Multiple Applications of a Novel Fluorescence Probe with Large Stokes Shift and Sensitivity for Rapid H2S Detection.
Herein, a novel fluorescence probe Fla-DNP based on flavonol has been designed and synthesized for rapid, specific detection of H2S. With the addition of H2S, Fla-DNP triggered thiolysis and released Fla displaying the "turn-on" fluorescence response at 566 nm, which is consistent with the reaction site predicted by calculating Electrostatic potential and ADCH charges. As an easily available H2S probe, Fla-DNP has the advantages of high selectivity, anti-interference, low detection limit (0.834 μM), short response time (6 min), and large Stokes shift (124 nm). The sensing mechanism of H2S was determined by HRMS analysis and DFT calculation. Moreover, Fla-DNP processes a wide range of multiple applications, including the detection of H2S in environmental water samples with good recovery rates ranging from 89.6% to 102.0%, as well as tracking the production of H2S during food spoilage. Meanwhile, the probe exhibits superior biocompatibility and can not only be available used for H2S detection in living cells but be further designed as an H2S-activated CO photoreleaser, based on which it can be developed as a targeted anti-cancer drug. A novel fluorescence probe Fla-DNP was synthesized utilizing 4-dimethylaminobenzoxanthone fluorescent dye (Fla) as the fluorophore, 2, 4-dinitrobenzenether group (DNP) as the recognition group, which can rapidly respond to H2S with high selectivity, anti-interference, low detection limit (0.834 μM), short response time (6 min), and large Stokes shift (124 nm) characteristics. The practical applications of Fla-DNP were further explored in water, foodstuffs samples and living cells. It is reflected that Fla-DNP can not only track H2S in complex environment water, but also can detect H2S produced during foodstuffs spoilage to monitor food freshness. More importantly, Fla-DNP can be available used for H2S detection in living cells and utilize the properties of the photoinduced release of CO from flavonols to be designed as a bifunctional platform for H2S detection and CO release. It is demonstrated that H2S-activated CO photoreleaser Fla-DNP has promise for development as an anti-cancer drug.


Meeting report of the sixth annual tri-service microbiome consortium symposium.
The Tri-Service Microbiome Consortium (TSMC) was founded to enhance collaboration, coordination, and communication of microbiome research among DoD organizations and to facilitate resource, material and information sharing amongst consortium members, which includes collaborators in academia and industry. The 6th Annual TSMC Symposium was a hybrid meeting held in Fairlee, Vermont on 27-28 September 2022 with presentations and discussions centered on microbiome-related topics within seven broad thematic areas: (1) Human Microbiomes: Stress Response; (2) Microbiome Analysis & Surveillance; (3) Human Microbiomes Enablers & Engineering; (4) Human Microbiomes: Countermeasures; (5) Human Microbiomes Discovery - Earth & Space; (6) Environmental Micro & Myco-biome; and (7) Environmental Microbiome Analysis & Engineering. Collectively, the symposium provided an update on the scope of current DoD microbiome research efforts, highlighted innovative research being done in academia and industry that can be leveraged by the DoD, and fostered collaborative opportunities. This report summarizes the activities and outcomes from the 6th annual TSMC symposium.


Perfluorocarbon reduces cell damage from blast injury by inhibiting signal paths of NF-κB, MAPK and Bcl-2/Bax signaling pathway in A549 cells.
Blast lung injury is a common type of blast injury and has very high mortality. Therefore, research to identify medical therapies for blast injury is important. Perfluorocarbon (PFC) is used to improve gas exchange in diseased lungs and has anti-inflammatory functions in vitro and in vivo. The aim of this study was to determine whether PFC reduces damage to A549 cells caused by blast injury and to elucidate its possible mechanisms of action. A549 alveolar epithelial cells exposed to blast waves were treated with and without PFC. Morphological changes and apoptosis of A549 cells were recorded. PCR and enzyme-linked immunosorbent assay (ELISA) were used to measure the mRNA or protein levels of IL-1β, IL-6 and TNF-α. Malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity levels were detected. Western blot was used to quantify the expression of NF-κB, Bax, Bcl-2, cleaved caspase-3 and MAPK cell signaling proteins. A549 cells exposed to blast wave shrank, with less cell-cell contact. The morphological change of A549 cells exposed to blast waves were alleviated by PFC. PFC significantly inhibited the apoptosis of A549 cells exposed to blast waves. IL-1β, IL-6 and TNF-α cytokine and mRNA expression levels were significantly inhibited by PFC. PFC significantly increased MDA levels and decreased SOD activity levels. Further studies indicated that NF-κB, Bax, caspase-3, phospho-p38, phosphor-ERK and phosphor-JNK proteins were also suppressed by PFC. The quantity of Bcl-2 protein was increased by PFC. Our research showed that PFC reduced A549 cell damage caused by blast injury. The potential mechanism may be associated with the following signaling pathways: 1) the signaling pathways of NF-κB and MAPK, which inhibit inflammation and reactive oxygen species (ROS); and 2) the signaling pathways of Bcl-2/Bax and caspase-3, which inhibit apoptosis.


Distinct effects of heat shock temperatures on mitotic progression by influencing the spindle assembly checkpoint.
Heat shock is a physiological and environmental stress that leads to the denaturation and inactivation of cellular proteins and is used in hyperthermia cancer therapy. Previously, we revealed that mild heat shock (42 °C) delays the mitotic progression by activating the spindle assembly checkpoint (SAC). However, it is unclear whether SAC activation is maintained at higher temperatures than 42 °C. Here, we demonstrated that a high temperature of 44 °C just before mitotic entry led to a prolonged mitotic delay in the early phase, which was shortened by the SAC inhibitor, AZ3146, indicating SAC activation. Interestingly, mitotic slippage was observed at 44 °C after a prolonged delay but not at 42 °C heat shock. Furthermore, the multinuclear cells were generated by mitotic slippage in 44 °C-treated cells. Immunofluorescence analysis revealed that heat shock at 44 °C reduces the kinetochore localization of MAD2, which is essential for mitotic checkpoint activation, in nocodazole-arrested mitotic cells. These results indicate that 44 °C heat shock causes SAC inactivation even after full activation of SAC and suggest that decreased localization of MAD2 at the kinetochore is involved in heat shock-induced mitotic slippage, resulting in multinucleation. Since mitotic slippage causes drug resistance and chromosomal instability, we propose that there may be a risk of cancer malignancy when the cells are exposed to high temperatures.


Vibrationally excited molecular hydrogen production from the water photochemistry.
Vibrationally excited molecular hydrogen has been commonly observed in the dense photo-dominated regions (PDRs). It plays an important role in understanding the chemical evolution in the interstellar medium. Until recently, it was widely accepted that vibrational excitation of interstellar H2 was achieved by shock wave or far-ultraviolet fluorescence pumping. Here we show a further pathway to produce vibrationally excited H2 via the water photochemistry. The results indicate that the H2 fragments identified in the O(1S) + H2(X1Σg+) channel following vacuum ultraviolet (VUV) photodissociation of H2O in the wavelength range of λ = ~100-112 nm are vibrationally excited. In particular, more than 90% of H2(X) fragments populate in a vibrational state v = 3 at λ~112.81 nm. The abundance of water and VUV photons in the interstellar space suggests that the contributions of these vibrationally excited H2 from the water photochemistry could be significant and should be recognized in appropriate interstellar chemistry models.


[Animal models of osteomyelitis].
Despite new approaches in biochemical testing, radiologic and nuclear medicine and advances in surgical techniques, the problem of diagnosis and therapy of acute and chronic osteitis has not been finally solved. Clinical research on osteitis is problematic as there are many variables influencing the inflammatory process and a wide spectrum in therapeutic options exists, hampering research under defined conditions. Consequently, there was an early need for animal models. In vivo experimental settings were established to gain reproducible and reliable results under standardized conditions on the pathogenesis and therapy of osteitis. In this article, an overview of the hitherto established experimental animal models and the results of osteitis research on these models is given.


Longitudinal trajectory of bacterial vaginosis during pregnancy.
This study was undertaken to characterize the course of bacterial vaginosis in pregnancy and to discern the bacterial morphotypes responsible for infection. Vaginal secretions were obtained in each trimester of pregnancy and were evaluated for bacterial vaginosis by Gram stain, categorized as normal or any of the following: Lactobacillus deficient, Gardnerella, Bacteroides, or Mobiluncus positive and by Nugent score. Results were evaluated for trends of bacterial vaginosis and Gram stain over pregnancy. One hundred forty-eight women were evaluated. Seventy-one women (48%) were bacterial vaginosis negative in all trimesters, compared with 14 (9.4%) who were positive throughout pregnancy. Among the 14 women who remained bacterial vaginosis positive, Gram stain findings were Gardnerella+Bacteroides+Lactobacillus, with approximately 50% harboring Mobiluncus. Few women become bacterial vaginosis positive as pregnancy progressed (6.1%). With each increasing week of pregnancy, the risk of becoming bacterial vaginosis positive decreased (0.93: 0.91-0.95; P < .001). In this population, the majority of pregnant women trend toward bacterial vaginosis negative status. Few women are bacterial vaginosis positive across their pregnancy.


A hairpin structure in the R region of the human immunodeficiency virus type 1 RNA genome is instrumental in polyadenylation site selection.
Some retroviruses with an extended repeat (R) region encode the polyadenylation signal within the R region such that this signal is present at both the 5' and 3' ends of the viral transcript. This necessitates differential regulation to either repress recognition of the 5' polyadenylation signal or enhance usage of the 3' signal. The human immunodeficiency virus type 1 (HIV-1) genome encodes an inherently efficient polyadenylation signal within the 97-nucleotide R region. Polyadenylation at the 5' HIV-1 polyadenylation site is inhibited by downstream splicing signals, and usage of the 3' polyadenylation site is triggered by an upstream enhancer element. In this paper, we demonstrate that this on-off switch of the HIV-1 polyadenylation signal is controlled by a secondary RNA structure that occludes part of the AAUAAA hexamer motif, which we have termed the polyA hairpin. Opening the 5' hairpin by mutation triggered premature polyadenylation and caused reduced synthesis of viral RNA, indicating that the RNA structure plays a pivotal role in repression of the 5' polyadenylation site. Apparently, the same hairpin structure does not interfere with efficient usage of the 3' polyadenylation site, which may be due to the presence of the upstream enhancer element. However, when the 3' hairpin was further stabilized by mutation, we measured a complete loss of 3' polyadenylation. Thus, the thermodynamic stability of the polyA hairpin is delicately balanced to allow nearly complete repression of the 5' site yet efficient activation of the 3' site. This is the first report of regulated polyadenylation that is mediated by RNA secondary structure. A similar hairpin motif that occludes the polyadenylation signal can be proposed for other lentiviruses and members of the spumaretroviruses, suggesting that this represents a more general gene expression strategy of complex retroviruses.


