predict preterm delivery among women aged 20 to 34?
To identify key demographic, lifestyle, and medical indicators for preterm births in women aged 20 to 34. A population-based, case-control study consisting of 987 women aged 20 to 34, who delivered a liveborn singleton infant at <37 weeks' gestation in Alberta between May 1999 and August 2000. Controls delivered liveborn infant(s) at > or =37 weeks' gestation. Information was obtained from computer-assisted telephone interviews, and the provincial Physician Notice of Stillbirth/Birth database. Analysis included bivariate and logistic regression techniques. Logistic regression modelling indicated that significant risk factors for preterm delivery included poor past pregnancy outcome (odds ratio [OR] 6.4), poor emotional health (OR 1.8), more than 3 years or less than 1 year between pregnancies (OR 1.4 and 1.9, respectively), polyhydramnios and oligohydramnios (OR 4.1), bleeding at greater than 20 weeks' gestation (OR 10.4), malpresentation (OR 2.9), gestational hyper- tension (OR 2.2), and gestational hypertension with proteinuria (OR 4.4). Women who had fewer than 10 prenatal visits, regardless of attending prenatal classes, were at highest risk of preterm delivery (OR 6.7). In this population of women aged 20 to 34 years, few prenatal visits, poor emotional health prior to pregnancy, and conditions of the current pregnancy were strongly associated with preterm singleton birth.


Bidirectional associations between periodontal disease and systemic diseases: a nationwide population-based study in Korea.
To evaluate the associations of periodontal disease (PD) with systemic diseases, including diabetes mellitus (DM) and cardiovascular disease (CVD), as well as the reciprocal association. The CVD included the cases of coronary heart disease and heart failure. A prospective study was conducted from 2007 to 2019 using linked data from three databases in Korea. Three separate study groups were formed to individually determine the risks of PD (n = 10,533), DM (n = 14,523) and CVD (n = 14,315). All diseases were confirmed based on physicians' diagnoses using medical records and self-reports. Cox proportional hazard regression was applied with 95% confidence intervals (CIs) to obtain hazard ratios (HRs). PD was significantly associated with an elevated risk of DM (HR [95% CI]: 1.22 [1.07-1.39]) after full adjustment for age, sex, lifestyle factors, body mass index, dental behaviour and CVD. PD was also found to increase the risk of CVD (1.27 [1.03-1.57]), whereas CVD increased the risk of PD (1.20 [1.09-1.32]) after full adjustment for other covariates including DM. This study found a bidirectional association between PD and CVD, as well as a positive association of PD with DM.


A role for the cerebellum in motor speech planning: evidence from foreign accent syndrome.
A 3 year follow-up study was performed in a patient with foreign accent syndrome (FAS) as the sole cognitive manifestation of a left fronto-parietal stroke. The hypothesis of involvement of the right cerebellum in this motor speech planning disorder was investigated by means of functional neuroimaging (SPECT) and neurobehavioral assessments. Based on the close parallelism between the evolution of FAS symptoms and the perfusional changes in the right cerebellum, it is argued that FAS may result from a disruption of a close functional interplay between the supra- and infratentorial speech centers involved in motor speech planning.


Correction: Locked Nucleic Acid Probe-Based Real-Time PCR Assay for the Rapid Detection of Rifampin-Resistant Mycobacterium tuberculosis.
[This corrects the article DOI: 10.1371/journal.pone.0143444.].


Catalyst-Controlled C-H Transformation of Pyrazolidinones with 1,3-Diynes for Highly Selective Synthesis of Functionalized Bisindoles and Indoles.
An efficacious synthetic solution to offer functionalized bisindoles and indoles has been developed based on catalyst-controlled C-H functionalization of pyrazolidinones and 1,3-diynes with highly selective control of both chemoselectivity and regioselectivity. This straightforward pathway conquers chemo- and regioselectivity challenges concerning the use of 1,3-diynes.


