ApoM-bound S1P decreased PV1 but increased occludin and β-catenin expression in LPS-treated RIMECs. Berberine in a dose-dependent manner raised hepatic ApoM mRNA and plasma ApoM level, but decreased septic hyperglycemia, insulin resistance and plasma TNF-α and IL-1β levels. Berberine reduced sepsis-induced PEPCK and TLR4 mRNA overexpression in the liver.

This study demonstrated berberine inhibited TLR4-mediated hyperglycemia, insulin resistance and proinflammatory molecule production, thereby increasing ApoM gene expression and plasma ApoM. Berberine protected the damaged GVB via modulation of ApoM/S1P pathway.

This study demonstrated berberine inhibited TLR4-mediated hyperglycemia, insulin resistance and proinflammatory molecule production, thereby increasing ApoM gene expression and plasma ApoM. Berberine protected the damaged GVB via modulation of ApoM/S1P pathway.

UDP-N-acetylmuramic-alanine ligase (MurC) is an enzyme catalyzing the addition of L-alanine to UDP-acetylmuramoyl nucleotide precursor in Mycobacterium tuberculosis (M. tuberculosis). This enzyme is a prerequisite for the biosynthesis of the peptidoglycans in M. tuberculosis.

This study aimed to identify the novel inhibitors of MurC using in silico approach.

The three dimensional (3D) structure of MurC was determined using comparative modeling and based on the template obtained from Haemophilus influenza (1P31). The structural analysis of the model structure shown that three residues (Lys126, Glu170, and Glu358) are critical for in the catalytic activity of the enzyme, and their inhibition will block the function of the enzyme. Ten thousand and ninety-five (10095) compounds obtained through virtual screening against Zinc and PubChem databases based on their ability to bind to MurC with minimum binding energies. These ligands screened for the physicochemical properties, molecular docking, and pharmacokinetic analyses.

Six compounds had desirable physicochemical and pharmacokinetic properties with excellent binding energy ranged between -12.27 and -10.09kcal/mol. These compounds subjected to Molecular Dynamic (MD) Simulation and Molecular Mechanics Generalized Born Surface Area (MM-GBSA) analyses. The outcome of the analysis revealed that four ligands (PubChem1548994, ZINC11882115, ZINC22241774, and ZINC12330603) formed a stable conformation in the substrate-binding site of the protein during the 50ns MD simulation.

Therefore, the ligands mentioned above might regard as novel inhibitors of M. tuberculosis which requires further in vitro and in vivo validation.

Therefore, the ligands mentioned above might regard as novel inhibitors of M. tuberculosis which requires further in vitro and in vivo validation.

RacGTPase-mediated proliferation and smooth muscle contraction in the lower urinary tract has been recently suggested and may offer putative targets for treamtment of lower urinary tract symptoms. However, RacGTPase function for proliferation of detrusor smooth muscle cells is unknown and the specificity of Rac inhibitors has been questioned. Here, we examined effects of Rac1 knockdown and of the Rac inhibitors NSC23766 and EHT1864 in human bladder smooth muscle cells (hBSMCs).

Rac1 expression was silenced by shRNA expression. Effects of silencing and Rac inhibitors were assessed by CCK-8 assay, EdU staining, RT-PCR, colony formation assay, flow cytometry, and phalloidin staining.

Silencing of Rac1 expression reduced the viability (up to 83% compared to scramble shRNA) and proliferation (virtually completely in proliferation assay), increased apoptosis (124%) and the number of dead cells (51%), and caused breakdown of actin organization (56% reduction of polymerized actin compared to scramble shRNA). Effects on proliferation, viability, and actin organization were mimicked by NSC23766 and EHT1864, while both compounds showed divergent effects on cell death (32-fold increase of dead cells by EHT1864, but not NSC23766). Effects of NSC23766 and EHT1864 on viability of hBSMCs were not altered by Rac1 knockdown.

Rac1 promotes proliferation, viability, and cytoskeletal organization, and suppresses apoptosis in bladder smooth muscle cells, which may be relevant in overactive bladder or diabetes-related bladder dysfunction. NSC23766 and EHT1864 mimick these effects, but may act Rac1-independently, by shared and divergent effects.

Rac1 promotes proliferation, viability, and cytoskeletal organization, and suppresses apoptosis in bladder smooth muscle cells, which may be relevant in overactive bladder or diabetes-related bladder dysfunction. NSC23766 and EHT1864 mimick these effects, but may act Rac1-independently, by shared and divergent effects.

Niclosamide (NIC) is an anthelmintic agent repurposed as a potent anticancer agent. However, its use is hindered by its poor solubility. We investigated the underlying mechanisms of NIC anticancer activity employing a novel oral NIC pluronic-based nanoformulation and tested its effect in thioacetamide-induced hepatocellular carcinoma (HCC) in rats. We evaluated its antitumor effect through regulating Wnt/β-catenin and Notch signaling pathways and apoptosis.

Niclosamide-loaded pluronic nanoparticles (NIC-NPs) were optimally developed and characterized with sustained release properties up to 7days. Sixteen weeks after HCC induction, NIC (70mg/kg) and an equivalent dose of NIC-NPs were administered orally for 3 consecutive weeks. Hepatocyte integrity was assessed by measuring serum levels of aminotransferases, ALP, GGT, bilirubin, albumin and total protein. HCC development was detected by measuring AFP expression. Necroinflammation and fibrosis were scored by histopathological examination. Wnt/β-catenin and Notch signaling were evaluated by measuring hepatic mRNA levels of Wnt3A, Lrp5 and Lrp6 Co-receptors, Dvl-2, Notch1 and Hes1 and β-catenin protein levels. Apoptosis was assessed by measuring mRNA and protein levels of cyclin D1 and caspase-3.

