Effectiveness of an Immersive Telemedicine Platform for Delivering Diabetes Medical Group Visits for African American, Black and Hispanic, or Latina Women With Uncontrolled Diabetes: The Women in Control 2.0 Noninferiority Randomized Clinical Trial.
Medically underserved people with type 2 diabetes mellitus face limited access to group-based diabetes care, placing them at risk for poor disease control and complications. Immersive technology and telemedicine solutions could bridge this gap. The purpose of this study was to compare the effectiveness of diabetes medical group visits (DMGVs) delivered in an immersive telemedicine platform versus an in-person (IP) setting and establish the noninferiority of the technology-enabled approach for changes in hemoglobin A1c (HbA1c) and physical activity (measured in metabolic equivalent of task [MET]) at 6 months. This study is a noninferiority randomized controlled trial conducted from February 2017 to December 2019 at an urban safety net health system and community health center. We enrolled adult women (aged ≥18 years) who self-reported African American or Black race or Hispanic or Latina ethnicity and had type 2 diabetes mellitus and HbA1c ≥8%. Participants attended 8 weekly DMGVs, which included diabetes self-management education, peer support, and clinician counseling using a culturally adapted curriculum in English or Spanish. In-person participants convened in clinical settings, while virtual world (VW) participants met remotely via an avatar-driven, 3D VW linked to video teleconferencing. Follow-up occurred 6 months post enrollment. Primary outcomes were mean changes in HbA1c and physical activity at 6 months, with noninferiority margins of 0.7% and 12 MET-hours, respectively. Secondary outcomes included changes in diabetes distress and depressive symptoms. Of 309 female participants (mean age 55, SD 10.6 years; n=195, 63% African American or Black; n=105, 34% Hispanic or Latina; n=151 IP; and n=158 in VW), 207 (67%) met per-protocol criteria. In the intention-to-treat analysis, we confirmed noninferiority for primary outcomes. We found similar improvements in mean HbA1c by group at 6 months (IP: -0.8%, SD 1.9%; VW: -0.5%, SD 1.8%; mean difference 0.3, 97.5% CI -∞ to 0.3; P<.001). However, there were no detectable improvements in physical activity (IP: -6.5, SD 43.6; VW: -9.6, SD 44.8 MET-hours; mean difference -3.1, 97.5% CI -6.9 to ∞; P=.02). The proportion of participants with significant diabetes distress and depressive symptoms at 6 months decreased in both groups. In this noninferiority randomized controlled trial, immersive telemedicine was a noninferior platform for delivering diabetes care, eliciting comparable glycemic control improvement, and enhancing patient engagement, compared to IP DMGVs. ClinicalTrials.gov NCT02726425; https://clinicaltrials.gov/ct2/show/NCT02726425.


A pH/ROS dual-responsive and targeting nanotherapy for vascular inflammatory diseases.
Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide. Vascular inflammation is closely related to the pathogenesis of a diverse group of CVDs. Currently, it remains a great challenge to achieve site-specific delivery and controlled release of therapeutics at vascular inflammatory sites. Herein we hypothesize that active targeting nanoparticles (NPs) simultaneously responsive to low pH and high levels of reactive oxygen species (ROS) can serve as an effective nanoplatform for precision delivery of therapeutic cargoes to the sites of vascular inflammation, in view of acidosis and oxidative stress at inflamed sites. The pH/ROS dual-responsive NPs were constructed by combination of a pH-sensitive material (ACD) and an oxidation-responsive material (OCD) that can be facilely synthesized by chemical functionalization of β-cyclodextrin, a cyclic oligosaccharide. Simply by regulating the weight ratio of ACD and OCD, the pH/ROS responsive capacity can be easily modulated, affording NPs with varied hydrolysis profiles under inflammatory microenvironment. Using rapamycin (RAP) as a candidate drug, we first demonstrated in vitro therapeutic advantages of RAP-containing NPs with optimal dual-responsive capability, i.e. RAP/AOCD NP, and a non-responsive nanotherapy (RAP/PLGA NP) and two single-responsive nanotherapies (RAP/ACD NP and RAP/OCD NP) were used as controls. In an animal model of vascular inflammation in rats subjected to balloon injury in carotid arteries, AOCD NP could accumulate at the diseased site after intravenous (i.v.) injection. Consistently, i. v. treatment with RAP/AOCD NP more effectively inhibited neointimal hyperplasia in rats with induced arterial injuries, compared to RAP/PLGA NP, RAP/ACD NP, and RAP/OCD NP. By surface decoration of AOCD NP with a peptide (KLWVLPKGGGC) targeting type IV collagen (Col-IV), the obtained Col-IV targeting, dual-responsive nanocarrier TAOCD NP showed dramatically increased accumulation at injured carotid arteries. Furthermore, RAP/TAOCD NP exhibited significantly potentiated in vivo efficacy in comparison to the passive targeting nanotherapy RAP/AOCD NP. Importantly, in vitro cell culture experiments and in vivo animal studies in both mice and rats revealed good safety for AOCD NP and RAP/AOCD NP, even after long-term treatment via i. v. injection. Consequently, our results demonstrated that the newly developed Col-IV targeting, pH/ROS dual-responsive NPs may serve as an effective and safe nanovehicle for precision therapy of arterial restenosis and other vascular inflammatory diseases.


Self-reported sleep quality and mental health mediate the relationship between chronic diseases and suicidal ideation among Chinese medical students.
High prevalence and strong associations of chronic disease, poor sleep quality, poor mental health, and suicidal ideation (SI) have been reported worldwide. However, the underlying mechanism remains unexamined. The participants were 2646 Chinese medical college students with an average age of 20.13 years. Pittsburgh Sleep Quality Index, the Kessler Psychological Distress Scale, and SI was evaluated. The lifetime SI, past 12-month SI, and chronic disease prevalence rates were 10.0%, 8.4%, and 4.6%, respectively. The results of logistic regression analysis in this study found that chronic disease, self-reported poor sleep quality, poor mental health, gender and scholarship were associated with lifetime SI. Similar results were also found for 12-month SI with an exception of region. This result indicated that the effects of chronic diseases on the SI were mediated by self-reported sleep quality and mental health. Physical diseases, sleep-related concerns, and mental health issues need to be addressed through a multidisciplinary team approach and various delivery systems to prevent SI among medical college students.