Traumatic aortic rupture: an additional roentgenographic sign.
Esophageal displacement to the right at the level of the aortic arch and isthmus, as marked by an opaque nasoesophageal tube on anteroposterior chest roentgenogram is a useful sign in diagnosing traumatic aortic rupture. Finding this esophageal displacement in patients with blunt chest trauma warrants an immediate thoracic aortogram for demonstration of possible aortic injury.


Knockdown of the DUF647 family member RUS4 impairs stamen development and pollen maturation in Arabidopsis.
ROOT UV-B SENSITIVE4 (RUS4) encodes a Domain of Unknown Function647 (DUF647) protein, whose function is poorly understood. We have previously shown the artificial microRNA knockdown Arabidopsis RUS4 plants, referred to as amiR-RUS4, have severely reduced male fertility with a defect in anther dehiscence. Here, we show that amiR-RUS4 plants are also defective in pollen maturation and germination. Promoter-reporter analysis shows that RUS4 is highly expressed in tapetal layer, developing microspores, mature and germinating pollen, strongly suggesting its role in the process of pollen maturation. As the translational RUS4-GFP fusion protein has been localized to the chloroplasts where the first step of jasmonic acid (JA) biosynthesis takes place, leading to the hypothesis that RUS4 may be involved in JA-mediated stamen development. We show that expression of several JA metabolic genes increased markedly in flower buds of the amiR-RUS4 plants compared to that of the wild-type. We further show that transcript abundance of a clade of the JA-responsive MYB transcript factor genes, especially MYB108, reduced significantly in stamens of amiR-RUS4 plants relative to the wild-type; these MYB transcript factors have been shown to be required for JA-mediated stamen and pollen maturation. Our data suggest that RUS4 may play a role in coordinating anther dehiscence and pollen maturation by affecting the expression of JA-related genes.


FAK-MAPK-dependent adhesion disassembly downstream of L1 contributes to semaphorin3A-induced collapse.
Axonal receptors for class 3 semaphorins (Sema3s) are heterocomplexes of neuropilins (Nrps) and Plexin-As signalling coreceptors. In the developing cerebral cortex, the Ig superfamily cell adhesion molecule L1 associates with Nrp1. Intriguingly, the genetic removal of L1 blocks axon responses of cortical neurons to Sema3A in vitro despite the expression of Plexin-As in the cortex, suggesting either that L1 substitutes for Plexin-As or that L1 and Plexin-A are both required and mediate distinct roles. We report that association of Nrp1 with L1 but not Plexin-As mediates the recruitment and activation of a Sema3A-induced focal adhesion kinase-mitogen-activated protein kinase cascade. This signalling downstream of L1 is needed for the disassembly of adherent points formed in growth cones and subsequently their collapse response to Sema3A. Plexin-As and L1 are coexpressed and present in common complexes in cortical neurons and both dominant-negative forms of Plexin-A and L1 impair their response to Sema3A. Consistently, Nrp1-expressing cortical projections are defective in mice lacking Plexin-A3, Plexin-A4 or L1. This reveals that specific signalling activities downstream of L1 and Plexin-As cooperate for mediating the axon guidance effects of Sema3A.


Electrocardiographic and hemodynamic effects of intravenous cocaine in awake and anesthetized dogs.
Graded bolus and infusion doses of cocaine were given to 18 dogs, 6 under general anesthesia and 12 awake, to determine the range of hemodynamic and electrocardiographic effects. Blood pressure, electrocardiographic measurements, cocaine plasma levels, temperature, electrolytes, and arterial blood gases were measured before and after the initial bolus and/or infusion at 10 minutes and each 30 minutes up to a maximum of 180 minutes. At the end of the infusion, a single large intravenous terminal bolus of cocaine was given. The hemodynamic and electrocardiographic changes occurred by 10 minutes after the bolus and resolved by 30 minutes, independent of the infusion rate and dose. Only anesthetized dogs could tolerate the highest cocaine doses. Three ranges of bolus doses were given: the lowest range was the average initial bolus dose received by the awake group; the intermediate range was the average initial bolus dose received by the anesthetized group; and the highest range was the average terminal bolus dose. The heart rate changes were unpredictable and did not change significantly at any dose range. The blood pressure increased in the lowest dose range, remained unchanged at intermediate doses, and fell at the highest doses in four of six dogs. Electrocardiographic intervals increased as the dose range increased. Only at the highest doses did potentially lethal ventricular arrhythmia (ventricular tachycardia and an idioventricular escape rhythm) occur. Intravenous cocaine causes hemodynamic and electrocardiographic effects that are related to the dose and rate of administration. At high doses, hypotension, arrhythmia, and electrocardiographic changes consistent with infranodal and/or intraventricular conduction slowing can occur.


Actinidin, a protease from kiwifruit, induces changes in morphology and adhesion of T84 intestinal epithelial cells.
Actinidin belongs to the papain-like family of cysteine proteases and is a major kiwifruit allergen. In this study, the effect of actinidin on cellular morphology and adhesion of T84 intestinal cells was investigated. Both rounding and detachment of T84 cells were observed upon actinidin treatment. The morphological changes and cell desquamation was protease-dependent, as well as time- and concentration-dependent. Changes of intercellular adhesion and adhesion of epithelial cells to collagen upon actinidin treatment could be responsible for the cell rounding and give rise to discontinuous breaches in the epithelial monolayer observed in this study. Actinidin's action on cell morphology, adhesion and monolayer integrity were not due to compromised viability of T84 epithelial cells, as confirmed by MTT assay and flow cytometric analysis of the cell cycle. Damage to the epithelial monolayer of the intestine induced by actinidin should be further evaluated as an important factor in the development of kiwifruit allergy and other intestinal disorders.


Student life - Tips for placement success.
Placements are an inevitable part of a nursing degree which provide a platform for on-the-job learning and development, greatly enhancing a student nurse's understanding of their career choice.


Perrottetiataronensis B.M.Barthol. & K.Armstr., sp. nov. (Dipentodontaceae), a new species from northwestern Yunnan Province, China and northern Kachin State, Myanmar and a re-examination of the Asian and Australasian taxa of Perrottetia.
Perrottetiataronensis from the Dulong Jiang valley in northwestern Yunnan Province, China and the Babulongtan mountain range in northern Kachin State, Myanmar is here described as a new species of the Dipentodontaceae. It is the third species of the genus to be recognized for China and the first to be reported for Myanmar. It is similar to P.alpestris s.s. but differs by characters of its leaf margins, inflorescences, and fruit. The three subspecies of P.alpestris recognized by Hou in "Flora Malesiana" are here recognized as three distinct species, i.e., P.alpestris, P.moluccana, and P.philippinensis on the basis of differences in diagnostic characters and distribution. The report in the "Flora of China" of the Taiwan species P.arisanensis from Yunnan is determined to be incorrect due to misidentification of two specimens at KUN.


Correlation of paraspinal atrophy and denervation in back pain and spinal stenosis relative to asymptomatic controls.
To determine the relationship among spinal stenosis, back pain, paraspinal muscle denervation, and paraspinal muscle atrophy. A prospective masked, double-controlled study. A university hospital and outpatient spine clinic. Ten asymptomatic subjects, 10 subjects with mechanical low back pain, and 15 subjects with symptomatic spinal stenosis; age range, 55-80 years old. Magnetic resonance imaging measurements of minimum spinal canal diameter, paraspinal muscle cross-sectional area at the level of the L5-S1 disk, and quantified paraspinal electrodiagnostic testing (MiniPM) were performed by examiners blinded to each other's results and to the participants' clinical information. Paraspinal muscle cross-sectional area and MiniPM scores. A paraspinal cross-sectional area decreased significantly from asymptomatic subjects (3872 mm(2)) to subjects with low back pain (3627 mm(2)) and to subjects with spinal stenosis (2985 mm(2)). In the stenosis group, there was a trend toward increased paraspinal denervation in the subjects with severe spinal stenosis, but this was not statistically significant. Symptomatic spinal stenosis results in greater paraspinal muscle atrophy than low back pain alone. The extent of paraspinal atrophy was not significantly explained by the extent of denervation, thus, it may be reversible, and the role of paraspinal muscle rehabilitation in patients with spinal stenosis deserves further study.


The Novacor left ventricular assist system: clinical experience from the Novacor registry.
The electrically powered Novacor left ventricular assist (LVAS) system was first used clinically as a bridge to transplant in 1984. The configuration has evolved to the current wearable model used clinically for the first time in 1993. In 1998, the inflow conduit was modified, reducing embolic events by 50%. Over 1100 implants have been performed worldwide with cumulative support greater than 300 patient years, and only 0.7% requiring replacement. The Novacor is a safe and effective device for bridge to transplant, bridge to recovery, or potentially permanent implant with reliable long-term support for periods as long as 4 years.


Methylation of microribonucleic acid Let-7b regulatory regions in endometriosis.
To evaluate whether Let-7b regulatory regions are methylated in endometriosis and whether there are specific CpG methylation sites that can be identified as key epigenetic regulatory locations. Laboratory study. Academic Medical Center. Twenty-one women with (n = 12) and without (n = 9) endometriosis. Laboratory investigation. In vitro assessment of Let-7b methylation. Four targeted regions upstream of Let-7b predicted to be the regulatory regions of this microribonucleic acid (miRNA) were amplified using bisulfite-specific polymerase chain reaction. Deoxyribonucleic acid sequences were analyzed to determine methylation status at each predicted regulatory region and CpG island. Regions were chosen on the basis of percent (%) GC content and data from Ensembl/ENCODE databases, which predict locations of promoters, enhancers, CTCF, and transcription factor binding sites as well as candidate cis-regulatory elements. A region 1,161 base pairs upstream of the Let-7b coding region was significantly differentially methylated in ectopic samples compared with eutopic endometrium from patients with endometriosis. Four specific CpG islands within this region 2 were further analyzed individually, and 1 was found to be significantly methylated in endometriosis. We identified that transcription factor SP1 was predicted to bind to a sequence that contained this specific methylated CpG in endometriosis. We identified differential Let-7b methylation in endometriosis, demonstrating that the epigenetic nature of the disease extends to the regulation of miRNAs. Methylation of this novel Let-7b regulatory region explains the decreased levels of this miRNA in endometriosis and is distinct from the regions implicated in regulating Let-7b in cancer. Understanding of the disease-specific mechanisms leading to diminished expression may allow for better understanding of the etiology of endometriosis as well as development of new treatment options.