The novel NIC-NPs restored liver integrity, reduced AFP levels and showed improved anticancer and proapoptotic activities compared to drug alone. The inhibitory effect of NIC on Wnt/β-catenin and Notch signaling pathways was potentiated by the NIC-NPs formulation.

We conclude that NIC acts by inhibiting Wnt/β-catenin and Notch signaling and inducing apoptosis in HCC. Developing pluronic-based nanoformulations may be a promising approach to improve NIC solubility and offer the possibility of controlled release.

We conclude that NIC acts by inhibiting Wnt/β-catenin and Notch signaling and inducing apoptosis in HCC. Developing pluronic-based nanoformulations may be a promising approach to improve NIC solubility and offer the possibility of controlled release.Rheumatoid arthritis is a chronic, inflammatory joint disease leading to inflammation of synovial membrane that lines the joints. This inflammation further progresses and results in destruction of joints and surrounding cartilages. The underlying factors can be oxidative stress, pro-inflammatory mediators, imbalance and attenuation between various enzymes and proteins (like nuclear factor erythroid 2 related factor 2/Nrf2 and ubiquitin). Protein degradation pathways comprises of lysosomal, proteasomal pathway, and autophagosome (that are carried out in mammalian cells) are regulated through ubiquitin. Ubiquitin proteasomal system is dominating pathway for carrying out non-lysosomal proteolysis of intracellularly proteins. Fundamental processes including cell cycle progression, process of division, apoptosis, modulation of immune responses and cell trafficking are regulated by process of ubiquitination. Ubiquitin proteasomal pathway (UPP) includes ubiquitin moieties which are covalently attached to proteins and guides them proteasome for degradation. Misfolded, oxidized and damaged proteins which are responsible for critical processes, are major targets of degradation process. Any alteration in this system leads to dysregulated cellular homeostasis; progressively leading to numerous diseases including rheumatoid arthritis. Factors including TAK1, TRAF6 undergo are required for the progression of disease and thus contributes towards pathology of inflammatory disorders such as rheumatoid arthritis. This review will include all linked aspects which contribute its major role in rheumatoid arthritis.

Blood coagulation is one of the most important host-defending mechanisms in vivo by maintaining the blood pressure after injury. However, besides maintaining homeostasis, blood coagulation and the contributing factors are directly linked to pathological conditions, such as thromboembolism and inflammation, leading to cardiovascular diseases, among others. As anti-inflammatory drugs may reduce cardiovascular events, we hypothesized in this study that the direct thrombin inhibitor dabigatran may reduce cytokine, growth factor and chemokine expression in vitro.

Initially, human whole blood was incubated in tubes for serum, EDTA plasma, and heparinized plasma. Furthermore, human PBMCs were isolated and incubated under different culture conditions, including the treatment with human serum or thrombin, respectively. The effect of the oral anticoagulant dabigatran on pro-inflammatory cytokines, growth factors and chemokines was investigated by ELISA.

Conditioned serum resulted in a significant alteration of the secretome’s protein levels after 24h. However, solely ANG showed a dose-dependent increment by the addition of serum (79.8±9.2ng/mL) in comparison to baseline (0.2±0.2ng/mL), as it was in trend for thrombin treatment. Furthermore, the pre-treatment of PBMCs with different doses of dabigatran significantly lowered supernatant protein levels measured. Moreover, dabigatran was shown to decrease most notably the growth factor and chemokine levels in the PBMC’s secretome that were treated with 200ng/mL thrombin in a dose-dependent manner.

In conclusion, novel oral anticoagulants, such as dabigatran, could help to reduce not only procoagulatory effects in inflammatory conditions but could also reduce proinflammatory stimuli via reduced expression of cytokines and chemokines.

In conclusion, novel oral anticoagulants, such as dabigatran, could help to reduce not only procoagulatory effects in inflammatory conditions but could also reduce proinflammatory stimuli via reduced expression of cytokines and chemokines.

Neurodegeneration of the optic nerve and retinal ganglion cells (RGCs) leads to progressive vision loss. As part of the central nervous system, RGCs show limited ability to regenerate and there is extensive search for neuroprotective agents for optic nerve damage. Methylene blue (MB) exhibits beneficial effects against various neurodegenerative diseases of the central nervous system. However, the mechanisms associated with its putative protection on neuronal survival and regeneration remain obscure. This study used the optic nerve transection model to examine the effects of MB on RGC survival, the expression of regenerative marker GAP-43 in RGCs and microglial activation.

Axons of RGCs were injured by cutting the optic nerve. MB was injected intravitreally either immediately post-injury or delayed to 3days post-injury. Using immunohistochemical staining, surviving RGCs, GAP-43-positive RGCs and microglial cells were quantified in wholemount retinas 7days post-injury.

Both immediate and delayed (a more clinically realistic situation) intravitreal injection of MB promoted RGC survival. MB also increased the number of GAP-43-positive RGCs, suggesting an enhanced ability of RGCs to regenerate. This was exemplified by the regenerative sprouting of axon-like processes from injured RGCs after MB treatment. The increase in RGC survival and GAP-43 expression correlated with an increase in the number of microglial cells.