Milky mushroom: A healthy nutritious diet.
Milky mushroom includes a group of macrofungi traditionally known for nutritional and medicinal properties. They are among the easiest and cheapest cultivable mushrooms in tropical regions. Thus, interest in this group of mushrooms has grown both commercially and medicinally over the years. This review critically discusses different aspects of milky mushroom based on their nutritive values and biological activities and also envisages the challenges which need holistic approaches to formulate functional compounds from these mushrooms. In the last 30 years, various health-promoting properties, as well as domestication techniques of milky mushrooms, have been documented by scientific forums. Besides, several bioactive compounds have been purified among which only a few have been studied in brief. Some unique activities also have been observed like fibrinolytic activity, synergism with standard antibiotics, antiobesity effects, antiaging, and others; however, the study on its active components and structure-activity relationship is an important requirement. An integrated approach from both the nutritional and medical field needs to be adopted for proper utilization of this mushroom as functional food, thus this review will contribute greatly to fill the lacuna in knowledge and unleashing the significance of these milky mushroom; Calocybe indica, Macrocybe gigantea, Macrocybe crassa and Macrocybe lobayensis in the pharmaceutical field.


Low frequency mechanical stimulation inhibits adipogenic differentiation of C3H10T1/2 mesenchymal stem cells.
Oscillatory mechanical stimulation at relatively high frequencies (0.1 Hz) has been shown to inhibit adipogenic and promote osteogenic differentiation of mesenchymal stem cells. However, for physiological interpretations and ease of implementation it is of interest to know whether different rates of mechanical stimulation can produce similar results. We hypothesized that relatively low frequency mechanical stimulation (0.01 Hz) can inhibit adipogenic differentiation of C3H10T1/2 mouse mesenchymal stem cells, even in a potent adipogenic differentiation medium. C3H10T1/2 cells were cultured in adipogenic medium under control (non-mechanically stimulated) conditions and under oscillatory surface stretch with 10% amplitude and 0.01 Hz frequency for 6h per day for up to 5 days. Cell population was assessed by counting and adipogenic differentiation was assessed by real-time quantitative PCR (qPCR) analysis of peroxisome proliferator-activated receptor gamma (PPARγ) and fatty acid binding protein 4 (FABP4) after 3 and 5 days. Involvement of the ERK signaling pathway was assessed by Western blot. Low frequency mechanical stimulation significantly decreased expression of PPARγ after 3 days and FABP4 after 3 and 5 days versus non-stimulated culture. ERK signaling was decreased in mechanically-stimulated culture, indicating a role in the inhibition of adipogenic differentiation. Application of this study: Low frequency mechanical stimulation may provide a technically simple means for control of mesenchymal stem cell differentiation in cell-based therapies, particularly for inhibition of differentiation toward undesired adipogenic lineages.


The steroidal antiestrogen ICI 182,780 is an inhibitor of cellular aromatase activity.
Two types of endocrine therapy that have been successfully applied to patients with hormone-dependent breast cancer are the non-steroidal antiestrogen tamoxifen, and inhibitors of aromatase, the enzyme that synthesizes estrogens. The major drawback with tamoxifen is that it acts as a partial estrogen-agonist and this is believed to mediate, at least in part, acquired tumor resistance to the drug as well as endometrial hyperplasia and carcinoma in some patients. The newer and more potent antiestrogen ICI 182,780 is a steroidal molecule that is devoid of estrogenic activity. We now report that ICI 182,780 is also an inhibitor of aromatase activity in fibroblasts isolated from the normal human breast as well as other carcinoma cell lines that express aromatase (MCF-7Ca breast cancer and JEG-3 choriocarcinoma). ICI 182,780 (1 microM) did not affect aromatase activity levels in human placental microsomes and only inhibited aromatase activity in each of the cell lines following a prolonged incubation period. In the fibroblasts, inhibition of aromatase activity by ICI 182,780 was shown to be time and dose-dependent. In contrast, tamoxifen and 17beta-estradiol were shown to have no effect on aromatase activity levels. ICI 182,780 inhibited aromatase activity levels with IC50 values of 16.80 nM in MCF-7Ca cells, 125.50 nM in JEG-3 cells and 386.1 nM in breast fibroblasts. These values were compared to those for known aromatase inhibitors, and in each of the cell lines the order of potency was letrozole>4-OHA>anastrozole>ICI 182,780. The inhibition of aromatase activity by ICI 182,780 was sustained even after the antiestrogen was removed from the cells indicating that ICI 182,780 may be remaining bound to the enzyme. Although ICI 182,780 had no effect on the proliferation of the fibroblasts, or JEG-3 cells, it significantly inhibited the growth of MCF-7Ca cells. This growth inhibition appeared to be due to the antiestrogenic activity of ICI 182,780 and not to its aromatase inhibiting effects. ICI 182,780 did not inhibit aromatase activity by down-regulating levels of the aromatase transcript. These results show that in addition to being a potent antiestrogen, ICI 182,780 is also an inhibitor of cellular aromatase activity, and suggest that by interfering with the actions of estrogen by two distinct mechanisms, ICI 182,780 may be a suitable drug for treating patients with hormone-dependent breast cancer.