Motor recovery by improvement of limb-kinetic apraxia in a chronic stroke patient.
We report on a chronic stroke patient who showed motor recovery by improvement of limb-kinetic apraxia (LKA) after undergoing intensive rehabilitation for a period of one month, which was demonstrated by diffusion tensor tractography (DTT) and transcranial magnetic stimulation (TMS). A 50-year-old male patient presented with severe paralysis of the left extremities at the onset of thalamic hemorrhage. At thirty months after onset, the patient exhibited moderate weakness of his left upper and lower extremities. In addition, he exhibited a slow, clumsy, and mutilated movement pattern during grasp-release movements of his left hand. During a one-month period of intensive rehabilitation, which was started at thrity months after onset, the patient showed 22% motor recovery of the left extremities. The slow, clumsy, and mutilated movement pattern of the left hand almost disappeared. DTTs of the corticospinal tract (CST) in both hemispheres originated from the cerebral cortex, including the primary motor cortex, and passed along the known CST pathway. The DTT of the right CST was located anterior to the old hemorrhagic lesion. TMS study performed at thirty and thirty-one months after onset showed normal and similar findings for motor evoked potential in terms of latency and amplitude of the left hand muscle. We think that the motor weakness of the left extremities in this patient was mainly ascribed to LKA and that most of the motor recovery during a one-month period of rehabilitation was attributed to improvement of LKA.


Electrokinetic movement of multiple chlorobenzenes in contaminated soils in the presence of beta-cyclodextrin.
This study investigated the electrokinetic (EK) behavior of multiple chlorobenzenes, including 1,2,3,4-tetrachlorobenzene (TeCB), 1,2,4,5-tetrachlorobenzene (i-TeCB), and 1,2,3-trichlorobenzene (TCB) in contaminated clayed soils. The effect of beta-cyclodextrin (beta-CD) on the EK removal of the chlorobenzenes was studied. The largest removal was obtained when Na2CO3/NaHCO3 buffer was used as anodic purging solution without beta-CD. The removal efficiencies were related to the aqueous solubilities of chlorobenzenes. With the same cumulative electroosmotic flow, greater solubility led to higher removal efficiency. The addition of beta-CD inhibited the EK removal efficiency of all chlorobenzenes. The inhibition increased with the increase of beta-CD concentration. With the same beta-CD concentration, the inhibition increased with the rise of electric potential. It was found that the inclusion compounds between beta-CD and chlorobenzenzes were less soluble than chlorobenzenes. The formation of the less soluble inclusion compounds reduced the aqueous solubility of chlorobenzenes and led to the partial immobilization of the chlorobenzenes that desorbed from soil. It was feasible to use the EK technology to remove chlorobenzenes in contaminated soils using water as the anodic flushing solution. The addition of beta-CD was not recommended for the EK removal of chlorobenzenes.


DIAGNOSTIC ROLE OF FLUORINE-18 (18F) FLUORODEOXYGLUCOSE POSITRON EMISSION TOMOGRAPHY COMPUTED TOMOGRAPHY IN DETECTING RECURRENT DISEASE IN PATIENTS WITH COLORECTAL CANCER AND ELEVATED CARCINOEMBRYONIC ANTIGEN.
Early detection of recurrence is an important factor for long term survival of patients with colorectal cancer. Measurement of serum levels of carcinoembryonic antigen has been commonly used in the postoperative surveillance of colorectal cancer. The purpose of this study was to evaluate the ability of positron emission tomography-computed tomography to detect pathological substrate of elevated serum carcinoembryonic antigen in patients with colorectal cancer. The patients with colorectal cancer who underwent curative surgical resection and/ or chemotherapy, who were found in our database, were analyzed retrospectively. Forty-eight 18F-fluorodeoxyglucose positron emission tomography-computed tomography studies including 45 patients (14 women, 31 men; mean age: 62.93 years) with elevated serum, carcinoembryonic antigen levels, which had been performed between January 2011 and January 2014, were evaluated. Serum levels of carcinoembryonic antigen were measured within 3 months after positron emission tomography-computed tomography examination. Final diagnosis of recurrence was made by histopathological findings, radiology studies or clinical follow-up. Recurrences were diagnosed in 37 patients, the prevalence being 77.1%. Liver metastases were found in 18 patients, abdominal, pelvic and/or mediastinal lymph nodes were positive in 19 patients, 11 patients had loco regional recurrences and 4 patients had pulmonary metastasis, and bone metastases were found in one patient. One patient was diagnosed with metastasis in scar tissue. The overall sensitivity and specificity of positron emission tomography-computed tomography was 90.24% and 71.42%, respectively. The positive and negative predictive values were 94.87% and 55.56%, respectively. 18F-fluorodeoxyglucose positron emission tomography-computed tomography is a powerful tool that could be used in determining colorectal cancer recurrence in patients with elevated carcinoembryonic antigen levels and could have an important clinical impact on the management in patients with suspected recurrent colorectal cancer.


Exosomes from circ-Astn1-modified adipose-derived mesenchymal stem cells enhance wound healing through miR-138-5p/SIRT1/FOXO1 axis regulation.
Wound healing impairment is a dysfunction induced by hyperglycemia and its effect on endothelial precursor cells (EPCs) in type 2 diabetes mellitus. There is increasing evidence showing that exosomes (Exos) derived from adipose-derived mesenchymal stem cells (ADSCs) exhibit the potential to improve endothelial cell function along with wound healing. However, the potential therapeutic mechanism by which ADSC Exos contribute to wound healing in diabetic mice remains unclear. To reveal the potential therapeutic mechanism of ADSC Exos in wound healing in diabetic mice. Exos from ADSCs and fibroblasts were used for high-throughput RNA sequencing (RNA-Seq). ADSC-Exo-mediated healing of full-thickness skin wounds in a diabetic mouse model was investigated. We employed EPCs to investigate the therapeutic function of Exos in cell damage and dysfunction caused by high glucose (HG). We utilized a luciferase reporter (LR) assay to analyze interactions among circular RNA astrotactin 1 (circ-Astn1), sirtuin (SIRT) and miR-138-5p. A diabetic mouse model was used to verify the therapeutic effect of circ-Astn1 on Exo-mediated wound healing. High-throughput RNA-Seq analysis showed that circ-Astn1 expression was increased in ADSC Exos compared with Exos from fibroblasts. Exos containing high concentrations of circ-Astn1 had enhanced therapeutic effects in restoring EPC function under HG conditions by promoting SIRT1 expression. Circ-Astn1 expression enhanced SIRT1 expression through miR-138-5p adsorption, which was validated by the LR assay along with bioinformatics analyses. Exos containing high concentrations of circ-Astn1 had better therapeutic effects on wound healing in vivo compared to wild-type ADSC Exos. Immunofluorescence and immunohistochemical investigations suggested that circ-Astn1 enhanced angiopoiesis through Exo treatment of wounded skin as well as by suppressing apoptosis through promotion of SIRT1 and decreased forkhead box O1 expression. Circ-Astn1 promotes the therapeutic effect of ADSC-Exos and thus improves wound healing in diabetes via miR-138-5p absorption and SIRT1 upregulation. Based on our data, we advocate targeting the circ-Astn1/miR-138-5p/SIRT1 axis as a potential therapeutic option for the treatment of diabetic ulcers.


[Effect of the treatment of relapsing bronchitis in children with combined interferon preparations applicated by different methods].
The clinico-immunological effect and significance of the rectal and inhalation methods of the application of recombinant IFN-alpha2 with complex immunoglobulin preparation (CIP) in the treatment of relapsing bronchitis in children have been determined. The determination of the levels of interferon activity in buccal secretions and in venous blood permits the objective evaluation of the immune responsiveness of the body and the treatment effect. The immunocorrecting action of the combined immunobiological preparation (recombinant IFN-alpha2 and CIP) is manifested by an increased level of endogenic interferon and the stimulation of phagocytic activity.


Evidence that platelets promote tube formation by endothelial cells on matrigel.
The involvement of platelets in neovascularization was investigated in the matrigel tube formation assay, an in vitro model of angiogenesis. Platelets promoted the formation of capillary-like structures (expressed as relative tube area) number- and time-dependently. Relative tube area increased from 0.98+/-0.02 (n = 8) in the presence of 6.25 x 10(4), to 3.21+/-0.12 (n=8) in the presence of 10(6) platelets/well compared to 0.54+/-0.04 (n=8) in their absence. This increase was unaffected by acetyl salicylic acid (ASA), apyrase, and hirudin. Photographs from representative experiments, showed that platelets adhered along the differentiating endothelium. Addition of alpha-thrombin (0.1-1 i.u. ml(-1)), the nitric oxide (NO) donor sodium nitroprusside (SNP; 1-100 microM) or the NO synthase inhibitor, L-NG-arginine-methylester (L-NAME, 30-300 microM) to the assay, had no effect on tube formation compared to that seen with platelets alone. Neuraminidase (0.01 i.u./10(7) platelets), which strips sialic acid residues from membrane glycoproteins, abolished the promoting effect of platelets on tube formation. The relative tube area in the presence of neuraminidase-treated platelets was 0.81+/-0.03 (n = 8), in the presence of untreated platelets 1.69+/-0.09, P<0.001 (n=8) and in the absence of platelets, 0.80+/-0.04 (n=8). The tetrapeptide Arg-Gly-Asp-Ser (RGDS; 20-200 microM) which inhibits von Willebrand factor, fibrinogen and fibronectin-mediated adhesion, had no effect on the promoting effect of platelets on tube formation. These results indicate that platelets promote angiogenesis in vitro. This effect is largely independent from activation by alpha-thrombin, is not modified by manipulating NO and prostaglandin metabolism and proceeds possibly through adhesion of the platelets to the differentiating endothelium.