These results reveal that MB has survival-promoting and growth-promoting effects on RGCs after optic nerve injury. Together with the established safety profile of MB in humans, MB is a promising treatment for neurodegeneration and injury of the optic nerve.

These results reveal that MB has survival-promoting and growth-promoting effects on RGCs after optic nerve injury. Together with the established safety profile of MB in humans, MB is a promising treatment for neurodegeneration and injury of the optic nerve.

Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder. Its molecular mechanism is still unclear. Endoplasmic reticulum (ER) stress has been highlighted in PD. Transient receptor potential vanilloid 4 (TRPV4) is a kind of nonselective calcium cation channel. A defined role for TRPV4 in PD has not been reported. The purpose of the present research was to investigate the molecular mechanisms by which TRPV4 regulates ER stress induced by the 1-methyl-4-phenylpyridinium ion (MPP

) in PC12 cells.

PC12 cells were pretreated with the TRPV4-specific antagonist HC067047 or transfected with TRPV4 siRNA followed by treatment with MPP

. Cell viability was measured by the CCK-8 Assay. The expression of TRPV4, sarco/endoplasmic reticulum Ca

-ATPase 2 (SERCA2), glucose-regulated protein 78 (GRP78), glucose-regulated protein 94 (GRP94), C/EBP homologous protein (CHOP), procaspase-12, and tyrosine hydroxylase (TH) was detected by western blot and RT-PCR.

The expression of TRPV4 was upregulated, while cell viability was decreased by MPP

, which was reversed by HC067047. The ER stress common molecular signature SERCA2 was depressed by MPP

. Moreover, MPP

induced upregulation of GRP78, GRP94, CHOP, and decrease in procaspase-12 and TH. HC067047 and TRPV4 siRNA reversed MPP

-induced ER stress and restored TH production.

TRPV4 functions upstream of ER stress induced by MPP

and holds promise as a prospective pharmacotherapy target for PD.

TRPV4 functions upstream of ER stress induced by MPP+ and holds promise as a prospective pharmacotherapy target for PD.

To describe the clinicopathologic features of patients with incidental prostatic amyloidosis.

We queried the genitourinary pathology database at Mayo Clinic Arizona for prostate specimens which showed amyloid deposits. Congo red stain was used for the diagnosis of amyloidosis and amyloid subtype was performed analysis using Liquid chromatography tandem mass spectrometry. We reviewed the patient’s medical charts for past or subsequent diagnosis of systemic amyloidosis and clinical course.

Prostatic amyloidosis was identified in 7 patients between 2008-2018. Median age was 79 years (range 69-84) and median follow-up was 5 years (range 0-11). Benign prostate tissue was found in 4 patients, and prostate cancer was diagnosed in 3 patients. Amyloid subtyping was available in 6 patients and was consistent with Amyloid transthyretin Amyloidosis. Liquid chromatography tandem mass spectrometry did not detect an amino acid sequence abnormality in the transthyretin protein in any of the patients. Five of 6 patients were diagnosed with cardiac amyloidosis, which preceded and followed the diagnosis of prostatic amyloidosis in 1 and 4 patients, respectively. Of these 4 patients, 2 were diagnosed immediately and as a consequence of the diagnosis of prostatic amyloidosis, and the remaining 2 3 and 4 years later.

Incidental prostatic amyloidosis should prompt systemic and cardiac evaluation for amyloidosis. In patients with suspected cardiac amyloidosis, prior prostate specimens should be reviewed for the presence of amyloidosis.

Incidental prostatic amyloidosis should prompt systemic and cardiac evaluation for amyloidosis. In patients with suspected cardiac amyloidosis, prior prostate specimens should be reviewed for the presence of amyloidosis.

To examine the geographic and pharmacy-type variation in costs for generic benign prostatic hyperplasia (BPH) medications in order to improve drug price transparency and reduce health disparities. Medical therapy for BPH can be expensive, having significant implications for uninsured and underinsured patients.

We generated a 20% random sample of all pharmacies in Pennsylvania and queried each for the uninsured cash price of a 30-day prescription of tamsulosin 0.4mg daily, finasteride 5mg daily, oxybutynin immediate release 5mg TID and oxybutynin XL 10mg daily. Our primary objectives were to identify price variation based on pharmacy type (i.e., big chain and independent) and between geographic regions (predetermined by the Pennsylvania Health Care Cost Containment Council Database). We fit multivariable quantile regression models to test for an association between drug price and region after controlling for pharmacy type.

Among 575 retail pharmacies contacted, 473 responded (82% response rate). The median cash price was significantly higher for big chain pharmacies than for independent pharmacies for tamsulosin ($66 vs. $15), finasteride ($68 vs. $15), oxybutynin immediate release ($49 vs. $35), and oxybutynin XL ($79 vs. $31) (all p < 0.05). When controlling for region, the median and 75

percentile price of all drugs was significantly higher for big chain pharmacies. When controlling for pharmacy type, regional variation was noted in all four drugs at the 75

percentile price and was greater for independent pharmacies.

Compared to independent pharmacies, big chain pharmacies charged significantly more for generic BPH medications to uninsured patients. However, independent pharmacies demonstrated more regional variation in their pricing.

Compared to independent pharmacies, big chain pharmacies charged significantly more for generic BPH medications to uninsured patients. However, independent pharmacies demonstrated more regional variation in their pricing.

To assess outcomes of a variant of traditional modeling („optimal modeling,” OM) in patients with residual curvature following prosthesis implantation.