Molecular surveillance of human rotaviruses in drinking water and investigation of the efficiency of their removal in Isfahan water treatment plant.
Enteric viruses, especially human rotaviruses present in aquatic environments, are microbial criteria in quality assessment of water resources. The present research aimed to investigate molecular monitoring of human rotavirus and efficacy evaluation of Isfahan water treatment plant (WTP) in the elimination of viruses. In total, 60 water samples were collected from different units of WTP. Zeta plus electropositive Virosorb cartridge filter and elution buffer was used for concentrating water samples. Enzyme-linked immunosorbent assay (ELISA) was used for detecting rotavirus antigen. Quantitative real-time reverse transcription PCR (qRT-PCR) with SYBR Green I fluorescent dye was performed for molecular detection of rotavirus. Multiplex nested reverse transcription-polymerase chain reaction (RT-PCR) was used for rotavirus G genotyping. Total coliform count varies from 102-103 CFU/mL in the raw water resources. Rotavirus antigen was detected in 17 samples (28.33%) by ELISA, and 13 samples (21.67%) were found positive by RT-PCR. These included 41.18% (7 cases) of raw water influent, 29.41% (5 cases) after sedimentation, 23.52% (4 cases) after ozonation, and 5.88% (1 case) after filtration in ELISA method. The highest number of rotaviruses was detected by qRT-PCR in autumn (46.15% (6 cases)). The commonest circulating G type in the sampling points was the mixed types, which was identified in 6 samples (46.15%), followed by non-typeable (23.07%), G3 (15.38%), G1 (7.69%), and G8 (7.69%), respectively. Despite the presence of rotavirus in raw water, after clarification and ozonation, filtration and treated water did not show the presence of rotavirus. The results of this study showed that multi-stage treatment has a positive effect on virus removal in WTP.


Evaluating the impact of thrombopoietin receptor agonist medications on patient outcomes and quality of life in paediatric immune thrombocytopenia through semi-structured interviews.
Over the last decade, treatment of immune thrombocytopenia (ITP) in children has advanced to include thrombopoietin receptor agonist (TPO-RA) medications. Concurrently, there has been an increased emphasis on patient-reported outcomes-especially quality of life-to guide treatment. Assessing the impact of TPO-RAs on quality of life in paediatric ITP is therefore a priority. In this single-centre integrative mixed-methods study, a cohort of children with ITP prescribed a TPO-RA was identified. These children and/or their caregivers were invited to participate in semi-structured interviews focussed on quality-of-life measures. Independently, a retrospective chart review collected ITP-related data (platelet count, bleeding events) and TPO-RA data (dosing, side effects). Among the 23 eligible patients, 20 were represented in interviews. On chart review, 11/20 patients responded to TPO-RA by meeting platelet count criteria of ≥50 × 109 /L for six or more weeks in the absence of rescue therapy. In interviews with these children and/or their parents, 19/20 expressed the TPO-RA had 'worked', with 11/20 reporting benefit to mood and 11/20 reporting increased participation in activities/sports. Concerns were raised in interviews about TPO-RA medication cost (17/20), medication administration (10/20) and potential side effects (10/20). In conclusion, this study suggests that TPO-RA use in children with ITP improves quality of life.


Cell Division: Here Comes the Kinesin Cavalry.
A new study finds that a spindle motor makes an unexpected contribution to kinetochore-microtubule attachments and chromosome segregation.