LIS1 functions in normal development and disease.
LIS1, the first gene to be identified as involved in a neuronal migration disease, is a dosage-sensitive gene whose proper levels are required for multiple aspects of cortical development. Deletions in LIS1 result in a severe brain malformation, known as lissencephaly, whereas duplications delay brain development. LIS1 affects the proliferation of progenitors, spindle orientation and interkinetic nuclear movement in the ventricular zone, as well as nucleokinesis and migration of neurons. LIS1 regulatory interaction with the minus end directed molecular motor cytoplasmic dynein is the key for understanding its complex cellular functions. LIS1-dynein interaction decreases the average velocity of the molecular motor in vitro, shows more complex effects in vivo, and may be of importance in high-load transport especially in neurons.


Investigation of halogenation during the biosynthesis of ramoplanin in Actinoplanes sp. ATCC33076.
Ramoplanin and enduracidin are lipopeptide antibiotics effective against Gram-positive pathogens, which share close similarity in structure and biosynthetic pathway. Both compounds have chlorine atoms attached to 4-hydroxyphenylglycine (Hpg) but with different chlorinating sites and levels. Here, to probe the factor affecting the site and level of halogenation, gene inactivation and heterologous expression were carried out in Actinoplanes sp. ATCC33076 by homologous recombination. Metabolite analysis confirmed that ram20 encodes the only halogenase in ramoplanin biosynthetic pathway, and enduracidin halogenase End30 could heterologously complement the ram20-deficient mutant. Additionally, the mannosyltransferase-deficient mutant produces a dichlorinated ramoplanin aglycone with the halogenation site at Hpg(13). This study has refined our understanding of how halogenation occurs in ramoplanin biosynthetic pathway, and lays the foundation for further exploitation of ramoplanin and enduracidin halogenase in combinatorial biosynthesis.


External fixator use in comminuted gunshot fractures of the proximal phalanx.
Comminuted low velocity gunshot fractures of the proximal phalanx were stabilized with an external fixator in 15 patients. This device was found to be useful. It allowed healing of the fracture in good alignment in 13 patients. And motion of the metacarpophalangeal joint was preserved.


Preparation of rotigotine-loaded microspheres and their combination use with L-DOPA to modify dyskinesias in 6-OHDA-lesioned rats.
To prepare rotigotine loaded microspheres (RoMS) to achieve continuous dopaminergic stimulation (CDS) for the treatment of Parkinson's disease (PD) and investigate both the therapeutic benefit and inducibility of AIMs of administration of RoMS combination with L-DOPA in 6-OHDA-leisioned rats. Rotigotine was encapsulated into poly(lactic-co-glycolic acid) (PLGA) microspheres by an oil-in-water emulsion solvent evaporation technique. In vitro characteristics and in vivo pharmacokinetics of RoMS either in rat blood or brain (by microdialysis) were investigated. Contraversive rotations and AIMs were observed to investigate the therapeutic benefit and the propensity to induce dyskinesia of RoMS or RoMS combination with L-DOPA in 6-OHDA-lesioned rats. RoMS displayed continuous-release characteristics of rotigotine in animals and exhibited a steady efficacy lasted for 2 weeks in 6-OHDA-lesioned rats. No significant difference of the therapeutic benefit between the treatment of RoMS and pulsatile L-DOPA combination and mono L-DOPA was found. While the dyskinesia was significantly decreased with the treatment of RoMS and pulsatile L-DOPA combination compared to mono L-DOPA. RoMS could supply an alternative of CDS for the treatment of PD and the study indicates a potential advantage of RoMS for the treatment of mild and advanced PD patient in combination with L-DOPA.


When does risk outweigh reward? Identifying potential scoring strategies with netball's new two-point rule.
Changing rules to promote scoring through more 'high-risk' play has become common in team sports. Australia's national netball league (i.e. Suncorp Super Netball) has recently taken this approach-introducing a two-point shooting rule. Teams will be awarded two-points for shots made from an 'outer circle' 3.0m-4.9m from the goal in the final five minutes of quarters. We sought to answer a series of questions regarding the implementation and potential strategies surrounding the two-point rule in Suncorp Super Netball. We used video coded data from the 2018 Suncorp Super Netball season to identify the total number of made and missed shots from different distances across the season. We also used shooting statistics from recent Fast5 Netball World Series (a competition with a two-point shooting rule already in place) as a comparator. The reward of two-points is relatively well-aligned to the relative risk of missing shots from the proposed outer versus inner circle (2.22 [1.98, 2.48 95% CIs]) based on existing shooting data from Suncorp Super Netball teams. We found that the relative risk of missing shots from 'long-' (i.e. 3.5m-4.0m) versus 'mid-range' (i.e. 3.0-3.5m) was only slightly elevated (1.52 [1.21, 1.86 95% CIs])-suggesting teams should favour long- over mid-range shots when the two-point shot is available. Based on the typical number of shots a team receives in a five-minute period, we found that teams may be able to score ~3.51 extra points per quarter when taking all versus no-shots from the two-point outer circle. Analysis of the Fast5 versus Suncorp Super Netball data did, however, reveal that shooting accuracy from long-range may decrease when a two-point shot is available. Teams may need to consider situational factors (e.g. altered opposition defensive strategies) when developing their shooting strategy for taking advantage of the two-point shot.


The role of neutrophil chemotactic cytokines in the pathogenesis of equine chronic obstructive pulmonary disease (COPD).
Chronic obstructive pulmonary disease (COPD) is defined as a chronic obstructive inflammatory disease affecting the small airways associated with hay dust exposure (Lowell, F.C., 1964. Observation on heaves. An asthma like syndrome in the horse, J. Allergy 35, 322-330). The disease corresponds histopathologically to a chronic bronchiolitis (Gerber, H., 1973. Chronic pulmonary disease in the horse, Equine Vet. J. 5, 26-33; Winder, N.C., Grünig, G., Hermann, M., Howald, B., von Fellenberg, R., 1989. Comparison of respiratory secretion cytology and pulmonary histology in horses, J. Vet. Med., A36, 32-38) and is mainly characterized by the presence of neutrophil granulocytes in the small bronchioles. Around 12-50% of all horses in Europe and the northern United States suffer from this disease (Mc Pherson, E.A., Lawson, G.H.K., Murphy, J.R., Nicholson, J.M., Fraser, J.A., Breeze, R.G., Pirie, H.M., 1978. Chronic obstructive pulmonary disease (COPD): Identification of affected horses, Eq. Vet. J. 10, 47-53; Larson, V.L., Busch, R.H., 1985. Equine tracheobronchial lavage: Comparison of lavage cytologic features in horses with chronic obstructive pulmonary disease, Am. J. Vet. Res., 46, 144-146; Bracher, V., von Fellenberg, R., Winder, N.C., Grünig, G., 1991. An investigation of the incidence of chronic obstructive pulmonary disease (COPD) in random populations of swiss horses, Equine Vet. J. 23, 136-141). The number of neutrophils in the bronchoalveolar lavage (BAL) and in tracheobronchial secretions (TBS) correlates with the severity of the disease. The present study is focused on the mechanisms which lead to the infiltration of neutrophil granulocytes in the lung of horses. We found that: (1). A strong chemotactic activity in the BAL fluid is associated with high levels of dust exposition. (2). In vitro stimulated alveolar macrophages have impaired phagocytosis efficiency and secrete two chemo-attractants specific for neutrophil granulocytes: Interleukin-8 (IL-8) (Wuyts, A., Proost, P., Put, W., Lenaerts, J.-P., Paemen, L., van Damme, J., 1994. Leucocyte recruitment by monocyte chemotactic proteins (MCPs) secreted by human phagocytes, J. Immunol. Meth. 174, 237-247) and macrophage inflammatory protein-2 (MIP-2) (Wolpe, S.D., Sherry, B., Juers, D., Davatelis, G. Yurt, R.W., Cerami, A., Identification and characterisation of macrophage inflammatory protein-2, Proc. Natl. Acad. Sci. USA 86, 612-616; Tekamp-Olson, P., Gallegos, C., Bauer, D., 1990. Cloning and characterisation of cDNAs for murine macrophage inflammatory protein-2 and its human homologues, J. Exp. Med., 172, 911-927; Driscoll, K.E., 1994. Macrophage inflammatory proteins: Biology and role in pulmonary inflammation. Exp. Lung Res., 20, 473-490). This is associated with the appearance of chemotactic activity in the supernatant. These data confirmed our working hypothesis that bronchiolar neutrophilia may be the consequence of a (over)stimulation of pulmonary macrophages leading to expression of cytokines chemotactic for neutrophil granulocytes.