Effect of injury severity on lower urinary tract function after experimental spinal cord injury.
Lower urinary tract dysfunction is a serious burden for patients following spinal cord injury. Patients are usually limited to treatment with urinary drainage catheters, which can lead to repeated urinary tract infections and lower quality of life. Most of the information previously obtained regarding lower urinary tract function after spinal cord injury has been in completely transected animals. After thoracic transection in the rat, plasticity of local lumbosacral spinal circuitry establishes a "reflex bladder," which results in partial recovery of micturition, albeit with reduced voiding efficiency. Since at least half of cord-injured patients exhibit neurologically incomplete injury, rat models of clinically relevant incomplete contusion injury have been developed. With respect to lower urinary tract function, recent anatomical and physiological studies have been performed after incomplete thoracic contusion injury. The results show greater recovery of lower urinary tract function that varies inversely with the severity of the initial trauma and is positively correlated with time after injury. Recovery, as measured by coordination of the bladder with the external urethral sphincter, occurs between 1 and 4 weeks after spinal cord injury. It is associated with normalization of: serotonin immunoreactivity and glutamate receptor subunit mRNA expression in the dorsolateral nucleus that innervates the external urethral sphincter muscle, the response to glutamatergic pharmacological probes administered at the lumbosacral spinal cord level, and c-Fos activation patterns in the lumbar spinal cord. Understanding the mechanisms involved in this recovery will provide a basis for enhancing lower urinary tract function in patients after incomplete spinal cord injury.


Acromegaly Quality of Life Questionnaire (AcroQoL).
Acromegaly is a chronic disease with an important impact on patients, Health Related Quality of Life (HRQoL). The ability to effectively measure Health Related Quality of Life is central to describing the impacts of disease or treatment upon the patient, therefore the importance of having a disease specific questionnaire for acromegaly. For the development of the AcroQoL questionnaire different sources of information were used: first a literature search was performed to identify relevant papers describing the impact of acromegaly in HRQoL, second the main domains of impact on HRQoL were identified by 10 experts endocrinologists, and third ten in-depth semi-structured interviews were conducted in acromegalic patients to identify domains and items related to the self-perceived impact of acromegaly in patients' life. After a proper qualitative analysis a preliminary 38 item questionnaire was obtained. Rasch analysis concluded with a final 22 item questionnaire. The measurement properties (validity and reliability) of the resulting final questionnaire were tested and compared using standard procedures (Cronbach's Alpha and item-total correlation). The evaluation of the item parameters confirmed the construct validity of the new instrument. Responsiveness to change was assessed in a small sample of 32 acromegalic patients with active disease in Spain who were administered the AcroQoL and the generic questionnaire EuroQoL 5-D. The results showed a statistically significant relationship between all the dimensions of AcroQoL and the VAS (visual analogic scale) of EQ-5D. An improvement in the global score of AcroQoL was related to a global improvement in the VAS of the EQ-5D. Following the current recommended standard methodology the Spanish questionnaire was translated into eleven other languages.


The Rapid Assessment for Adolescent Preventive Services (RAAPS): providers' assessment of its usefulness in their clinical practice settings.
The purpose of this study was to evaluate health providers' use of the Rapid Assessment for Adolescent Preventive Services (RAAPS) screening tool to identify adolescent high-risk behaviors, its ease of use and efficiency, and its impact on provider/patient discussions of sensitive risk behaviors. This mixed methods descriptive study used an online survey to assess providers' use of the RAAPS and their perspectives on its implementation and effect on adolescent-provider communication. The survey was completed by providers from a variety of settings across the United States (N = 201). Quantitative and qualitative analyses indicated that the RAAPS facilitated identification of risk behaviors and risk discussions and provided efficient and consistent assessments; 86% of providers believed that the RAAPS positively influenced their practice. Adoption of the RAAPS in practice settings could lead to more effective adolescent preventive services by giving providers a tool to systematically assess and identify adolescents at risk. Implementation of RAAPS offers health providers an efficient, consistent, and "adolescent friendly" way to identify risky behaviors and open the discussion needed to tailor interventions to meet their needs.


Impact of Kidney Disease on Peripheral Arterial Interventions: A Systematic Review and Meta-Analysis.
There are limited data on outcomes of patients undergoing peripheral arterial disease (PAD) interventions who have comorbid CKD/ESRD versus those who do not have such comorbid condition. We performed a systematic review and meta-analysis to analyze outcomes in this patient population. Five databases were searched for studies comparing outcomes of lower extremity PAD interventions for claudication and critical limb ischemia (CLI) in patients with CKD/ESRD versus non-CKD/non-ESRD from January 2000 to June 2019. Our study included 16 observational studies with 44,138 patients. Mean follow-up was 48.9 ± 27.4 months. Major amputation was higher with CKD/ESRD compared with non-CKD/non-ESRD (odds ratio [OR 1.97] [95% confidence interval [CI] 1.39-2.80], p = 0.001). Higher major amputations with CKD/ESRD versus non-CKD/non-ESRD were only observed when indication for procedure was CLI (OR 2.27 [95% CI 1.53-3.36], p < 0.0001) but were similar for claudication (OR 1.15 [95% CI 0.53-2.49], p = 0.72). The risk of early mortality was high with CKD/ESRD patients undergoing PAD interventions compared with non-CKD/non-ESRD (OR 2.55 [95% CI 1.65-3.96], p < 0.0001), which when stratified based on indication, remained higher with CLI (OR 3.14 [95% CI 1.80-5.48], p < 0.0001) but was similar with claudication (OR 1.83 [95% CI 0.90-3.72], p = 0.1). Funnel plot of included studies showed moderate bias. Patients undergoing lower extremity PAD interventions for CLI who also have comorbid CKD/ESRD have an increased risk of experiencing major amputations and early mortality. Randomized trials to understand outcomes of PAD interventions in this at-risk population are essential.


Cibacron blue allosterically modulates the rat P2X4 receptor.
We have used whole-cell patch clamp electrophysiology to characterise the actions of the P2 antagonist, cibacron blue, on the rat recombinant P2X4 receptor, stably expressed in human embryonic kidney 293 (HEK293) cells. In single cells, adenosine triphosphate (ATP) evoked inward currents, but the response was subject to considerable run down which precluded obtaining quantitative data. However, when recordings were made from cells that were part of a group of 20-40 electrically coupled cells (cell rafts), run-down of current was not observed and reproducible responses could be obtained. When studied using cell rafts, cibacron blue was a weak antagonist of the rat P2X4 receptor (IC50 > 300 microM) when co-applied with ATP. However, when cell rafts were preincubated with low concentrations of cibacron blue (3-30 microM) for 5 min prior to ATP addition, cibacron blue increased responses to ATP by increasing its potency (up to 4-fold) without affecting the maximum current. Potentiation of ATP-evoked currents was also observed following washout of high, inhibitory concentrations of cibacron blue (300 microM). In contrast to these effects on P2X4 receptors, cibacron blue inhibited the ATP-induced response in both single cells and rafts of HEK293 cells expressing the P2X2 receptor (IC50 approximately 600-800 nM). The effects of cibacron blue on the P2X4 receptor were quantitatively similar to those of Zn2+ which also increased ATP-evoked currents by decreasing the EC50 of ATP (up to 3.5-fold). These data are consistent with the concept that cibacron blue, like zinc, allosterically regulates the function of the P2X4 receptor.


Convergent total syntheses of the Amaryllidaceae alkaloids lycoranine A, lycoranine B, and 2-methoxypratosine.
The title alkaloids, 1, 2, and 3 respectively, have been prepared in a convergent manner by two related routes. The superior one involves C-H functionalization of the relevant 5-methoxyindole at C-7 using Hartwig's protocol and thus forming the corresponding borolated indole that could be coupled with the requisite 2-bromobenzoate to deliver the title natural products. Single crystal X-ray analyses of the synthetically derived samples of compounds 1 and 2 are reported.


Notch signaling in skeletal stem cells.
The skeleton originates from stem cells residing in the sclerotome and neural crest that undergo proliferation, migration, and commitment. The development of the skeletal stem cells is influenced by many signaling pathways that govern cell fate determination, proliferation, differentiation, and apoptosis. This review will focus on Notch signaling functions in regulating the different cell types that form the skeletal system as well as the interplay between them to maintain homeostasis. Osteochondroprogenitors require Notch signaling to maintain multipotency and to prevent premature differentiation into osteoblasts. Subsequently, overactivation of Notch signaling suppresses osteoblast maturation. Moreover, Notch signaling in osteochondroprogenitors is required for chondrocyte proliferation and hypertrophy and suppresses terminal differentiation. Translational studies demonstrated a crucial role of Notch signaling in osteosarcoma and osteoarthritis, where concepts derived from developmental pathways are often recapitulated. This brings hope of taking advantage of the molecular mechanisms learned from development to approach the pathological processes underlying abnormal bone/cartilage metabolism or tumorigenesis. Pharmacological agents that target Notch receptors or ligands in a tissue-specific fashion would offer new opportunities for treating bone/cartilage diseases caused by dysregulation of Notch signaling.


Hb40-61a: Novel analogues help expanding the knowledge on chemistry, properties and candidacidal action of this bovine α-hemoglobin-derived peptide.
This study expands the knowledge on chemical synthesis and properties of Hb40-61a as well as provides results of the first steps given towards knowing how it kills Candida cells. For the first time, this peptide, its all-D analogue (D-Hb40-61a) and its fluorescently labeled analogue (FAM-Hb40-61a) were successfully assembled on resin at 60°C using conventional heating in all steps. Purified and characterized, these peptides exhibited very low toxicity on human erythrocytes. Hb40-61a and D-Hb40-61a were equally active against Candida strains, ruling out sterically specific interactions on their working mechanism. Cell permeabilization assays confirmed progressive damage of the yeast plasma membrane with increasing concentrations of Hb40-61a. While experiment using the fluorescent probe DiBAC4(5) revealed that this synthetic hemocidin alters the yeast plasma membrane potential, test employing DPH indicated that Hb40-61a might affect its dynamics. Exposure of the yeast cells to FAM-Hb40-61a showed that the peptide accumulates in the cell membrane at the ½ MIC, but stains about 97% of the cells at the MIC. Such effect is salt-dependent and partially energy-dependent. These new findings indicate that the central target of Hb40-61a in Candida cells is the plasma membrane and that this synthetic hemocidin should be considered as a potential candidacidal for topic uses.