Peroxynitrite may affect fibrinolysis via the reduction of platelet-related fibrinolysis resistance and alteration of clot structure.
We tested the hypothesis that in vitro peroxynitrite (ONOO(-), a product of activated inflammatory cells) may affect fibrinolysis in human blood through the reduction of platelet-related fibrinolysis resistance. It was found that ONOO(-) (25-300 µM) accelerated lysis of platelet-fibrin clots (in PRP) dose-dependently, whereas fibrinolysis of platelet-free clots was slightly inhibited by ≥ 1000 µM stressor. Concentrations of ONOO(-) affecting the lysis of platelet-rich clots, inhibited clot retraction (CR) in a dose-dependent manner. Thromboelastometry (ROTEM) measurements performed in PRP showed that treatment with ONOO(-) (threshold conc. 100 µM) prolongs clotting time, and reduces alpha angle, and clot formation velocity parameters indicating for reduced thrombin formation rate. In PRP, ONOO(-) (threshold conc. 100 µM) reduced the collagen-evoked exposure of phosphatidylserine (PS) on platelets' plasma membrane, the shedding of platelet-derived microparticles (PMP), and inhibited platelet-dependent thrombin generation (measured in artificial system), dose-dependently. As judged by confocal microscopy, similar ONOO(-) concentrations altered the architecture of clots formed in collagen-treated PRP. Clots formed in the presence of ONOO(-) were less dense and were composed of thicker fibers, which make them more susceptible to lysis. In platelet-depleted plasma, ONOO(-) (up to milimolar concentration) did not alter clot structure. Blockage of PS exposed on platelets resulted in an alteration of clot architecture toward more prone to lysis. ONOO(-), at lysis-affecting concentrations, inhibited the collagen-evoked secretion of fibrinolytic inhibitors from platelets. We conclude that physiologically relevant ONOO(-) concentrations may accelerate the lysis of platelet-fibrin clots predominantly via downregulation of platelet-related mechanisms including: platelet secretion, clot retraction, platelet procoagulant response, and the alteration in clot architecture associated with it.


Treatment outcomes of pediatric acute myeloid leukemia in Western Kenya before and after the implementation of the SIOP PODC treatment guideline.
The Pediatric Oncology in Developing Countries (PODC) committee of the International Society of Pediatric Oncology (SIOP) published a pediatric acute myeloid leukemia (AML)-specific adapted treatment guideline for low- and middle-income countries. We evaluated the outcomes of children with AML at a large Kenyan academic hospital before (period 1) and after (period 2) implementing this guideline. Records of children (≤17 years) newly diagnosed with AML between 2010 and 2021 were retrospectively studied. In period 1, induction therapy comprised two courses with doxorubicin and cytarabine, and consolidation comprised two courses with etoposide and cytarabine. In period 2, a prephase with intravenous low-dose etoposide was administered prior to induction therapy, induction course I was intensified, and consolidation was adapted to two high-dose cytarabine courses. Probabilities of event-free survival (pEFS) and overall survival (pOS) were estimated using the Kaplan-Meier method. One-hundred twenty-two children with AML were included - 83 in period 1 and 39 in period 2. Overall, 95 patients received chemotherapy. The abandonment rate was 19% (16/83) in period 1 and 3% (1/39) in period 2. The early death, treatment-related mortality, complete remission, and relapse rates in periods 1 and 2 were 46% (29/63) versus 44% (14/32), 36% (12/33) versus 47% (8/17), 33% (21/63) versus 38% (12/32), and 57% (12/21) versus 17% (2/12), respectively. The 2-year pEFS and pOS in periods 1 and 2 were 5% versus 15% (p = .53), and 8% versus 16% (p = .93), respectively. The implementation of the SIOP PODC guideline did not result in improved outcomes of Kenyan children with AML. Survival of these children remains dismal, mainly attributable to early mortality.