Sociocultural and identity predictors of body dissatisfaction in ethnically diverse college women.
Emerging research suggests that ethnic identity and American identity are associated with mental health in ethnic minorities and European Americans, respectively. Furthermore, although ethnic identity is associated with diminished body dissatisfaction in minority women, the relationship between American identity and body dissatisfaction is unexplored in all ethnic groups. Accordingly, this study examined the relationships among ethnic identity, American identity, thin-ideal internalization, pressures for thinness, and body dissatisfaction in 1018 ethnically diverse college women. Ethnic identity negatively predicted body dissatisfaction for African Americans, and attenuated the relationship between pressures for thinness and body dissatisfaction for African Americans and Asian Americans, but not European Americans or Latina Americans. Results for American identity were inconclusive. Findings suggest that ethnic identity may be a protective factor against eating pathology for Asian American and African American women.


Radiation-induced pulmonary endothelial dysfunction in rats: modification by an inhibitor of angiotensin converting enzyme.
The ability of the angiotensin converting enzyme (ACE) inhibitor Captopril to modify radiation-induced pulmonary endothelial dysfunction was determined in male rats sacrificed 2 months after a single dose of 10-30 Gy of 60Co gamma rays to the right hemithorax. Half of each dose group consumed feed containing 0.12% w/w Captopril (60 mg/kg/day) continuously after irradiation, and half consumed control feed. Four markers of endothelial function were monitored: ACE activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. All data were plotted as dose-response curves, and subjected to linear regression analysis. The Captopril modifying effect was expressed as the ratio of isoeffective doses at a common intermediate response (DRF), or as the ratio of the response curve slopes. Right lung ACE and PLA activity decreased linearly, and PGI2 and TXA2 production increased linearly with increasing radiation dose. Captopril exhibited DRF values of 1.4-2.1, and slope ratios of 1.4-5.1 for all four functional markers (p less than 0.05). Thus, the ACE inhibitor Captopril ameliorates radiation-induced pulmonary endothelial dysfunction in rats sacrificed 2 months postirradiation. Although the mechanism of Captopril action is not clear at present, these data suggest a novel application for this class of compounds as injury-modifying agents in irradiated lung.


The expression of I-Ed molecules in F1 hybrid mice detected with antigen-specific, I-Ed-restricted cloned T-cell lines.
The expression of polymorphic determinants on I-E molecules is largely dependent on allelic variation in the E beta chain. We have previously analyzed the expression of Ek beta and Eb beta chains in F1 hybrid mice by a combination of techniques, and have shown that functional variation detected by the responsiveness of cloned T-cell lines specific for these molecules correlates well with serological determination of E beta expression. In the present study, we have extended our analysis to Ed beta expression in F1 hybrid mice. We show that Ed beta is relatively poorly expressed in three F1 combinations: H-2d X H-2b, H-2d X H-2s, and H-2d X H-2u. The former two crosses express E alpha chains from the H-2d parent only; when recombinant strains carrying Eb beta or Es beta and an active E alpha gene are used, Ed beta expression is significantly increased. On the other hand, H-2u mice synthesize E alpha chains; the poor expression of Ed beta chains in this F1 hybrid apparently reflects the strong preferential association of Eu beta chains with all E alpha molecules thus far analyzed. These results confirm that E beta chains compete for binding to E alpha chains and that preferential association of different allelic forms of E beta chains with E alpha chains is a generalized phenomenon. They also illustrate the importance of the rate of biosynthesis of Ia chains for cell-surface expression.


Development of a conventional immunochemical detection system for determination of Nδ-(5-hydro-5-methyl-4-imidazolone-2-yl)-ornithine in methylglyoxal-modified proteins.
Methylglyoxal (MGO) produced during glycolysis is known to react with arginine residues on proteins to generate advanced glycation end products, such as Nδ-(5-hydro-5-methyl-4-imidazolone-2-yl)-ornithine (MG-H1). Since the production of MGO is increased during hyperglycemia or metabolic disorders in vivo, it is considered that the measurement of MG-H1 is useful for evaluating abnormalities in carbohydrate metabolism. Thus, we prepared a monoclonal antibody against MG-H1 to develop a conventional measurement system for MG-H1. Reactivity and specificity of the antibody to MGO-modified protein were confirmed by enzyme-linked immunosorbent assay and western blotting, respectively. The measurement of MG-H1 content by the antibody was positively correlated with that by electrospray ionization-liquid chromatography-tandem mass spectrometry and the ratio of modified arginine residues by amino acid analysis. Our results demonstrated that immunochemical methods could be useful for the estimation of MG-H1 content in modified proteins.