Comparisons of lipid dynamics and packing in fully interdigitated monoarachidoylphosphatidylcholine and non-interdigitated dipalmitoylphosphatidylcholine bilayers: cross polarization/magic angle spinning 13C-NMR studies.
13C-NMR spectra have been obtained at 50.3 MHz for monoarachidoylphosphatidylcholine (MAPC) and dipalmitoylphosphatidylcholine (DPPC) dispersions from 25 degrees C to 55 degrees C and for DPPC polycrystals at 25 degrees C using the cross polarization/magic angle spinning technique. Differential scanning calorimetric studies on DPPC and MAPC dispersions show comparable lipid phase transitions with transition temperatures at 41 degrees C and 45 degrees C, respectively, and thus enable the comparison of thermal, structural and dynamic differences between these two systems at corresponding temperatures. Conformational-dependent 13C chemical shift studies on DPPC dispersions demonstrate not only the coexistence of the tilted gel (L beta') and liquid-crystalline (L alpha) phases in the rippled gel (P beta') phase, but also the presence of an intermediate third microscopic phase as evidenced by three resolvable peaks for omega - 1 methylene carbon signals at the temperature interval between Tp and Tm. By comparing chemical shifts of MAPC in the hydrocarbon chain region with those of DPPC at similar reduced temperatures, it can be concluded that the packings are perturbed markedly in the middle segment of the fatty acyl chain during the lamellar to micellar transition. However, terminal methylene and methyl groups of interdigitated MAPC lamellae were found to be more ordered than those of non-interdigitated DPPC bilayers in the gel state. Interestingly, the terminal methyl groups of MAPC in the micelles remain to be relatively ordered; in fact, they are more ordered than the corresponding acyl chain end of DPPC in the liquid-crystalline state. Analysis of data obtained from rotating frame proton spin-lattice relaxation measurements shows a highly mobile phosphocholine headgroup, a rigid carbonyl group and an ordered hydrocarbon chain for lamellar MAPC in the interdigitated state. Furthermore, results suggest that free rotations of the glycerol C2-C3 bond within MAPC molecules may occur in the interdigitated bilayer, whereas intramolecular exchange between two conformations of the glycerol backbone in DPPC become possible at temperatures close to the pretransition temperature. Without isotope enrichment, we conclude that high-resolution solid-state 13C-NMR is indeed a useful technique which can be employed to study the packing and dynamics of phospholipids.


Long-term oncological outcomes after oral cancer surgery using propofol-based total intravenous anesthesia versus sevoflurane-based inhalation anesthesia: A retrospective cohort study.
Previous studies have shown that the anesthetic technique may influence long-term outcomes after cancer surgery. However, the association between the anesthetic technique and long-term oncological outcomes after oral cancer surgery remains unclear. Therefore, we conducted this study to address this gap. We reviewed the electronic medical records of patients who underwent elective oral cancer surgery between January 2014 and December 2015. The patients were grouped based on the anesthesia maintenance: either propofol or sevoflurane. Propensity score matching in a 1:1 ratio was performed to deal with the potential confounding effects of baseline characteristics. Univariate and multivariate Cox regression analyses were performed to compare hazard ratios (HRs) and identify the risk factors for death and recurrence. Survival analysis was performed using the Kaplan-Meier method, and survival curves were constructed from the date of surgery to death. In total, 1347 patients were eligible for analysis, with 343 and 1004 patients in the propofol and sevoflurane groups, respectively. After propensity score matching, 302 patients remained in each group. Kaplan-Meier survival curves demonstrated the 5-year overall and recurrence-free survival rates of 59.3% and 56.0% and 62.7% and 56.5% in the propofol and sevoflurane groups, respectively. There was no significant difference in overall survival or recurrence-free survival between the groups. The multivariate Cox analysis verified this conclusion with HRs of 1.10 and 1.11 for overall survival and recurrence-free survival, respectively, in the sevoflurane group. Older age, advanced tumor-node-metastasis (TNM) stage, and American Society of Anesthesiologists class III were associated with poor overall survival. Patients with advanced TNM stage and poorly differentiated squamous cell carcinoma had a higher recurrence risk than their counterparts. The overall and recurrence-free survival rates were similar between propofol-based intravenous anesthesia and sevoflurane volatile anesthesia in patients who underwent oral cancer surgery.


Target molecular treatment markers in Intrahepatic Cholangiocarcinoma based on Chinese population.
As more and more molecular markers have been identified in Intrahepatic Cholangiocarcinoma (ICC), target treatments are promising all around the world. However, geographical and ethnic variations in the ICC epidemiology suggest different genetic variance prevalence in western and eastern countries. Six genetic variations in Chinese ICC populations were analyzed by fluorescent in situ hybridization (FISH) or Sanger sequencing, listed as IDH1/2 mutation, FGFR2 translocation, NTRK1 amplification, MDM2 amplification, HER2 amplification and MET amplification, all of which have corresponding target drugs; meanwhile, they were compared with these gene prevalence in Spanish population based on the cBioPortal database. The incidences of IDH1/2 mutation, FGFR2 translocation, NTRK1 amplification, MDM2 amplification, HER2 amplification and MET amplification were 29.5 %, 12.9 %, 1.51 %, 2.27 %, 3.03 % and 0.75 %, respectively, in the Spanish population and 7.14 %, 5.71 %, 7.86 %, 5.71 %,4.29 % and 2.14 %, respectively, in the Chinese population. For the gene NTRK1, 11 samples showed signal apart companied amplified using FISH break-apart probes but none of them demonstrated genetic fusion by next-generation sequencing. As to clinicopathological characteristics, patients carrying IDH1/2 mutation showed longer overall survival in the Chinese population, while those carrying FGFR2 translocation tended to be younger in the Spanish population. For HER2, MDM2 and MET, gene amplification predicted protein high-expression, whereas FGFR2 translocation and NTRK1 amplification did not predict protein high-expression. Although many target drugs have been speeded up for approval such as BGJ398 for FGFR2 fusion positive ICC patients in western countries, the beneficiary populations are very small in China. The regular target drug such as trastuzumab for HER2 amplification and Crizotinib for MET amplification may be potential candidates in target treatment based on the Chinese population.


Extending the window for thrombolysis for treatment of acute ischaemic stroke during pregnancy: a review.
Historically, safety of intravenous recombinant tissue plasminogen activator (IV rt-PA) for the treatment of acute ischaemic stroke (AIS) is limited to use within 4.5 hours from symptom onset. Recent studies suggest the treatment window may be extended when patients have salvageable brain tissue on advanced neuroimaging. This paper describes a novel use of IV rt-PA for treatment of AIS in a pregnant patient within an extended-time window (>4.5 hours, and <9 hours) based on advanced neuroimaging with a favourable outcome. TWEETABLE ABSTRACT: Novel use of IV rt-PA for treatment of AIS in pregnancy within an extended-time window based on advanced imaging with a favourable outcome.


Things left unsaid: important topics that are not discussed between patients with systemic sclerosis, their carers and their healthcare professionals-a discourse analysis.
Systemic sclerosis (SSc) is a rare condition that can be complicated by interstitial lung fibrosis (SSc-ILD)-a major cause of mortality. This study explored information and communication needs of patients with SSc-ILD and their carers to understand what they are and whether they are met. Qualitative research was performed, including in-depth individual interviews and observed conversations between pairs of patients, physicians and nurses, and between patients and physicians discussing experiences of SSc-ILD. The study was performed in Germany, Italy, Spain, the UK and the USA. Participants included 42 SSc-treating physicians, 21 patients with diagnosed SSc-ILD, 16 specialist nurses and five carers. Prognosis and mortality were the main unspoken topics acknowledged by patients, carers and healthcare professionals. Patients and carers felt afraid to ask physicians about mortality, and most physicians reported avoiding the question because their duty was to give patients hope and avoid causing additional distress. Patients often felt unable to ask physicians about relationships, family and work because of time constraints or because they felt these were not topics physicians would be concerned about. Often, specialist nurses felt that they had insufficient knowledge to provide adequate support. Key topics, including mortality and prognosis, are rarely openly discussed, leaving patients uncertain and anxious about the future. By communicating about difficult but important topics, physicians and nurses could help patients and carers manage and plan their lives. This study shows that a multi-professional team-based communication approach is likely to better address patient needs and priorities. • Key topics in SSc or SSc-ILD, such as mortality and prognosis, are rarely openly discussed in clinical consultations. • By communicating difficult but important topics, physicians and nurses could help patients manage their disease and plan their lives. • A multi-professional team-based communication approach is likely to better address patient needs and priorities and could be easily implemented without the need for significant additional resources.


Insights on the potential oncogenic impact of long non-coding RNA nicotinamide nucleotide transhydrogenase antisense RNA 1 in different cancer types; integrating pathway(s) and clinical outcome(s) association.
Long non-coding RNAs (lncRNAs) are becoming more prevalent in the cancer field arena, with functional roles in both oncogenic and onco-suppressive pathways. Despite their widespread aberrant expression in a range of human malignancies, the biological activities of the ncRNAs majority are unknown. All showed the involvement of the lncRNA nicotinamide nucleotide transhydrogenase antisense RNA 1 (NNT-AS1). Since NNT-AS1 influences cellular proliferation, invasion, migration, apoptosis, and metastasis, this lncRNA appears to be linked to deregulating the normal cellular processes driving malignancy. This was observed in breast cancer (BC), gastric cancer (GC), colorectal cancer (CRC), epithelial ovarian cancer (EOC), and hepatocellular carcinoma (HCC). The current narrative non-systematic review will discuss "the significance of lncRNAs in cancer", as well as "lncRNAs future potential application(s) as diagnostic or predictive biomarkers", therefore, comprising an opportunity as treatment target(s). The review will have a special emphasis on lncRNA NNT-AS1.


Foot and Ankle Injuries in Runners.
Foot and ankle injuries account for nearly one-third of running injuries. Achilles tendinopathy, plantar fasciopathy, and ankle sprains are 3 of the most common types of injuries sustained during training. Other common injuries include other tendinopathies of the foot and ankle, bone stress injuries, nerve conditions including neuromas, and joint disease including osteoarthritis. This review provides an evidence-based framework for the evaluation and optimal management of these conditions to ensure safe return to running participation and reduce risk for future injury.


Study of the mode of action of ribosomal vaccines from Klebsiella and Streptococcus pneumoniae and their ribonucleic and protein fractions using passive immunization.
The vaccinating potency of ribosomal fractions of Klebsiella pneumoniae and Streptococcus pneumoniae as well as their ribosomal RNA and protein fractions has been studied with respect to their ability to induce cellular or humoral immunity. Experiments with transfer of serum or spleen cells from vaccinated animals have shown that anti-Klebsiella immunity is essentially cellular, while streptococcal immunity is exclusively humoral. Results have been discussed as a function of differential results for the various fractions under study.