We performed a retrospective review of all patients who underwent penile implant insertion. Patients with >30° of residual curvature after cylinder placement and inflation underwent OM and were compared 11 to a demographically-matched cohort who received implantation without ancillary straightening. Optimal modeling was performed by forcibly bending the erect penis in the direction opposite the point of maximal curvature while maintaining glanular pressure to prevent urethral injury. This was performed for 90-second intervals for as many cycles as necessary to achieve <15° curvature.

Eighty patients were included in the final analysis; 40 (50.0%) underwent optimal modeling while 40 (50.0%) did not need additional straightening following surgery. The mean premodeling curvature was 47.8° (range 30°-90°) while post-modeling curvature improved to a mean of 10.6° (range 0°-30°, P < .001); 87.5% of patients had <15° of residual curvature. Patients in the OM cohort experienced longer operative times (82.7 vs 75.8 min, P = .15). No patient in either group experienced an intraoperative or postoperative complication at a mean follow-up of 29.9 months.

Although many prosthetic urologists forego manual modeling in cases of moderate-severe penile curvature, our contemporary series shows it to be both safe and effective. OM may preclude the need for more time-consuming and complex surgical procedures.

Although many prosthetic urologists forego manual modeling in cases of moderate-severe penile curvature, our contemporary series shows it to be both safe and effective. OM may preclude the need for more time-consuming and complex surgical procedures.

To report our initial experience with ureteral appendiceal interposition (UAI) in a series of adult patients undergoing ureteral reconstruction for ureteral stricture.

We retrospectively collected data of patients who underwent UAI for ureteral stricture disease from December 2015 to March of 2020. Success of surgery was defined as one that required no subsequent procedural intervention for recurrent ureteral stricture disease, or loss of kidney function.

Eleven patients underwent UAI for ureteral stricture. Etiologies for stricture disease included radiation exposure, nephrolithiasis, and iatrogenic injury. Median follow-up was 363 days. Three patients had Clavien-Dindo class III complications during their hospitalization. No patient required repeat intervention due to recurrent ureteral stricture disease. On imaging, 9 patients had no obstruction on Lasix renal scan postoperatively, or improvement in hydronephrosis on CT scan. Two patients with poor renal function preop continued to show poor function after surgery.

The use of the appendix is a safe and feasible option for ureteral reconstruction in appropriately selected adult patients when primary ureteral repair is not possible.

The use of the appendix is a safe and feasible option for ureteral reconstruction in appropriately selected adult patients when primary ureteral repair is not possible.

To report our single center experience in the management of untreated adult classical bladder exstrophy.

A retrospective review of 25 adults aged ≥18 years who underwent repair of the classical bladder exstrophy from April 2000 to February 2020 was performed. Patients with prior repair and neoplastic changes in the exposed bladder mucosa were excluded. The patients and primary caretakers were actively involved in the decision-making of the surgical procedures best suited them. Work-up included upper tract evaluation and random bladder mucosal biopsy.

The mean age of presentation was 25 years. Primary schooling was completed by only 32% patients. The majority (72%) of the patients opted continent catheterizable pouch. Penn pouch was the most common pouch performed. In 3 patients, a complete primary repair was done in a single setting. In 4 patients with lack of education and difficult access to nearby health care settings, ileal conduit was performed. In all except 3 (13.1%), abdominal wall closed primarily. None of the patients required osteotomy. At a mean follow-up of 6.5 years, all patients with continent pouches were continent. One patient required revision of left ureteroneocystostomy at 20 months follow-up. All except one patient, who had complete primary repair were continent at a mean follow-up of 6 years.

Management of adult classical bladder exstrophy is challenging. The various pouches extend the surgical options. Ileal conduit may be a simple alternative to complex reconstructions in unmotivated patients with poor access to the hospital.

Management of adult classical bladder exstrophy is challenging. The various pouches extend the surgical options. Ileal conduit may be a simple alternative to complex reconstructions in unmotivated patients with poor access to the hospital.

To identify the incidence of radiation-induced urologic complication requiring procedural intervention following high-dose radiotherapy for cervical carcinoma, and to identify predictors of complication occurrence.

We performed a retrospective chart review of cervical cancer patients undergoing radiotherapy with primary focus on procedural complications (Clavien-Dindo ≥ III). Clinical data were collected including radiation dose, procedure performed, timing of complication, and need for additional procedures. Univariate and multivariate logistic regression modeling was performed to assess predictive value of demographic and clinical variables.