Sarcoidosis presenting as multilobular limbal corneal nodules.
To review reported external ocular manifestations of sarcoidosis and to present bilateral, multilobular, nodular, limbal, corneal nodules as being a unique manifestation of the disease. A 16-year-old Saudi girl presented with bilateral, multilobular, solid, limbal nodules, with a vascular supply from the conjunctival vessel, and associated membraneous conjunctivitis and healed trachoma. The Schirmer's test revealed less than 2 mm in both eyes with tear meniscus less than 2 mm. Biopsy of an associated palpebral conjunctival nodule was performed, in addition to a gallium scan, chest X-ray, and a serum angiotensin-converting enzyme (SACE) level. The culture showed beta-hemolytic streptococci. Gallium scan showed intake by both lacrimal glands. Her chest X-ray results were normal, as was the SACE level. Biopsy of the excised conjunctival nodule disclosed a noncaseating granulomatous reaction with epithelioid and giant cells, and chronic inflammatory cell infiltrate confirming a diagnosis of sarcoidosis. A multilobular, nodular, perilimbal mass as a unique manifestation of sarcoidosis is presented. A streptococcal membraneous conjunctivitis and healed trachoma superimposed. A review of sarcoidosis of the external eye is included.


Recent trends and developments on integrated biochemical conversion process for valorization of dairy waste to value added bioproducts: A review.
In this review article, discuss the many ways utilized by the dairy sector to treat pollutants, emphasizing their influence on the quality and efficiency with which contamination is removed. It focuses on biotechnology possibilities for valorizing dairy waste in particular. The findings revealed that dairy waste may be treated using physicochemical, biological, and biotechnological techniques. Notably, this article highlighted the possibility of dairy waste being used as a feedstock not only for the generation of biogas, bioethanol, biohydrogen, microbial fuel cells, lactic acid, and fumaric acid via microbial technology but also for the production of biooil and biochar by pyrolysis. In addition, this article critically evaluates the many treatment techniques available for recovering energy and materials from dairy waste, their combinations, and implementation prospects. Valorization of dairy waste streams presents an opportunity to extend the dairy industry's presence in the fermented functional beverage sector.


Hyphomicrobium album sp. nov., isolated from mountain soil and emended description of genus Hyphomicrobium.
A soil bacterium, designated XQ2T, was isolated from Lang Mountain in Hunan province, P. R. China. The strain is Gram stain negative, facultative anaerobic, and the cells are motile and rod-shaped. The 16S rRNA gene sequence of strain XQ2T shared the highest similarities with Hyphomicrobium sulfonivorans S1T (97.1%), Pedomicrobium manganicum ACM 3038T (95.9%) and Hyphomicrobium aestuarii DSM 1564T (95.4%) and grouped with H. sulfonivorans S1T. The average nucleotide identity (ANI) values and the DNA-DNA hybridization (dDDH) values between strain XQ2T and H. sulfonivorans S1T were 86.6% and 55.4% respectively. Strain XQ2T had a genome size of 3.91 Mb and the average G+C content was 65.1%. The major fatty acids (> 5%) were C18:1ω6c, C18:1ω7c, C19:0 cyclo ω8c, C16:0 and C18:0. The major respiratory quinone was Q-9 (82.8%) and the minor one was Q-8 (17.2%). The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, unidentified phospholipid and two unidentified lipids. On the basis of phenotypic, chemotaxonomic and phylogenetic characteristics, strain XQ2T represents a novel species of the genus Hyphomicrobium, for which the name Hyphomicrobium album sp. nov. is proposed. The type strain is XQ2T (= KCTC 82378T = CCTCC AB 2020178T). The genus description is also emended.


Loss of PTEN is associated with progression to androgen independence.
Progression to a lethal androgen-independent (AI) stage of advanced prostate cancer is a critical clinical obstacle limiting patient survival. PTEN inactivation is frequently observed in advanced prostate cancer and correlates with a poor prognosis. However, the functional significance of PTEN inactivation in AI progression has not been demonstrated. PTEN expression was examined in benign, hormone naïve and AI human prostate cancer specimens, and in recurrent AI Shionogi tumors. The effect of antisense oligonucleotide (ASO)-mediated PTEN downregulation in AI progression of the Shionogi tumor model was determined. Significantly reduced PTEN expression was observed in AI versus benign and hormone naïve prostate tumors. Seven of 14 AI Shionogi tumors exhibited marked downregulation or complete loss of PTEN. ASO-mediated PTEN inhibition reduced androgen-withdrawal induced regression of Shionogi tumors and accelerated AI progression. These data suggest that PTEN inactivation may play a role in progression to androgen independence.


Tolerance to the neurotoxic effects of methamphetamine in young rats.
The present study examined whether exposure to methamphetamine during adolescence (as determined in post-natal day 40 rats) might alter its effects when used in young adulthood (as assessed in post-natal day 90 rats). Results confirm that high-dose methamphetamine administration (4x10 mg/kg/injection, s.c., 2-h intervals) decreases striatal dopamine uptake and transporter ligand binding in post-natal day 90 rats; effects that were blocked if animals received six biweekly methamphetamine pretreatments (15 mg/kg; s.c.) beginning at post-natal day 40. This neuroprotection was not likely due to pharmacokinetic tolerance, since brain methamphetamine concentrations did not differ 1 h after the high-dose methamphetamine regimen among treated rats regardless of pretreatment. The methamphetamine biweekly pretreatment attenuated the hyperthermia caused by the neurotoxic methamphetamine regimen; a phenomenon that may have contributed to the neuroprotection.


Prevalence, risk factors, management, and treatment outcomes of first-line antituberculous drug-induced liver injury: a prospective cohort study.
Antituberculosis drug-induced liver injury (ATDILI) is one of the most deleterious side effects associated with chemotherapy against tuberculosis (TB). In this study, our objective was to determine the incidence, risk factors, and management of ATDILI and analyze its impact on the treatment outcome in patients receiving standard anti-TB chemotherapy. A prospective cohort study of ATDILI prevalence was conducted in 938 enrolled patients of the 1426 TB cases in Shanghai from March 2011 to September 2012. Patients were followed up until February 2014. Univariate and multivariate logistic regression analyses were used to determine the risk factors of ATDILI. Successful therapeutic outcome, rates of drug resistance conversion, sputum smear/culture conversion, and lung cavity closure were analyzed. Hepatitis B surface antigen/hepatitis B e antigen-positive hepatitis B carriers, complicated with systemic lupus erythematosus, albumin ≤ 25 g/L, and chronic alcoholism were independent risk factors for ATDILI. Of the 121 cases with ATDILI (incidence rate of 12.9%), 84 (69.4%) used modified anti-TB therapy after recovery of liver function. Compared with the non-ATDILI group, patients with ATDILI exhibited remarkably decreased lung cavity closure rate (84.6% vs. 93.0%, P < 0.001) along with significantly reduced sputum smear/culture conversion rate (85.4% vs. 94.0%, P < 0.001). Our findings indicated that 12.9% patients developed ATDILI during standard anti-TB therapy, resulting in poor therapeutic outcome. Hepatitis B carriers with systemic lupus erythematosus, albumin ≤ 25 g/L, and chronic alcoholism manifested increased risks for ATDILI. Copyright © 2016 John Wiley & Sons, Ltd.