Mechanical effects of traction on lumbar intervertebral discs: A magnetic resonance imaging study.
Although traction has long been used for treating patients with low back pain (LBP), its effects are still inconclusive mainly because of limited high-quality evidence. To provide evidence of the mechanism of traction on lumbar intervertebral discs. A quantitative approach with a repeated measurement protocol. Nine participants (mean age = 22.1 ± 0.8 years) without any LBP history were recruited. Magnetic Resonance Images of the lumbar spine of each participant were recorded before and after 30 min of horizontal lying and directly after 30 min of horizontal traction of 42% body weight. The average, anterior, central, and posterior disc height and tilt angle of each lumbar disc and lumbar lordosis were measured. A significant increase in the average disc height for all lumbar discs, a significant reduction of lumbar lordosis and changes in tilt angle were observed after the application of 30 min of resting followed by 30 min of traction. A significant increase in the average disc height was observed only in lower lumbar discs after 30 min of traction. The increase in the posterior disc height was more apparent than that in the anterior disc height. Horizontal traction was evidently effective in increasing the disc height of lower lumbar levels, particularly in the posterior regions of the discs. Further evidence of the effects of traction of different modes, magnitudes, and durations on the change in disc height is required for proper control of traction applied to specific disc levels.


A distributed system for support and explanation of shared decision-making in the prenatal testing domain.
Medical domains involve numerous tests and treatments, the sheer variety of which confounds both care providers and patients. Many of the decisions depend on the patient's preferences. Shared decision-making, which explicitly involves the patients and their preferences, is therefore imperative, but requires also a sufficient explanatory infrastructure. We introduce a distributed application, PANDEX, that, by using decision-analytic methods, assists patients and care providers to reach optimal decisions. Based on a generic architecture, the PANDEX prototype, which focuses on the domain of genetic prenatal consultation, is designed to calculate the optimal treatment strategy based on the patient's clinical data and preferences. A major focus of our study was on developing several types of in-depth sensitivity and importance analysis methods and on the implementation of the respective graphical tools embedded in the system, to help the patient fully understand the recommended strategy. A preliminary assessment of PANDEX by six genetic consultants demonstrated a relative unwillingness to work with PANDEX (mean=2.16+/-0.98 (SD), on a scale of 1-5), but a tendency to agree with its recommended strategies (mean=3.48+/-1.4) and with its capability to provide insights into the recommended strategies (3.28+/-1.23). PANDEX was considered by the consultants to be a potentially useful tool for patients.


Anatomical and electrophysiological analysis of the trigeminal nerve in a teleost fish, Oncorhynchus mykiss.
The trigeminal nerve in the rainbow trout, Oncorhynchus mykiss, was examined for the presence of A-delta and C fibres. Sections of the three branches of the trigeminal nerve were found to comprise a range of fibre types including A-delta and C fibres. The size range of the cell bodies of the trigeminal ganglion reflected the fibre range since they correlated with the size range of axons in the nerve branches. Electrophysiological recordings of evoked activity from the ganglion confirmed the presence of these fibre types and the proportion of these mirrored the proportion of fibre types in the anatomical analyses. A-beta fibres were most common followed by A-delta fibres, then A-alpha fibres with C fibres being the fewest fibre type found. In higher vertebrates, A-delta and C fibres in the trigeminal nerve convey both somatosensory and nociceptive information to the brain. The evolutionary significance of these results is discussed as well as the potential for nociceptive capability in a lower vertebrate.


Accelerated degradation of low-density polyethylene in air and in sea water.
Accelerated weathering of LDPE laminates, with samples exposed to ultraviolet radiation (UVR) in air and while floating in seawater at the same temperature, was investigated in this study. The depth profiles of the concentrations of oxidation products in the two sets of samples was assessed by FTIR (Fourier Transform Infrared Spectroscopy) and suggest the oxidation on weathering to be diffusion-controlled in both air and in seawater, localizing the reaction to a thin surface layer. While the thickness of this layer is several hundred microns in air-weathered samples it is too small to be discernible by FTIR spectroscopy in sea water-weathered samples. A naturally weathered polyethylene microplastic pellet from floating ocean debris was also similarly studied by FTIR and the depth profile compared with that from accelerated weathering of LDPE laminates. Tensile properties of the LDPE weathered in air and in sea water were also compared to better understand the impact of diffusion-controlled oxidation on their mechanical integrity. How the origin of apparent retardation of the rate of weathering degradation of LDPE in seawater relative to that in air, is related diffusion-controlled oxidation due to the low concentrations of dissolved oxygen in seawater, is also discussed.


Prevention of childhood drowning accidents.
The data from the Brisban Drowning Study have been analysed in this article to provide guidelines for preventive strategies. The separate causal links comprising the drowning chain have been identified, and quantitative scores have been assigned to the three identifiable groups of causative factors--environmental, parent-related and victim-related. The identifiable causes of child drowning are absence of a safety barrier or fence around the water hazard, non-supervision of a child, a parental "vulnerable period", an inadequate safety barrier, and tempting objects in or on the water. Effective environmental control can be achieved only through legislation. The complementary role of a public educational thrust in discussed. Increasing the tempo of "drownproofing* and of teaching children to swim will help, but the expected reduction in deaths and near-deaths from this strategy alone cannot yet be assessed. Compulsory first aid training for pool owners is required. Costs of implementing a total drowning preventive programme are presented.


Accommodation of hydroxyl groups and their hydrogen bond system in a hydrocarbon matrix.
From data of a single crystal analysis of 12-D-hydroxyoctadecanoic acid methyl ester principles for the incorporation of hydroxyl groups into a hydrocarbon chain matrix can be deduced. In the crystalline compound infinite hydrogen bond systems are accommodated in an orthorhombic perpendicular chain arrangement. The orthorhombic perpendicular hydrocarbon subcell is expanded towards a hexagonal packing pattern, allowing more space and optimal geometry for the hydrogen bond system. The arrangement of the bond system in the orthorhombic perpendicular subcell requires that hydrogen bonded carbon chains carry alternatingly hydroxyl groups with opposite configuration. For the enantiomeric compound this requirement is met by a head to tail packing of molecules in a single layer arrangement. The corresponding racemates on the other hand pack head to head in double layers as confirmed by X-ray powder and IR studies. In monolayers both enantiomers and racemates behave identically. The hydrogen bonding of the hydroxyl groups apparently leads to the formation of lipid clusters, in which the geometric conditions for both a close packing of hydrocarbon chains and the formation of an extensive hydrogen bond system do not exist.


Microgeographic variation in body size and development time in the waterstrider, Limnoporus notabilis.
Body size and development time were compared among four population of Limnoporus notabilis (Heteroptera: Gerridae), in the southwestern corner of mainland British Columbia, Canada. Comparisons based on both field-caught and lab-reared animals indicated significant, heritable variability in body size among these four populations. Although body size and development time tended to be positively correlated, the variability in development time among populations was significant only for females. Comparisons of food availability at two of the study sites indicated that the observed patterns of variability in body size and development time could not be the result of genetic or phenotypic adaptations to food supply. These patterns also do not appear to reflect direct adaptation to season length. Both body size and development time were, however, positively associated with environmental heterogeneity, as indicated by habitat stability and continuity. In seasonal habitats, this positive association is complicated by selection for rapid development, leading to populations of large L. notabilis with relatively short development times. The hypothesis is thus advanced that microgeographic variability in body size and development time in L. notabilis reflects the interplay between selective adaptation to environmental heterogeneity, as proposed by Roff (1977, 1978) and dingle et al. (1980), and selection for rapid development in seasonal habitats.


A review of medicinal plants showing anticonvulsant activity.
The term epilepsy is collectively designated for a group of chronic central nervous system disorders characterized by spontaneous occurrence of seizures generally associated with the loss of consciousness and body movements (convulsions). The disease has its origin from an early age. Anticonvulsant drugs are used to control the convulsions by inhibiting the discharge and then producing hypnosis. Various synthetic drugs, viz. sodium diphenyl hydantoin (Dialtin) barbiturates, pyrimidon, succinamides, diazepines etc. are used for the treatment. In this paper various medicinal plants and plant components, which are being used as anticonvulsant and antiepileptic, are discussed.


Intraplacental choriocarcinoma in a term pregnancy: Is serial postpartum hCG assessment necessary?
Intraplacental choriocarcinoma (IC), or choriocarcinoma in situ, is a rare disease on the gestational trophoblastic disease (GTD) spectrum, with <100 case reports available in the literature. We propose that many patients with IC are likely to be missed as the majority of patients do not present with metastases. Currently, there are no standardized protocols in existence for postpartum monitoring of these patients. We present a case of IC identified in the term placenta of a 21-year-old who delivered by primary cesarean due to concern for fetal intolerance of labor. Subsequently, we review the recommendations available on postpartum monitoring of this likely under-diagnosed condition.


Cognitive Efficacy (SIB) of 13.3 Versus 4.6 mg/24 h Rivastigmine Patch in Severe Alzheimer's Disease.
Severe Impairment Battery (SIB) data from the 24-week, randomized, double-blind ACTivities of daily living and cognitION (ACTION) study suggest that patients with severe Alzheimer's disease (AD) benefit from treatment with 13.3 versus 4.6 mg/24 h rivastigmine patch. The objective of this retrospective analysis was to further examine the cognitive efficacy of 13.3 versus 4.6 mg/24 h rivastigmine patch on individual SIB items, and SIB domains derived using factor analysis of these items. Change from baseline at Week 24 on 9 new factor-defined domains and individual items was calculated and compared using effect sizes (Cohen's d). Numerically less decline was observed with 13.3 versus 4.6 mg/24 h patch on all domains and the majority of individual items. Largest least squares mean treatment differences were observed on "visuospatial reasoning," "object naming," "recognition," "design copying," "social agency," "ideational praxis," and "comprehension" domains. These findings suggest 13.3 mg/24 h rivastigmine patch demonstrates broad cognitive efficacy across a range of SIB items and domains in patients with severe AD.


[Adult congenital heart disease: Medical and psychosocial issues].
The population of adults with congenital heart disease (ACHD) is continuously increasing with now a higher prevalence than that of the pediatric population. This concerns above all complex congenital heart diseases. Heart failure is the primary cause of death followed by arrhythmia, which is very common in ACHD. A specialized follow-up by dedicated centers is significantly associated with an improvement of survival of ACHD patients compared to non-expert follow-up. Extracardiac disorders (liver, kidney, respiratory) are frequent and require an accurate and specific management. The psychosocial impact, particularly the professional difficulties, is common and may require implementation of appropriate measures to improve the patient social life. Unplanned pregnancy and/or a lack of information about contraception may induce severe cardiovascular complications in ACHD women. Education about contraceptive methods at adolescence and pre-conceptional counseling are requested in this population.