A total of 126 patients with FIGO stage 1A2-4B cervical cancer were included in study analysis, with 18 patients experiencing procedural complication (14.3%). A total of 22 complications were identified, representing an average of 1.2 complications per patient with complication. The most common complications were ureteral stricture and radiation cystitis. The mostnagement given their complexity. These findings suggest a need for awareness and plans for multidisciplinary management of urologic complications in this patient population.There is a persistent male gender predominance in urology, especially with respect to female representation in leadership. We review the current status of women in urology leadership, discuss challenges women face in leadership positions, present the case for adopting inclusive practices that increase diversity and gender equity in urology leadership, and review the potential benefits of such an expansion. We discuss practical strategies to grow the role of women in urologic leadership, including increasing mentorship, modifying academic promotion criteria, and addressing implicit bias, while presenting a roadmap toward achieving equity and diversity at the highest ranks of urologic leadership.The coronavirus disease 2019 pandemic presents unprecedented challenges for the health care system. The pressure on health care staff continues to intensify, accentuated by the confinement (lockdown) of the population and the unprecedented duration of this emergency. Separately and especially together, overwork, degraded conditions of care because of the never-ending emergency, and the risk of exposure to the virus can lead to acute psychological distress or signs of burnout. This original program was developed at Cochin Hospital in Paris, France to prevent these potentially dramatic psychological consequences, support the medical staff, and identify those most affected to offer them specific care. A program and a space for relaxation and support for hospital caregivers by hospital caregivers, the Port Royal Bulle (the Bubble) offers these workers help in decompression and relaxation. It combines a warm and caring welcome that promotes attention, listening, conversations, and exchanges as needed, empathetic support, and the ability to participate in soothing, relaxing, or low-impact physical activities. It takes care of caregivers. The Bubble is a program that is simple to set up and that appears to meet professionals’ expectations. Making it permanent and enlarging its scale, as a complement to existing programs, might help to support health care personnel in their work.

Near the end of life when patients experience refractory symptoms, palliative sedation may be considered as a last treatment. Clinical guidelines have been developed, but they are mainly based on expert opinion or retrospective chart reviews. Therefore, evidence for the clinical aspects of palliative sedation is needed.

To explore clinical aspects of palliative sedation in recent prospective studies.

Systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and registered at PROSPERO. PubMed, CINAHL, Cochrane, MEDLINE, and EMBASE were searched (January 2014-December 2019), combining sedation, palliative care, and prospective. Article quality was assessed.

Ten prospective articles were included, involving predominantly patients with cancer. Most frequently reported refractory symptoms were delirium (41%-83%), pain (25%-65%), and dyspnea (16%-59%). In some articles, psychological and existential distress were mentioned (16%-59%). Only a few agical and existential evaluation by expert clinicians working in teams. Future research needs to evaluate the effectiveness of palliative sedation for refractory symptom relief.The Apolipoprotein-E (APOE) gene is now known to be associated with individual differences in cognitive health in ageing. However, while the APOE ε4 allele confers significantly increased risk of developing Alzheimer’s disease (AD), the APOE ε2 allele is hypothesized to be protective against the development of AD. This is in line with neuroimaging and pathological findings associated with ε2 APOE allele, which go in the opposite direction to those observed in AD-related pathology. However, the precise impact of this allele on cognition remains inconclusive, with some small-cohort studies raising the possibility of an advantageous memory performance in these individuals. Here, we tested short-term memory (STM) performance in a large cohort of individuals, 300 of which were ε2/ε3 carriers. Their performance was compared to 554 ε3/ε3 carriers. We included participants from a wide age range spanning young, middle-aged and elderly adults. All of them performed a STM task that has previously been shown to be sensitive to subtle changes in memory in various patient and at-risk cohorts. Individuals carrying the APOE-ε2 allele exhibited a significant memory advantage, regardless of STM task difficulty and across all ages. The observed memory advantage was present across the age range, suggestive of a phenotypical effect of this allele on cognition, possibly independent of any effects of this genetic allele that occur later life in these individuals.Various actions trigger pleasure (reward) or aversion (punishment) as emotional responses. Emotional factors that negatively affect brain neural control processes for long periods of time might cause various mental diseases by inducing neuronal changes. In the present study, newly developed PC12m12 cells which are　highly sensitivity to neurotransmitters such as acetylcholine (ACh), were used. Exposing the cells to plasma from rats that had been subjected to intracranial self-stimulation (ICSS) markedly upregulated neurite outgrowth. In addition, voluntary running in a wheel or forced on a rotating rod was used to induce behavioral excitation in rats, and examinations of their plasma confirmed that the ICSS-induced neurite outgrowth was not associated with the ICSS behavior itself. Furthermore, immunoblotting and treatment with U0126, an ERK (extracellular signal-regulated kinase) antagonist, showed that the ICSS-induced neurite outgrowth was related to neuronal ERK activity. Exposing the same cells to plasma from rats that had been subjected to immobilization (IMM) also increased neurite outgrowth. Although the degree of enhancement was not as great as that seen after the ICSS rat plasma treatment, it was less than that observed after treatment with ACh as a positive control. These results indicate that ICSS or IMM lead to varying degrees of morphological changes, such as enhanced neurite outgrowth, in PC12m12 cells, but the neuronal signal transduction pathways underlying these effects differ; i.e.,the former morphological change might involve the activation of the ERK pathway, whereas the latter changes might not. Using PC12m12 cells which exhibit sensitivity to neurotransmitters, it might be possible to clarify the pathogeneses of mental diseases at the neuronal level and search for therapeutic drugs.Early ethanol exposure alters neonatal breathing plasticity. Respiratory EtOH’s effects are attributed to central respiratory network disruptions, particularly in the medullary serotonin (5HT) system. In this study we evaluated the effects of neonatal pre-exposure to low/moderate doses upon breathing rates, activation patterns of brainstem’s nuclei and expression of 5HT 2A and 2C receptors. At PD9, breathing frequencies, tidal volumes and apneas were examined in pups pre-exposed to vehicle or ethanol (2.0 g/kg) at PDs 3, 5 and 7. This developmental stage is equivalent to the 3rd human gestational trimester, characterized by increased levels of synaptogenesis. Pups were tested under sobriety or under the state of ethanol intoxication and when subjected to normoxia or hypoxia. Number of c-Fos and 5HT immunolabelled cells and relative mRNA expression of 5HT 2A and 2C receptors were quantified in the brainstem. Under normoxia, ethanol pre-exposed pups exhibited breathing depressions and a high number of apneas. An opposite phenomenon was found in ethanol pre-treated pups tested under hypoxia where an exacerbated hypoxic ventilatory response (HVR) was observed. The breathing depression was associated with an increase in the neural activation levels of the raphe obscurus (ROb) and a high mRNA expression of the 5HT 2A receptor in the brainstem while desactivation of the ROb and high activation levels in the solitary tract nucleus and area postrema were associated to the exacerbated HVR. In summary, early ethanol experience induces respiratory disruptions indicative of sensitization processes. Neuroadaptive changes in central respiratory areas under consideration appear to be strongly associated with changes in their respiratory plasticity.