Endoscopic electrosurgical polypectomies of the upper gastrointestinal tract.
The electrosurgical removal of polypoid lesions from the upper gastrointestinal tract with the esophagogastroduodenoscope has proven to be safe, effective and relatively inexpensive procedure. Thirty polypectomies performed on 26 different patients are presented. Polyps were removed from the distal esophagus, stomach, duodenum and jejunum. There were no significant complications.


Enhanced fluorescence of silver nanoclusters stabilized with branched oligonucleotides.
DNA stabilized silver nanoclusters (AgNCs) are promising optical materials, whose fluorescence properties can be tuned by the selection of the DNA sequence employed. In this work we have used modified oligonucleotides in the preparation of AgNCs. The fluorescent intensity obtained was 60 times higher than that achieved with standard oligonucleotides.


Evaluation of Revogene® Carba C assay for the rapid detection of carbapenemase genes in gram-negative pathogens.
The rapid detection of carbapenemase-producing microorganisms is crucial for clinical and infection control purposes. Here we evaluated Revogene®Carba C assay on 154 carbapenemase-producing and -nonproducing Gram-negatives. Up to 8 samples per 70 minutes were processed by Revogene®Carba C assay which showed excellent performances with 100% sensitivity, 99.5% specificity,100% NPV, and 97.8% positive predictive value.


Interaction of plant pigment brazilin with synthetic and natural DNA: spectroscopic and in silico perspective.
The interactions between the molecules and DNA shape up an avenue for DNA targeted therapeutics. For the first time, brazilin, a major component of Caesalpinia sappan L., has been investigated for its interaction with natural and synthetic DNA. Detailed analyses of the binding property of brazilin dye with DNA by UV-vis, FTIR and Circular Dichroism were carried out. In addition, in silico studies have been conducted via tools of energy minimization and ligand optimization using Yasara and Argus Lab softwares along with the molecular docking server integrating Auto Dock, Mavin and Mopac. Results show that brazilin dye has commendable proficiency in being moulded as a binder with DNA. The specificity of the dye to stain nuclei in tissue sections positively indicates its interaction with nucleic acid. As the intracellular target for the majority of anticancer and antibiotic drugs is DNA, the study on the interaction between molecules like brazilin and DNA has great significance and implications in several biological applications.


Genetic analysis of a ganciclovir-resistant human cytomegalovirus mutant.
We isolated a ganciclovir (GCV)-resistant human cytomegalovirus (HCMV) from a laboratory strain, AD169, and analysed the mutant. Attempts were also made to identify directly the mutated gene. The 50% inhibitory concentration (IC50) of GCV for the mutant strain was five times higher than that of the wild-type strain. The mutant strain showed similar sensitivity to phosphonoacetic acid and cidofovir as the wild-type strain. These data suggest mutation in the UL97 gene encoding for the phosphotransferase that phosphorylates GCV. Molecular analysis of the mutant strain revealed that a single base substitution of adenine by cytosine occurred at the 1796 nucleotide position of the UL97 gene region, resulting in the substitution of lysine by threonine at codon 599 in the UL97 gene product. Marker transfer experiment confirmed that this mutation conferred HCMV resistance to GCV. The mutation at codon 599 was easily identified by means of RsaI digestion of the selected PCR product.


Regenerative endodontic treatment of an immature permanent tooth at an early stage of root development: a case report.
Regenerative endodontic treatment (RET) has been used in treating nonvital immature permanent tooth whose root formation ranged from approximately two-thirds of the full root length to almost completely developed root with open apex at least 1.1 mm in diameter according to the reported cases. However, this case report was to introduce RET in an affected tooth at an early stage of root development. The premolar #29 in an 8-year-old girl had pulpal necrosis and apical periodontitis caused by the fracture of dens evaginatus. Its root was at the beginning of formation. Copious hemorrhagic drainage was observed after preparing of an access cavity. The canal was irrigated with 3% NaOCl solution, sterile normal saline, and chlorhexidine. Root dressing with triple antibiotic was then performed and left for 4 weeks. We used a K-file to create bleeding into the canal after flushing and drying the root canal. Mineral trioxide aggregate was carefully placed over the formed blood clot. Clinical examination at 1, 3, 6, 9, and 12 months revealed an asymptomatic tooth. Radiographic examination revealed resolution of periapical radiolucency, increased thickening of the canal wall, and lengthening of the root, which demonstrated the continual development of the tooth root. Noticeably, the first-month postoperative radiograph showed radiopaque image in the root canal like an isolated island, which was gradually obvious during follow-up. Cone-beam computed tomography revealed that the calcification was attached with dentin wall in buccolingual direction, and the root canal was not completely obliterated. RET is feasible for a tooth at an early stage of root development that has necrotic pulp and periapical lesion.


Avian metapneumovirus subtype A in China and subtypes A and B in Nigeria.
In order to detect and characterize avian metapneumovirus, organs or swabs were collected from 697 chicken and 110 turkeys from commercial farms in Southwestern Nigeria and from 107 chickens from live bird markets in Southeastern China. In Nigeria, 15% and 6% of the chicken and turkey samples, respectively, and 39% of the chicken samples from China, were positive for aMPV genome by PCR. The sequence of a 400 nt fragment of the attachment protein gene (G gene) revealed the presence of aMPV subtype A in both Nigeria and Southeastern China. Essentially identical subtype A viruses were found in both countries and were also previously reported from Brazil and the United Kingdom, suggesting a link between these countries or a common source of this subtype. In Nigeria, subtype B was also found, which may be a reflection of chicken importations from most major poultry-producing countries in Europe and Asia. In order to justify countermeasures, further studies are warranted to better understand the metapneumoviruses and their impact on poultry production.


Sensitivity and specificity of high frequency ultrasound score (DCEC) in diabetic peripheral neuropathy.
To summarize the ultrasonic characteristics of peripheral nerve damage in type 2 diabetes and to verify the diagnostic value of DCEC score for DPN. A total of 289 patients with type 2 diabetes evaluated peripheral neuropathy with neuroultrasound and nerve conduction at the Affiliated Hospital of Guizhou Medical University from June 2016 to June 2020. According to the diagnostic criteria from 2017 guidelines of China, 289 patients with type 2 diabetes were divided into three groups: DPN group: 203 cases; subclinical group: 48 cases; and non-DPN group: 38 cases. Kruskal Wallis test was used to identify the differences and characteristics of ultrasound scores between the all groups. The best cut-off value, sensitivity and specificity of DCEC score were obtained by receiver operator characteristic curve. Taking the diagnostic standard of diabetes peripheral neuropathy as the "gold standard", the best diagnostic threshold, sensitivity and specificity were obtained by drawing the ROC curve of DCEC score, and then the diagnostic value of DCEC score for DPN was verified. Compared with non-DPN group, DCEC score in DPN group was significantly higher (P < 0.05). Otherwise,according to the ROC curve, the best cut-off value of DCEC score for DPN diagnosis was 12.5 (sensitivity 69.7%, specificity 71.1%). The DCEC score system can effectively diagnose DPN with length-dependence,mainly including the increase of definition score.