GEE for multinomial responses using a local odds ratios parameterization.
In this article, we propose a generalized estimating equations (GEE) approach for correlated ordinal or nominal multinomial responses using a local odds ratios parameterization. Our motivation lies upon observing that: (i) modeling the dependence between correlated multinomial responses via the local odds ratios is meaningful both for ordinal and nominal response scales and (ii) ordinary GEE methods might not ensure the joint existence of the estimates of the marginal regression parameters and of the dependence structure. To avoid (ii), we treat the so-called "working" association vector α as a "nuisance" parameter vector that defines the local odds ratios structure at the marginalized contingency tables after tabulating the responses without a covariate adjustment at each time pair. To estimate α and simultaneously approximate adequately possible underlying dependence structures, we employ the family of association models proposed by Goodman. In simulations, the parameter estimators with the proposed GEE method for a marginal cumulative probit model appear to be less biased and more efficient than those with the independence "working" model, especially for studies having time-varying covariates and strong correlation.


Complement-dependent outer membrane perturbation sensitizes Gram-negative bacteria to Gram-positive specific antibiotics.
Gram-negative bacteria are refractory to the action of many antibiotics due to their impermeable outer membrane. An important player of the immune system is the complement system, a protein network in serum that directly kills Gram-negative bacteria through pore-formation by the Membrane Attack Complexes (MAC). We here show that the MAC rapidly perforates the outer membrane but that inner membrane damage, which is essential for killing, is relatively slow. Importantly, we demonstrate that MAC-induced outer membrane damage sensitizes Gram-negative bacteria to otherwise ineffective, Gram-positive-specific, antimicrobials. Synergy between serum and nisin was observed for 22 out of 53 tested Gram-negative clinical isolates and for multi-drug resistant (MDR) blood isolates. The in vivo relevance of this process is further highlighted by the fact that blood sensitizes a MDR K. pneumoniae strain to vancomycin. Altogether, these data imply that antibiotics that are considered ineffective to treat infections with Gram-negatives may have different functional outcomes in patients, due to the presence of the complement system.


Multiple structural and functional abnormalities in the p450 aromatase expressing transgenic male mice are ameliorated by a p450 aromatase inhibitor.
The present study was undertaken to analyze the effect of a P450 aromatase inhibitor (finrozole) on 4-month-old transgenic mice expressing human P450 aromatase (P450arom) under the human ubiquitin C promoter (AROM+). AROM+ mice present several dysfunctions, such as adrenal and pituitary hyperplasia, cryptorchidism, Leydig cell hypertrophy and hyperplasia, and gynecomastia. The present study demonstrates that these abnormalities were efficiently treated by administration of a P450arom inhibitor, finrozole. The treatment normalized the reduced intratesticular and serum testosterone levels, while those of estradiol were decreased. The body weight and several affected organ weights were normalized with the treatment. Histological analysis revealed that both the pituitary and adrenal hyperplasia were diminished. Furthermore, the cryptorchid testes present in the untreated AROM+ males descended to scrotum, 4 to 15 days after inhibitor treatment. In addition, the disrupted spermatogenesis was recovered and qualitatively complete spermatogenesis appeared with the inhibitor treatment. This was associated with normalized structure of the interstitial tissue, as analyzed by immunohistochemical staining for Leydig cells and macrophages. One of the features was that the Leydig cell hypertrophy was markedly diminished in the treated mice. AROM+ mice also present with severe gynecomastia, while the development and differentiation of the mammary gland in AROM+ males was markedly diminished with the inhibitor treatment. Interestingly, the mammary gland involution was associated with the induction of androgen receptor in the epithelial cells, while estrogen receptors were still detectable in the epithelium. The data show that AROM+ mouse model is a novel tool to further analyze the use of P450arom inhibitors in the treatment of the dysfunctions in males associated with misbalanced estrogen to androgen ratio, such as pituitary adenoma, testicular dysfunction, and gynecomastia.


Midwifery interventions to reduce fear of childbirth in pregnant women: a scoping review protocol.
The objective of the review is to map and analyze midwifery interventions to reduce fear of childbirth in pregnant women. Fear of childbirth is a phenomenon negatively affecting women's health and well-being before and during pregnancy, as well as after childbirth. During the previous few decades, there has been a growing interest in research into interventions to reduce the fear of childbirth in childbearing women. Currently, providing an appropriate model of care for pregnant women with fear of childbirth is a challenge in midwifery care. Therefore, further efforts are needed to identify and examine the characteristics of different midwifery interventions to reduce fear of childbirth in pregnant women. This scoping review will consider studies that include interventions to reduce fear of childbirth in pregnant women, led and implemented by midwives, during the antenatal period, in all possible birth scenarios. Quantitative, qualitative, and mixed methods studies will be included. The JBI methodology for conducting scoping reviews will be employed. Published and unpublished literature in English, Portuguese, and Spanish, from 1981 to the present, will be included. MEDLINE, CINAHL Complete, Scopus, Web of Science, Embase, and Cochrane Library databases will be searched. Searches for gray literature will be performed. Data will be extracted using a tool developed specifically for the scoping review objectives.


Evaluating survey quality in health services research: a decision framework for assessing nonresponse bias.
To address the issue of nonresponse as problematic and offer appropriate strategies for assessing nonresponse bias. A review of current strategies used to assess the quality of survey data and the challenges associated with these strategies is provided along with appropriate post-data collection techniques that researchers should consider. Response rates are an incomplete assessment of survey data quality, and quick reactions to response rate should be avoided. Based on a five-question decision making framework, we offer potential ways to assess nonresponse bias, along with a description of the advantages and disadvantages to each. It is important that the quality of survey data be considered to assess the relative contribution to the literature of a given study. Authors and funding agencies should consider the potential effects of nonresponse bias both before and after survey administration and report the results of assessments of nonresponse bias in addition to response rates.


Hypospadias repair. Preoperative preparation, intraoperative techniques, postoperative care.
The location of the defect and the need for surgery causes these children and their parents more emotional concern than the actual defect. Voiding usually prevents no problem, especially because they are still in diapers. Children this age are not affected by an altered body image, but their parents' are concerned about their children having an acceptable physical appearance and adequate future sexual competency. These fears can be transmitted to the children. It is important to communicate with the parents and the children about realistic expectations of the surgery--this will help avert problems later problems. The overall success rate to correct hypospadias is approximately 85%. The goals of hypospadias repair are restoration of normal urination, relief of chordee, assurance of a sexually adequate penis, and placement of the urethral meatus at the tip of the glans penis. A successful surgery will enable the child to void in the standing position by voluntarily directing the stream in the usual manner.


Downregulation of sodium transporters and NHERF proteins in IBD patients and mouse colitis models: potential contributors to IBD-associated diarrhea.
One of the most common symptoms among patients with inflammatory bowel disease (IBD) is diarrhea, which is thought to be contributed by changes in electrolyte transport associated with intestinal inflammation. This study was designed to test the hypothesis that intestinal Na(+)-related transporters/channels and their regulatory proteins may be downregulated as a potential contributor to IBD-associated diarrhea. SDS-PAGE and Western blotting and/or confocal immunomicroscopy were used to examine the expression of Na(+)/H(+)-exchangers 1-3 (NHE1-3), epithelial Na(+) channel (ENaC), Na(+)/K(+)-ATPase, the intracellular Cl(-) channel 5 (ClC-5), and NHE3 regulatory factors (NHERF1,2) in ileal and colonic pinch biopsies from IBD patients and noninflammatory controls, as well as from colonic mucosa of dextran sodium sulfate (DSS)- and TNBS-induced acute murine IBD models. NHE1,3 (but not NHE2), beta-ENaC, Na(+)/K(+)-ATPase-alpha, ClC-5, and NHERF1 were all downregulated in sigmoid mucosal biopsies from most cases of active UC and/or CD compared to controls. NHE3 was also decreased in ileal mucosal biopsies of active CD, as well as in approximately 50% of sigmoid biopsies from inactive UC or CD. Importantly, similar downregulation of NHE1,3, beta-ENaC, and NHERF1,2 was also observed in the mouse colon (but not ileum) of DSS- and TNBS-induced colitis. IBD-associated diarrhea may be due to a coordinated downregulation of multiple Na(+) transporter and related regulatory proteins, including NHE1,3, Na(+)/K(+)-ATPase, and ENaC, as well as NHERF1,2, and ClC-5, all of which are involved directly or indirectly in intestinal Na(+) absorption.


The hypodense meningioma: report of two cases.
Cystic or necrotic hypodense areas are occasionally seen within meningiomas on CT scans. Two diffusely hypodense endotheliomatous meningiomas are reported. The low density was due to a microcystic structure, which caused a spongy appearance and consistency.


Identification of metabolites of honokiol in rat urine using 13C stable isotope labeling and liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry.
A general approach based on stable isotope labeling and UPLC/Q-TOF-MS analysis of in vivo novel metabolites of honokiol has been developed in our study. In this method, urine samples were collected after intravenous administration of mixture of regular and [(13)C6]-labeled honokiol at 1:1 ratio to healthy rats. The metabolites could be easily recognized by the determination of a chromatographically co-eluted pair of isotopomers (MS doublet peaks) with similar peak intensities and mass difference corresponding to that between isotope-labeled and non-isotope-labeled honokiol. A total of 51 metabolites were detected, 37 of which were tentatively identified based on mass accuracy (<5 ppm). Among them, 33 of honokiol metabolites were first reported with 5 metabolites belonging to phase I and other 32 metabolites belonging to phase II metabolites. Our results highlighted that the main phase I metabolic pathways of honokiol in rats were oxidation, and the phase II metabolic pathways were sulfation, glucuronidation, acetylation as well as amino acids conjugation. This was the first research focused on the biotransformation of honokiol in rats, and the identification of these metabolites might provide us essential information for further pharmacological and clinical studies of honokiol.


Intensity of pain due to separators in adolescent orthodontic patients.
To investigate the intensity of pain adolescent orthodontic patients experience following the insertion of separators. Elastomeric separators were placed mesially and distally to the first molars in 62 adolescents (20 male, 42 female, age 12-15 years), and the participants were given self-administrated questionnaires to document perceived pain, pain upon chewing, and the severity of pain's affecting daily life, using a visual analog scale for seven days. The mean perceived pain scores out of 100 on the first 3 days were 54.6 ± 32.7, 51.7 ± 29.9, and 32.3 ± 28.4, respectively; chewing pain scores were: 61.9 ± 35.3, 52.6 ± 30.4, and 39.5 ± 32.1, respectively; the pain's affecting daily life scores were 24.9 ± 35.5, 21.1 ± 30.9, and 11.9 ± 23.7, respectively. A Kruskal-Wallis test showed a statistically significant difference in the reported pain between the three studied parameters. A Mann-Whitney U-test showed an insignificant difference between male and female adolescents. Pain perception varies among adolescent patients, but it decreases significantly after the first 2 days, with no gender differences.