The aim of this study was to conduct a micro-computed tomographic assessment of the effectiveness of 3 supplementary cleaning techniques in reducing the residual volume of gutta-percha and a bioceramic sealer after performing endodontic retreatment procedures in teeth with oval canals.

Thirty-six mandibular premolars were instrumented with the ProTaper Next system (instruments X1-X3; Dentsply Maillefer, Ballaigues, Switzerland) and filled with gutta-percha and Bio-C Sealer (Angelus, Londrina, PR, Brazil) using the single-cone technique. The teeth were reinstrumented with the Reciproc R40 instrument (VDW, Munich, Germany) and divided into 3 groups according to the supplementary cleaning technique used (n = 12) ultrasonic-assisted irrigation (UAI), EndoActivator (Dentsply Tulsa Dental Specialties, Tulsa, OK) irrigation (EAI), or the XP-endo Finisher R system (XPR; FKG Dentaire, La Chaux-de-Fonds, Switzerland). Micro-computed tomographic imaging was used to quantify the residual volume of filling material. One-way analysis of variance complemented by the Tukey test was used to perform the statistical analysis (P < .05).

Significant reductions were obtained in the residual filling material after supplementary cleaning (P < .05). XPR (47.5%) led to significantly greater (P < .05) filling material removal than UAI (16.6%) or EAI (22.6%). The removal values of the 2 latter systems were not significantly different.

XPR was more effective than UAI and EAI in removing filling material in mandibular premolars with oval canals. None of the tested supplementary cleaning techniques completely removed the residual filling material.

XPR was more effective than UAI and EAI in removing filling material in mandibular premolars with oval canals. None of the tested supplementary cleaning techniques completely removed the residual filling material.

This study aimed to compare the torsional resistances and fracture modes of WaveOne Gold (Dentsply Sirona, Ballaigues, Switzerland) and Reciproc Blue (VDW, Munich, Germany) using the repetitive torsional loading (RTL) method and the conventional single-rotation (STL) method.

A 3-mm file tip was fixed with a brass plate, and a torsional load was applied using a custom device. In the RTL method, the file was driven counterclockwise at 50 rpm until it achieved the preset torque of 0.5 Ncm; thereafter, it was returned to its original position. This recovery of the file to its original position was defined as 1 torsional loading cycle; the number of repetitive load cycles until fracture was counted. In the STL method, the files were rotated at a constant rate of 2 rpm in a counterclockwise direction until file fracture. The fragments fractured by the 2 methods were compared under a scanning electron microscope to examine the topographic features of the fractured surfaces and longitudinal aspects.

With the RTL method, Reciproc Blue showed a higher number of repetitive load cycles until fracture than WaveOne Gold (P < .05). With the STL method, Reciproc Blue also had a higher ultimate strength than WaveOne Gold (P < .05). Scanning electron microscopic findings of the fractured specimens from the 2 test methods showed different features of torsional failure.

Within the study limitations, both the RTL and STL methods conferred similar torsional resistance. Therefore, the clinically relevant RTL method with repetitive and reciprocation motion can be used for testing torsional resistance.