Searching for information on chemical substances in selected biomedical bibliographic databases.
A method was developed which allows effective searching for information on chemical substances in databases. Several searches for chemicals in bibliographic databases were carried out to analyse the method of indexing chemical names. The recall rates of documents were compared to evaluate information resources as well as searching strategies. Recall rates of documents searched with the CAS Nos. were compared to those searched with substance name. It turned out that searching for substances is most specific and fastest with CAS Nos. They should always be used whenever possible. However, this is not sufficient in many BDs, making an additional search using chemical names necessary. Specific search options that have to be considered for each database are reported.


Impact of optical coherence tomography findings on clinical outcomes in ST-segment elevation myocardial infarction patients: a MATRIX (Minimizing Adverse Hemorrhagic Events by Trans-radial Access Site and angioX) OCT sub-study.
To investigate the association of the degree of stent expansion, as assessed by optical coherence tomography (OCT), following stent implantation, and clinical outcomes in ST-segment elevation myocardial infarction (STEMI) patients. STEMI patients from the MATRIX (Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and angioX) OCT study were selected; Clinical outcomes were collected through 1 year. Stent expansion index is a minimum stent area (MSA) divided by average lumen area (average of proximal and distal reference lumen area). The following variables were measured: MSA (< 4.5mm2), dissection (> 200 µm in width and < 5 mm from stent segment), malapposition (> 200 µm distance of stent from vessel wall), a thrombus (area > 5% of lumen area) were compared. A total of 151 patients were included; after excluding patients with suboptimal OCT quality, the population with available OCT was classified into 2 groups: under-expanded < 90% (N = 72, 51%) and well-expanded ≥ 90% (N = 67, 49%). In the well-expanded group, a significant number of the proximal vessels had a lumen area < 4.5mm2 (16.1%, p < 0.001) and a greater thrombus burden within stent (56.7%, p = 0.042). The overall 30 day and 1 year major adverse cardiovascular event (MACE) rates were 5% and 6.1%, respectively. Irrespective of the degree of stent expansion, the OCT findings, in STEMI patients, and the MACE at 30 days and one year follow up was low; further, well-expanded stents led to a more significant residual thrombotic burden within the stent but seemed to have insignificant clinical impact. Acknowledged stent optimization criteria, traditionally related to worse outcomes in stable patients, do not seem to be associated with worse outcomes in this STEMI population.


Meibomian gland dysfunction and ocular discomfort in video display terminal workers.
Meibomian gland dysfunction (MGD) is one of the most common ocular disorders encountered in clinical practice. The clinical manifestations of MGD are related to the changes in the tear film and ocular surface with symptoms of ocular discomfort. In recent years, many surveys have evaluated symptoms associated with the use of Video Display Terminals (VDT), and VDT use is recognized as a risk factor for eye discomfort. The aim of the present study was to determine if the presence of MGD contributes to the signs and symptoms of ocular discomfort during the use of VDT. In course of a routine health surveillance programme, a group of 70 subjects fulfilled the inclusion criteria and responded to a questionnaire about symptoms of ocular discomfort. The following ocular tests were performed: tear break-up time, fluorescein corneal stain, and basal tear secretion test. A total of 52 subjects out of 70 (74.3%) had MGD. A statistically significant correlation between the symptoms of ocular discomfort and hours spent on VDT work was observed in the total population (r=0.358; P=0.002; 95% CI 0.13-0.54) and in the group of subjects with MGD (r=0.365; P=0.009; 95% CI 0.103-0.58). Such correlation was not shown in subjects without MGD. The high prevalence of MGD among the subjects with symptoms of ocular discomfort suggests that this diagnosis should be considered when occupational health practitioners encounter ocular complaints among VDT operators. It appears that MGD can contribute to the development of ocular discomfort in VDT operators.


[1.3-Dipolar cycloaddition products of 8-azidotetrazol[1,5a][1,8]naphthyridines with alkynes].
A series of new 1,2,3-triazol derivatives, obtained by reaction of 8-azidotetrazol[1,5-a][1,8]naphthyridine with alkynes, is described. Some of the tested compounds showed activity against hypoxia in mice.


Urinary phthalate metabolites in primary school starters in Pearl River Delta, China: Occurrences, risks and possible sources.
Assessment of children's exposure risks of phthalates before puberty is important, as phthalates are ubiquitous and are associated with reproductive development. However, relevant data in Pearl River Delta, China are scarce. Nineteen phthalate metabolites were analyzed in urine samples from 1490 primary school starters (6-8 years old) recruited in 2016-2017 using ultra-performance liquid chromatography and tandem mass spectrometry (UHPLC-MS/MS). Nine phthalate metabolites were detected more than 80% of the urine samples. Monobutyl phthalate (MnBP) was the highest metabolite (median, 212 μg/g creatinine), followed by two short chained phthalate metabolites, four secondary metabolites of di(2-ethylhexyl) phthalate (DEHP), and the primary metabolites of DEHP. The MnBP level was the third highest of those reported worldwide while other metabolites were in the lower range compared with previous studies. Significantly positive associations were found between urinary metabolite levels and family income as well as parent education levels (p < 0.05). Duration since the latest interior decoration was inversely associated with phthalate metabolites (p < 0.05). Significantly positive associations had also been found between the frequency of eating takeaway food and four DEHP metabolites (p < 0.01). The geometric mean of estimated daily intake (EDI) of di-n-butyl phthalate (DnBP), DEHP, di-iso-butyl phthalate (DiBP), dimethyl phthalate, diethyl phthalate and butylbenzyl phthalate (BBzP) were 6.24, 2.67, 1.06, 0.64, 0.44, and 0.01 μg/kg bw/day, respectively. Hazard quotient (HQ) was defined as the ratio of EDI and the tolerable daily intake (TDI). Approximately 38% children had HQ DnBP >1 indicating potential reproductive risks caused by DnBP. To evaluate cumulative exposure risks, hazard index (HI) was calculated as the sum of the HQs of DnBP, DiBP, DEHP, and BBzP. Nearly 48% children had HI > 1 suggesting extremely high cumulative risks in children in Pearl River Delta, China. To our best knowledge, this was the largest study on evaluating phthalate exposure among children in China.