The Myth of "Metavalency" in Phase-Change Materials.
Phase-change memory materials (PCMs) have unusual properties and important applications, and recent efforts to find improved materials have focused on their bonding mechanisms. "Metavalent bonding" or "metavalency," intermediate between "metallic" and "covalent" bonding and comprising single-electron bonds, has been proposed as a fundamentally new mechanism that is relevant both here and for halide perovskite materials. However, it is shown that PCMs, which violate the octet rule, have two types of covalent bond: two-center, two-electron (2c-2e) bonds, and electron-rich, multicenter bonds (3c-4e bonds, hyperbonds) involving lone-pair electrons. The latter have bond orders less than one and are examples of the century-old concept of "partial" bonds.


Coaching the Fundamentals: Exploring the Applicability and Usefulness of a Novel Skills-Based Feedback Modality.
Receiving and integrating feedback is a key to medical trainee development. To assist trainees seeking improvement through daily formative feedback and deliberate practice, the authors created a new skills-based framework called microskills, derived from the Accreditation Council for Graduate Medical Education (ACMGE) milestones and entrustable professional activities. The authors then explored pediatric resident perceptions around the applicability and usefulness of microskills. The authors conducted 4 qualitative semistructured focus groups of 28 pediatric residents. Focus group prompts asked participants to reflect on microskills as a new feedback modality and microskills in relation to existing feedback and assessment approaches. Focus group transcripts were analyzed through inductive thematic analysis through an iterative process until theoretical saturation was reached. Participants felt microskills could facilitate skill-building and improvement, allow for consistent, targeted feedback, and establish a practice of coaching. Participants also perceived microskills' future success to be dependent on how the modality is adopted and utilized alongside existing assessment tools. Trainees found microskills to be a granular, context-based, coaching tool that could improve skill-building and the feedback process. Microskills' emphasis on feedback and their delineation of clinical skills that can be repeatedly practiced has the potential to provide a roadmap for trainee growth. Though microskills could fill a current need in the medical training landscape, they are not a substitute for existing assessment frameworks.


Efficacy and Safety of Analog Insulin in Comparison With Human Insulin for Hyperglycemia in Hospitalized Patients With Acute Stroke: A Randomized, Open-Label, Single-Center Trial.
To assess the efficacy and safety of analog insulins in comparison with human insulins for hyperglycemia in hospitalized patients with acute stroke. In this single-center, open-label, randomized trial, 102 patients (age 59.4 ± 11.7 years, 54 women) admitted with acute stroke (52 ischemic, 50 hemorrhagic) and hyperglycemia were assigned to analog insulin (n = 52) or human insulin (n = 50) group during February to June 2021. Insulin was initiated and titrated according to the predefined standard protocol. The capillary blood glucose (BG) level was monitored by standardized glucometers. The primary outcomes were mean daily BG and the number of hypoglycemic events. Between the 2 treatment groups, there was no significant difference in the mean daily BG (P >.05 for all days) or in the frequency of hypoglycemic episodes (P =.727). Four participants experienced severe hypoglycemia; all were receiving human insulin (P =.054). In the analog insulin group, there was a tendency toward lower daily total requirement for insulin (P =.053). The difference in bolus insulin dose was significantly lower in the analog insulin group (P =.029), but the difference in basal insulin dose was similar (P =.167). Between the 2 groups, there were no significant differences in the hospital mortality rate, modified Rankin Scale score on outcome, or length of hospital stay (P =.729,.658, and.918, respectively). Hospitalized patients acute stroke and hyperglycemia exhibited similar mean BG but a trend of lower incidence of severe hypoglycemia when treated with analog insulins in comparison with human insulin.


Willingness to pay, familiarity and political attitudes: The case of integrating people with intellectual disabilities.
Integrating people with intellectual disabilities into the community has become a major goal in improving society in general. Our study adds an important layer to discussions of how to achieve this goal. We examine both the willingness to integrate people into the community and their willingness to pay for this integration. Using a representative sample of 813 Israeli respondents, we consider two factors in these attitudes: familiarity with the issue and people's political attitudes. We found that most people are willing to integrate people with intellectual disabilities into the community and some people are willing to pay for this integration. Those who are familiar with people with intellectual disabilities and those from the left side of the political map are more willing to pay to achieve this goal. Familiarity and political attitudes matter in the willingness to pay to integrate people with intellectual disabilities into the community.


[Surgical treatment of lip precanceroses and neoplasms].
The "plastic" aspect of surgery in precancer and cancer of the lips, and, where feasible, its advantage over radiotherapy are described. The techniques of vermillectomy, Abbé flaps and Estlander flaps are discussed.


A catalog of stability-associated sequence elements in 3' UTRs of yeast mRNAs.
In recent years, intensive computational efforts have been directed towards the discovery of promoter motifs that correlate with mRNA expression profiles. Nevertheless, it is still not always possible to predict steady-state mRNA expression levels based on promoter signals alone, suggesting that other factors may be involved. Other genic regions, in particular 3' UTRs, which are known to exert regulatory effects especially through controlling RNA stability and localization, were less comprehensively investigated, and deciphering regulatory motifs within them is thus crucial. By analyzing 3' UTR sequences and mRNA decay profiles of Saccharomyces cerevisiae genes, we derived a catalog of 53 sequence motifs that may be implicated in stabilization or destabilization of mRNAs. Some of the motifs correspond to known RNA-binding protein sites, and one of them may act in destabilization of ribosome biogenesis genes during stress response. In addition, we present for the first time a catalog of 23 motifs associated with subcellular localization. A significant proportion of the 3' UTR motifs is highly conserved in orthologous yeast genes, and some of the motifs are strikingly similar to recently published mammalian 3' UTR motifs. We classified all genes into those regulated only at transcription initiation level, only at degradation level, and those regulated by a combination of both. Interestingly, different biological functionalities and expression patterns correspond to such classification. The present motif catalogs are a first step towards the understanding of the regulation of mRNA degradation and subcellular localization, two important processes which--together with transcription regulation--determine the cell transcriptome.


A fingerprint of plasma proteome alteration after local tissue damage induced by Bothrops leucurus snake venom in mice.
Bothrops spp. is responsible for about 70% of snakebites in Brazil, causing a diverse and complex pathophysiological condition. Bothrops leucurus is the main species of medical relevance found in the Atlantic coast in the Brazilian Northeast region. The pathophysiological effects involved B. leucurus snakebite as well as the organism's reaction in response to this envenoming, it has not been explored yet. Thus, edema was induced in mice paw using 1.2, 2.5, and 5.0 μg of B. leucurus venom, the percentage of edema was measured 30 min after injection and the blood plasma was collected and analyzed by shotgun proteomic strategy. We identified 80 common plasma proteins with differential abundance among the experimental groups and we can understand the early aspects of this snake envenomation, regardless of the suggestive severity of an ophidian accident. The results showed B. leucurus venom triggers a thromboinflammation scenario where family's proteins of the Serpins, Apolipoproteins, Complement factors and Component subunits, Cathepsins, Kinases, Oxidoreductases, Proteases inhibitors, Proteases, Collagens, Growth factors are related to inflammation, complement and coagulation systems, modulators platelets and neutrophils, lipid and retinoid metabolism, oxidative stress and tissue repair. Our findings set precedents for future studies in the area of early diagnosis and/or treatment of snakebites. SIGNIFICANCE: The physiopathological effects that the snake venoms can cause have been investigated through classical and reductionist tools, which allowed, so far, the identification of action mechanisms of individual components associated with specific tissue damage. The currently incomplete limitations of this knowledge must be expanded through new approaches, such as proteomics, which may represent a big leap in understanding the venom-modulated pathological process. The exploration of the complete protein set that suffer modifications by the simultaneous action of multiple toxins, provides a map of the establishment of physiopathological phenotypes, which favors the identification of multiple toxin targets, that may or may not act in synergy, as well as favoring the discovery of biomarkers and therapeutic targets for manifestations that are not neutralized by the antivenom.


Coagulase-negative staphylococcal endophthalmitis: clinical severity and outcomes based on speciation.
To identify characteristics and visual outcomes of coagulase-negative staphylococcal (CoNS) endophthalmitis in the era after the Endophthalmitis Vitrectomy Study. Single-centre retrospective analysis. Forty-two samples from 40 patients with documented CoNS endophthalmitis. Visual acuity outcomes of CoNS endophthalmitis were assessed in relation to species and type of treatment instituted (i.e., pars plana vitrectomy [PPV] versus vitreous tap and injection of intravitreal antibiotics [T&I]) on 42 samples from 40 patients. Staphylococcus epidermidis was the most prevalent CoNS in our study. Cataract surgery and intravitreal injections were the most common sources for acute CoNS endophthalmitis. Eyes presenting with hand motion or better vision had similar mean final vision after either intravitreal antibiotics or PPV, whereas those with light perception or worse vision at onset had better outcomes after PPV only. Subanalysis showed that patients with S. epidermidis endophthalmitis (n = 39 eyes) had similar visual outcomes with either intravitreal injections or PPV regardless of visual acuity. Hypopyon and vitritis are not always present. Patients with S. epidermidis endophthalmitis may benefit similarly from either early vitrectomy or intravitreal antibiotic injections regardless of visual acuity. This finding may be a supplement to the complements the management standards set forth by the Endophthalmitis Vitrectomy Study.


Hyperleptinemia as a contributing factor for the impairment of glucose intolerance in obesity.
Obesity has emerged as a major risk factor for insulin resistance leading to the development of type 2 diabetes (T2D). The condition is characterized by high circulating levels of the adipose-derived hormone leptin and a state of chronic low-grade inflammation. Pro-inflammatory signaling in the hypothalamus is associated with a decrease of central leptin- and insulin action leading to impaired systemic glucose tolerance. Intriguingly, leptin not only regulates body weight and glucose homeostasis but also acts as a pro-inflammatory cytokine. Here we demonstrate that increasing leptin levels (62,5 µg/kg/d, PEGylated leptin) in mice fed a high-fat diet (HFD) exacerbated body weight gain and aggravated hypothalamic micro- as well as astrogliosis. In contrast, administration of a predetermined dose of a long-acting leptin antagonist (100 µg/kg/d, PESLAN) chosen to block excessive leptin signaling during diet-induced obesity (DIO) showed the opposite effect and significantly improved glucose tolerance as well as decreased the total number of microglia and astrocytes in the hypothalamus of mice fed HFD. These results suggest that high levels of leptin, such as in obesity, worsen HFD-induced micro-and astrogliosis, whereas the partial reduction of hyperleptinemia in DIO mice may have beneficial metabolic effects and improves hypothalamic gliosis.