Within the study limitations, both the RTL and STL methods conferred similar torsional resistance. Therefore, the clinically relevant RTL method with repetitive and reciprocation motion can be used for testing torsional resistance.Foot-and-mouth disease (FMD) is a persistent, major economic concern for livestock productivity, which is highly exacerbated by outbreaks in Thailand. FMD virus (FMDV) serotype A is more highly antigenic and genetically diverse than other serotypes, which has important implications for vaccine development as well as selection. Therefore, it is essential to continuously monitor antigenic and genetic changes of field isolates of FMDV serotype A. Here we used antisera against three vaccine strains (A/118/87, A/Sakolnakorn/97, and A/Lopburi/2012) to analyze the antigenicity of 133 field isolates of FMDV serotypes A in Thailand from 2007 to 2019. The majority of the isolates from 2007 to 2008 reacted only with the antiserum against strain A/118/87. In contrast, antigenic analysis revealed broad cross-reactivity and antigenic variations of the isolates from 2009 through 2019 against strains A/Sakolnakorn/97 and A/Lopburi/2012. These results indicate periodic changes in the antigenicity of field isolates of FMDV serotype A. Phylogenetic analysis of the VP1 region revealed that all isolates were of the Sea-97 lineage within the ASIA topotype. Analysis of the L-fragment genome sequences of 30 FMDV isolates collected throughout Thailand revealed highly variable amino acid sequences of VP1 and 3A, with the lowest average identity (94.56 %) and invariant (78.43 %) rates, respectively. The present findings indicate the importance of an active routine surveillance system incorporating antigenic and genetic analysis designated to continually update information about field isolates of FMDV serotype A. Such a system is essential for establishing and improving measures to control FMDV infections in Thailand and in neighboring Asian countries.The defining feature of the eukaryotic cell is the possession of a nucleus that uncouples transcription from translation. According to the updated Viral Eukaryogenesis (VE) hypothesis presented here, the eukaryotic nucleus descends from the viral factory of a DNA virus that infected the archaeal ancestor of the eukaryotes. The VE hypothesis implies that many unique features of the nucleus, including the mechanisms by which the eukaryotic nucleus uncouples transcription from translation, should be viral rather than cellular in origin. The modern eukaryotic nucleus uncouples transcription from translation using a complex process employing hundreds of eukaryotic specific genes acting in concert. This intricate process is primed by the eukaryote specific 7-methylguanylate (m7G) cap on eukaryotic mRNA that targets mRNA for splicing, nuclear export, and cytoplasmic translation. It is shown here that homologues of the eukaryotic m7G capping apparatus are present in viruses of the Mimiviridae yet are apparently absent from archaea generally, and specifically from Lokiarchaeota, a proposed archaeal relative of the eukaryotes. Phylogenetic analysis of the m7G capping apparatus shows that eukaryotic nuclei and Mimiviridae obtained this shared pathway from a common ancestral source that predated the origin of the Last Eukaryotic Common Ancestor (LECA). These results are consistent with the hypothesis that the eukaryotic nucleus and the Mimiviridae obtained these abilities from an ancient virus that could be considered the 'First Eukaryotic Nuclear Ancestor’ (FENA).The cornea’s intense innervation is responsible for corneal trophism and ocular surface hemostasis maintenance. Corneal diabetic neuropathy affects subbasal nerve plexus, with progressive alteration of nerves’ morphology and density. The quantitative analysis of nerve fibers can be performed with in vivo corneal confocal microscopy considering the main parameters such as corneal nerve fibers length, corneal nerve fibers density, corneal nerve branching density, tortuosity coefficient, and beadings frequency. As the nerve examination permits the detection of early changes occurring in diabetes, the invivo corneal confocal microscopy becomes, over time, an important tool for diabetic polyneuropathy assessment and follow-up. In this review, we summarize the actual evidence about corneal nerve changes in diabetes and the relationship between the grade of alterations and the duration and severity of the disease. We aim at understanding how diabetes impacts corneal nerves and how it correlates with sensorimotor peripheral polyneuropathy and retinal complications. We also attempt to analyze the safety of the most common surgical procedures such as cataract and refractive surgery in diabetic patients and to highlight the specific risk factors. We believe that information about the corneal nerve fibers’ condition obtained from the in vivo subbasal nerve plexus investigation may be crucial in monitoring peripheral small fiber polyneuropathy and that it will help with decision-making in ophthalmic surgery in diabetic patients.Age-related macular degeneration, the leading cause of irreversible visual loss among older adults in developed countries, is a chronic, multifactorial, and progressive disease with the development of painless, central vision loss. Retinal pigment epithelial cell dysfunction is a core change in age-related macular degeneration that results from aging and the accumulated effects of genetic and environmental factors that, in part, is both caused by and leads to oxidative stress. In this review, we describe the role of oxidative stress, the cytoprotective oxidative stress pathways, and the impact of oxidative stress on critical cellular processes involved in age-related macular degeneration pathobiology. We also offer targeted therapy that may define how antioxidant therapy can either prevent or improve specific stages of age-related macular degeneration.The Global Program to Eliminate Lymphatic Filariasis (GPELF) relies heavily on a rapid diagnostic test (RDT) to a Wuchereria bancrofti circulating filarial antigen (Wb-CFA) to identify endemic areas and for determining when mass drug administration can stop. The antigen contains a carbohydrate epitope that is recognized by monoclonal antibody AD12. Og4C3, a monoclonal antibody that is used in a commercial ELISA for Wb-CFA recognizes the same moiety. Despite its diagnostic importance, little is known about the structure and function of this „AD12 epitope”. It is also present on other W. bancrofti glycoproteins and on glycoproteins of other filarial worms, but such antigens are not detected in the sera of individuals with most other filarial infections. We report here functional and biochemical analyses that shed light on the interaction between filarial glycoproteins and AD12 and/or Og4C3. Binding of these monoclonal antibodies to a mammalian glycan array suggests the reactive moiety has structural similarity to terminal β-d-glucuronic acid in a 1-3 linkage to other hexoses. However, sera collected from individuals with patent W. bancrofti infection had very low or undetectable serum antibodies to the GlcA-containing array glycans. Unlike other filarial glycoproteins, the Wb-CFA is relatively resistant to protease digestion by pronase and trypsin and completely resistant to the mucinase O-sialoglycoprotein endopeptidase (OSGE). The protease resistance of the Wb-CFA may contribute to its consistent detection in Wb-infected sera.The cellular membranes of Trypanosoma cruzi, like all eukaryotes, contain varying amounts of phospholipids, sphingolipids, neutral lipids and sterols. A multitude of pathways exist for the de novo synthesis of these lipid families but Trypanosoma cruzi has also become adapted to scavenge some of these lipids from the host. Completion of the TriTryp genomes has led to the identification of many putative genes involved in lipid synthesis, revealing some interesting differences to higher eukaryotes. Although many enzymes involved in lipid synthesis have yet to be characterised, completed experiments have shown the indispensability of some lipid metabolic pathways. Furthermore, the bioactive lipids of Trypanosoma cruzi and their effects on the host are becoming increasingly studied. Further studies on lipid metabolism in Trypanosoma cruzi will no doubt reveal some attractive targets for therapeutic intervention as well as reveal the interplay between parasite lipids, host response and pathogenesis.Since 2014, Tasmania has experienced unprecedented rates of hospitalisations related to mental health issues. To address reliance on such acute-based care, government funding was invested to enhance community-based care, which, in turn, led to the development of MyCare. This paper represents the initial phase of a larger body of work (i.e. an effectiveness-controlled trial of MyCare) that describes the MyCare program and the successful implementation strategy underpinning the program. The implementation of MyCare was evaluated with 41 key stakeholders (staff, clients and senior executives) using semistructured interviews and focus groups, informed by the Consolidated Framework for Implementation Research (CFIR). According to stakeholders, three CFIR constructs that were directly addressed by the program, namely Tension for Change, Evidence Strength and Quality, and Available Resources for Implementation, facilitated the successful implementation of MyCare. In contrast, a feature of the program that impeded implementation was Patient Needs and Resources, which restricted program access to those with the most severe mental health issues. The reporting of implementation strategies underpinning mental health programs is rare. This study describes the implementation strategy underpinning a community-based mental health program that was successful in facilitating program uptake. We encourage other researchers to not only report on implementation findings, which may help avoid replication failure, but also to apply these innovative implementation processes (i.e. address the tension for change and ensure the program is evidence informed and that sufficient resources are available for implementation) within mental health programs to aid successful uptake.