Flow field mapping by multi-zone adiabatic passage excitation.
This paper describes a robust method for flow field mapping by multi-zone adiabatic fast passage (AFP). It provides a quick and simple way to simultaneously acquire flow profiles at several locations and arbitrary orientations inside the field-of-view. The flow profile is the time-averaged evolution of the labeled flowing material. Results obtained using a carotid bifurcation and jet phantoms are similar to the previous experimental studies employing Laser Doppler Anemometry (LDA), and other flow visualization techniques. In addition, the preliminary results obtained with a human volunteer support the feasibility of the technique for in vivo flow quantification.


The role of pulmocutaneous baroreceptors in the control of lymphatic heart rate in the toad Bufo marinus.
The influence of increased pulmocutaneous arterial systolic pressure on amphibian lymph heart activity was determined in Bufo marinus. Arginine vasotocin-induced increases in systolic arterial pressure of greater than 0.5 kPa significantly (P<0.0002) decreased lymph heart rate. Denervation of the recurrent laryngeal nerve led to an increase in arterial pressure of 3.88 kPa in test animals compared to control animals. Denervation abolished lymph heart response to increased arterial pressure for an average of 38 min. Direct stimulation to the recurrent laryngeal nerve stopped lymph heart activity without an increase in arterial pressure. These data indicate that baroreceptors in the pulmocutaneous artery can decrease lymph heart rate during periods of either direct stimulation or elevated arterial pressure. The data also support lymph hearts as effectors for aortic and carotid baroreceptors.


EARL compliance measurements on the biograph vision Quadra PET/CT system with a long axial field of view.
Our aim was to determine sets of reconstruction parameters for the Biograph Vision Quadra (Siemens Healthineers) PET/CT system that result in quantitative images compliant with the European Association of Nuclear Medicine Research Ltd. (EARL) criteria. Using the Biograph Vision 600 (Siemens Healthineers) PET/CT technology but extending the axial field of view to 106 cm, gives the Vision Quadra currently an around fivefold higher sensitivity over the Vision 600 with otherwise comparable spatial resolution. Therefore, we also investigated how the number of incident positron decays-i.e., exposure-affects EARL compliance. This will allow estimating a minimal acquisition time or a minimal applied dose in clinical scans while retaining data comparability. We measured activity recovery curves on a NEMA IEC body phantom filled with an aqueous 18F solution and a sphere to background ratio of 10-1 according to the latest EARL guidelines. Reconstructing 3570 image sets with varying OSEM PSF iterations, post-reconstruction Gaussian filter full width at half maximum (FWHM), and varying exposure from 59 kDecays/ml (= 3 s frame duration) to 59.2 MDecays/ml (= 1 h), allowed us to determine sets of parameters to achieve compliance with the current EARL 1 and EARL 2 standards. Recovery coefficients (RCs) were calculated for the metrics RCmax, RCmean, and RCpeak, and the respective recovery curves were analyzed for monotonicity. The background's coefficient of variation (COV) was also calculated. Using 6 iterations, 5 subsets and 7.8 mm Gauss filtering resulted in optimal EARL1 compliance and recovery curve monotonicity in all analyzed frames, except in the 3 s frames. Most robust EARL2 compliance and monotonicity were achieved with 2 iterations, 5 subsets, and 3.6 mm Gauss FWHM in frames with durations between 30 s and 10 min. RCpeak only impeded EARL2 compliance in the 10 s and 3 s frames. While EARL1 compliance was robust over most exposure ranges, EARL2 compliance required exposures between 1.2 MDecays/ml to 11.5 MDecays/ml. The Biograph Vision Quadra's high sensitivity makes frames as short as 10 s feasible for comparable quantitative images. Lowering EARL2 RCmax limits closer to unity would possibly even permit shorter frames.


Cardiovascular responses to static handgrip exercise and postexercise ischemia in heart failure with preserved ejection fraction.
Heart failure with preserved ejection fraction (HFpEF) is characterized by reduced ability to sustain physical activity that may be due partly to disease-related changes in autonomic function that contribute to dysregulated cardiovascular control during muscular contraction. Thus, we used a combination of static handgrip exercise (HG) and postexercise ischemia (PEI) to examine the pressor response to exercise and isolate the skeletal muscle metaboreflex, respectively. Mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), and total peripheral resistance (TPR) were assessed during 2-min of static HG at 30 and 40% of maximum voluntary contraction (MVC) and subsequent PEI in 16 patients with HFpEF and 17 healthy, similarly aged controls. Changes in MAP were lower in patients with HFpEF compared with controls during both 30%MVC (Δ11 ± 7 vs. Δ15 ± 8 mmHg) and 40%MVC (Δ19 ± 14 vs. Δ30 ± 8 mmHg), and a similar pattern of response was evident during PEI (30%MVC: Δ8 ± 5 vs. Δ12 ± 8 mmHg; 40%MVC: Δ13 ± 10 vs. Δ18 ± 9 mmHg) (group effect: P = 0.078 and P = 0.017 at 30% and 40% MVC, respectively). Changes in HR, CO, and TPR did not differ between groups during HG or PEI (P > 0.05). Taken together, these data suggest a reduced pressor response to static muscle contractions in patients with HFpEF compared with similarly aged controls that may be mediated partly by a blunted muscle metaboreflex. These findings support a disease-related dysregulation in neural cardiovascular control that may reduce an ability to sustain physical activity in HFpEF.NEW & NOTEWORTHY The current investigation has identified a diminution in the exercise-induced rise in arterial blood pressure (BP) that persisted during postexercise ischemia (PEI) in an intensity-dependent manner in patients with heart failure with preserved ejection fraction (HFpEF) compared with older, healthy controls. These findings suggest that the pressor response to exercise is reduced in patients with HFpEF, and this deficit may be mediated, in part, by a blunted muscle metaboreflex, highlighting the consequences of impaired neural cardiovascular control during exercise in this patient group.