Medications and breast-feeding: Current concepts.
To describe the various factors that come into play when a breast-feeding mother is taking medications, including use of prescription drugs, over-the-counter medications, recreational drugs, galactogogues, and herbal remedies and to provide a framework used for counseling breast-feeding women. Community and hospital pharmacy and health care settings. Consultative services provided to breast-feeding mothers who had been prescribed or were using medications. Use of pharmacokinetic factors, maternal and child factors, a list of questions to ask breast-feeding mothers, and a stepwise approach to counsel breast-feeding mothers on the compatibility of using medications while breast-feeding. By positive intervention of pharmacists and health care providers, up to 1 million breast-feeding mothers, who must use medications, can continue to breast-feed while taking medications. Objectively weighing the benefits of drugs and breast-feeding versus the risks of drugs and not breast-feeding, in most cases, allows for pharmacists to give current and practical advice to mothers and other health professionals who counsel mothers.


An Experimental Cold Gas Cannon for the Study of Porcine Lung Contusion and Behind Armor Blunt Trauma.
Behind armor blunt trauma (BABT) is a non-penetrating injury caused by the rapid deformation of body armor, by a projectile, which may in extreme circumstances cause death. The understanding of the mechanisms is still low, in relation to what is needed for safety threshold levels. Few models of graded kinetic energy transfer to the body exist. We established an experimental model for graded BABT. The cold gas cannon was air-driven, consisted of a pressure vessel, a barrel, and a pressure actuator. It required short training to operate and was constructed by standard components. It produced standardized expulsion of plastic projectiles with 65 mm and weight 58 g. Velocity correlated linearly to pressure (R 0.9602, p < 0.0001), equation Y = 6.558*X + 46.50. Maximum tested pressure was 10 bar, velocity 110 m/s and kinetic energy (Ek) 351 J. Crossbred male swine (n = 10) mean weight (SD) 56 ± 3 kg, were subjected to BABT, mean Ek (SD) 318 (61) J, to a fix point on the right lateral thorax. Pulmonary contusion was confirmed by physiological parameters pO2 (p < 0.05), SaO2 (p < 0.01), pCO2 (p < 0.01), etCO2 (p < 0.01), MPAP (p < 0.01), Cstat (p < 0.01), intrapulmonary shunt (Q's/Q't) (p < 0.05), and qualified trans-thoracic ultrasound (p < 0.0001). The consistent injury profile enabled for the addition of future experimental interventions.


Novel, cell-penetrating molecular transporters with flexible backbones and permanently charged side-chains.
Various cell-penetrating peptides have been discovered recently that can translocate across plasma membranes and can even carry large cargo molecules into the cells. Because under physiological conditions most of these peptides carry considerable positive charges due to the presence of basic amino acids such as arginine, we decided to investigate whether molecular transporters composed of permanently charged side-chains also possess such cell penetrating ability. Arginine-rich oligomers that have a backbone with increased flexibility due to incorporation of non-alpha-amino acids (epsilon-aminocaproic acid) have been found to be effective molecular transporters. Here, we report the preparation of analogue structures by replacing the arginine residues with the quaternary form of a novel redox amino acid (Nys(+)) that contain a trigonelline moiety; it has already been shown possible to replace the original basic amino acid side-chain of neuropeptides without significant activity-loss due to the sufficiently close steric and electronic analogy between the new Nys(+) and the original side-chains (in their protonated form, e.g., Arg(+), Lys(+)). A nonamer analogue showed transporter activity resulting in increased cellular uptake in human carcinoma (HeLa) cells.


De novo backbone trace of GroEL from single particle electron cryomicroscopy.
In this work, we employ single-particle electron cryo-microscopy (cryo-EM) to reconstruct GroEL to approximately 4 A resolution with both D7 and C7 symmetry. Using a newly developed skeletonization algorithm and secondary structure element identification in combination with sequence-based secondary structure prediction, we demonstrate that it is possible to achieve a de novo Calpha trace directly from a cryo-EM reconstruction. The topology of our backbone trace is completely accurate, though subtle alterations illustrate significant differences from existing crystal structures. In the map with C7 symmetry, the seven monomers in each ring are identical; however, the subunits have a subtly different structure in each ring, particularly in the equatorial domain. These differences include an asymmetric salt bridge, density in the nucleotide-binding pocket of only one ring, and small shifts in alpha helix positions. This asymmetric conformation is different from previous asymmetric structures, including GroES-bound GroEL, and may represent a "primed state" in the chaperonin pathway.