Youth mental health has been politicised by high-profile health advocates, and often leads the Australian national policy agenda. The ensuing debate is being conducted at multiple levels scientific, clinical, economic and political. These levels interact, and we explore how scholars’ experiences with early intervention (EI) shape their roles as health advocates and political lobbyists.

Health advocacy influences major government decisions. EI researchers have been successful as health advocates in Australia, attracting substantial government funding for selected youth mental health programmes. Positive experiences with the short-term gains of EI might encourage the necessary optimism amongst researchers for successful health advocacy. However, as medical experts, clinicians are aware that most patients and carers face a huge burden from schizophrenia, even after high-quality EI. These patients require fully integrated and well-funded mental healthcare across the lifespan.

Health advocacy influences major government decisions. EI researchers have been successful as health advocates in Australia, attracting substantial government funding for selected youth mental health programmes. Positive experiences with the short-term gains of EI might encourage the necessary optimism amongst researchers for successful health advocacy. However, as medical experts, clinicians are aware that most patients and carers face a huge burden from schizophrenia, even after high-quality EI. These patients require fully integrated and well-funded mental healthcare across the lifespan.

Cognitive impairments contribute to difficulty in obtaining employment for people with severe mental illnesses (SMIs). We describe a pilot evaluation of a programme, Employ Your Mind (EYM), which integrates cognitive remediation therapy (CRT) with vocational rehabilitation.

Sixty participants with SMIs enrolled in EYM, a 6-month programme that combines CRT exercises, individual project work and group reflection sessions about social interaction and cognitive functioning. Participants completed assessments of cognitive function (Audio Recorded Cognitive Screen, Wechsler Digit Span Task), psychosocial function (Work and Social Adjustment Scale, General Self-Efficacy Scale) and abilities related to work (Dialogue about Working Ability, Self-Assessment of Thinking Skills) at baseline and postprogramme. Paired

tests were used to compare assessments of participants who completed the programme between the two time points.

The programme was completed by 22 individuals. These individuals demonstrated significant improvement in cognitive function, social and work-related function, and subjective thinking ability after completing the EYM programme.

The EYM programme is effective in improving cognition, impairments related to work and social function, and subjective thinking skills for some individuals with SMIs. Future evaluation of the programme should focus on enhanced retention and assessment of employment outcomes.

The EYM programme is effective in improving cognition, impairments related to work and social function, and subjective thinking skills for some individuals with SMIs. Future evaluation of the programme should focus on enhanced retention and assessment of employment outcomes.

First, to conduct a historical review of the evidence for repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder and determine a clinical algorithm. Second, to identify opportunities for research.

Literature searches were conducted of the MEDLINE database, UpToDate and the Australian National University Library SuperSearch from 1 January 2000 to 30 September 2019. The search terms used were 'transcranial magnetic stimulation’, 'major depressive disorder’ and 'depression’.

There were 24 meta-analyses identified, demonstrating a clear clinical effect. Left high-frequency rTMS had the most evidence. Ideal clinical parameters and study design were explored.

Use of rTMS for some patients with depression is justified. Open research questions include the comparative efficacy of right low-frequency and bilateral stimulation, the role of rTMS in medication-naïve patients, and maintenance of effect.

Use of rTMS for some patients with depression is justified. Open research questions include the comparative efficacy of right low-frequency and bilateral stimulation, the role of rTMS in medication-naïve patients, and maintenance of effect.

Because of the COVID-19 pandemic, the implementation of quarantine for returning travellers and the effect this has on people’s mental health has become a topical issue. This article briefly describes the historical context of quarantine, research around its impact on people’s well-being, and the experiences of a clinical psychologist providing support to people in quarantine.

Mental health professionals are in a unique position to assist people in quarantine, both in terms of counselling and ongoing research.

Mental health professionals are in a unique position to assist people in quarantine, both in terms of counselling and ongoing research.