Spatio-temporal neighborhood impacts on internalizing and externalizing behaviors in U.S. elementary school children: Effect modification by child and family socio-demographics.
Increasing evidence from experimental and non-experimental research has shown that children residing in disadvantaged neighborhoods exhibit greater levels of internalizing and externalizing behaviors, above and beyond individual characteristics, and family or school contexts. Using the ECLS-K, a nationally representative, longitudinal survey of U.S. school children, this study examined direct neighborhood effects on internalizing (N = 14,870; N = 10,610) and externalizing (N = 14,960; N = 10,730) behaviors at the beginning and end of elementary school. Using IPTW propensity scores to mitigate selection bias and ordinary least squares regression, we examined direct neighborhood effects when children were 7 years old (1st grade) and when they were 11 years old (5th grade). We also examined neighborhood effect modification by child child race/ethnicity, sex, family structure, and family SES. Both the direct effect and effect modification models indicated that living in disadvantaged neighborhoods had no impact on either internalizing or externalizing behaviors at the beginning of elementary school (age 7). At the end of elementary school (age 11), we found small, yet significant direct neighborhood associations with effect sizes ranging from 0.12 to 0.18 standard deviations. The effect modification analysis revealed that being black (relative to white) was the strongest moderator of the relationship between neighborhood context and internalizing and externalizing behaviors in 5th grade, with effect sizes ranging from 0.27 to 0.59 standard deviations. Being Hispanic in high poverty neighborhoods was found to be protective for externalizing behaviors, suggesting the presence of the Hispanic health paradox. We also found, that in some neighborhood contexts, child sex, family structure, and family socioeconomic status amplified or dampened the effect of neighborhood, but only for externalizing behaviors. These results demonstrate the importance of age-dependent neighborhood effects and that children with different demographic profiles respond differently to the social contexts in which they are exposed.


A point mutation in a type I procollagen gene converts glycine 748 of the alpha 1 chain to cysteine and destabilizes the triple helix in a lethal variant of osteogenesis imperfecta.
Synthesis of type I procollagen was examined in fibroblasts from a proband with a lethal perinatal variant of osteogenesis imperfecta. After trypsin digestion of the type I procollagen, a portion of the alpha 1 (I) chains was recovered as disulfide-linked dimers. Digestion of the protein with vertebrate collagenase and mapping of cyanogen bromide peptides suggested that a new cysteine residue was present between residues 551 and 775 of the alpha 1 (I) chain. Sequencing of cloned cDNAs prepared using mRNA from the proband's fibroblasts demonstrated that some of the clones contained a single base mutation that converted the glycine codon in amino acid position 748 of the alpha 1 (I) chain to a cysteine codon. About 80% of the type I procollagen synthesized by the proband's fibroblasts had a decreased thermal stability. The results, therefore, were consistent with the conclusion that normal pro-alpha 1 (I) chains and pro-alpha 1 (I) chains containing a cysteine residue in the alpha chain domain were synthesized in about equal amounts and incorporated randomly into type I procollagen. However, only about 10% of the alpha 1 (I) chains generated by trypsin digestion were disulfide-linked. Further studies demonstrated a decreased rate of secretion of type I procollagen containing the new cysteine residue and decreased processing of the protein by procollagen N-proteinase in cultures of postconfluent fibroblasts. Both parents were phenotypically normal and their fibroblasts synthesized only normal type I procollagen. Therefore, the mutation in the proband was a sporadic one and is very likely to have caused the connective tissue fragility that produced the lethal phenotype.


Wide Grain 3, a GRAS Protein, Interacts with DLT to Regulate Grain Size and Brassinosteroid Signaling in Rice.
Grain size is a direct determinant of grain weight and yield in rice; however, the genetic and molecular mechanisms determining grain size remain largely unknown. We identified a mutant, wide grain 3 (wg3), which exhibited significantly increased grain width and 1000-grain weight. Cytological analysis showed that WG3 regulates grain size by affecting cell proliferation. MutMap-based gene cloning and a transgenic experiment demonstrated that WG3 encodes a GRAS protein. Moreover, we found that WG3 directly interacts with DWARF AND LOW-TILLERING (DLT), a previously reported GRAS protein, and a genetic experiment demonstrated that WG3 and DLT function in a common pathway to regulate grain size. Additionally, a brassinosteroid (BR) sensitivity test suggested that WG3 has a positive role in BR signaling in rice. Collectively, our results reveal a new genetic and molecular mechanism for the regulation of grain size in rice by the WG3-DLT complex, and highlight the important functions of the GRAS protein complex in plants. WG3 functions directly in regulating grain size and BR signaling in rice.


A systemic review and meta-analysis on the efficacy and safety of ferumoxytol for anemia in chronic kidney disease patients.
To evaluate the efficacy of ferumoxytol, relative to conventional iron supplement formulations, on hemoglobin levels, ferritin level, and adverse event incidence in chronic kidney disease patients. We performed a systematic search of six academic databases (EMBASE, CENTRAL, Scopus, PubMed, Web of sciences, and MEDLINE), adhering to PRISMA guidelines. We performed a meta-analysis on relevant studies to evaluate the overall influence of ferumoxytol, relative to conventional iron supplement formulations, on hemoglobin levels, ferritin level, and treatment related treatment emergent adverse events (TEAEs) incidence in chronic kidney disease patients. Seven eligible studies were identified from a total of 1397 studies. These studies contained data on 3315 participants with chronic kidney disease (mean age: 59.2 ± 4.6 years). A meta-analysis revealed that ferumoxytol administration had positive effects on hemoglobin levels (Hedge's g statistic: 0.51) and ferritin level (0.88), transferrin saturation (0.39). Besides, we also report reduced incidence of treatment related TEAEs (-0.24) for patients consuming ferumoxytol as compared conventional iron supplement formulations. This meta-analysis provides preliminary evidence that ferumoxytol use exerts beneficial effects on the overall hematological outcomes in patients with chronic kidney disease. This study also reports improved treatment related safety profile for ferumoxytol when compared with conventional iron formulations. The findings from this study can have direct implications in forming best practice guidelines for managing anemia in patients with chronic kidney disease.


Indoor physical activity reduces all-cause and cardiovascular disease mortality among elderly women.
The aim of this study was to investigate whether a medium to high degree of total physical activity and indoor physical activity were associated with reduced all-cause and cardiovascular mortality among elderly Korean women. A prospective cohort study was done to evaluate the association between physical activity and mortality. The cohort was made up of elderly (≥ 65 years of age) subjects. Baseline information was collected with a self-administered questionnaire and linked to death certificates retrieved from a database. Cox proportional hazard models were used to estimate the hazard ratios (HRs) with 95% confidence interval (CI) levels. Women who did not suffer from stroke, cancer, or ischemic heart disease were followed for a median of 8 years (n=5079). A total of 1798 all-cause deaths were recorded, of which 607 (33.8%) were due to cardiovascular disease. The group with the highest level of total physical activity and indoor physical activity was significantly associated to a reduced all-cause mortality (HR, 0.60; 95% CI, 0.51 to 0.71 and HR, 0.58; 95% CI, 0.50 to 0.67, respectively) compared to the group with the lowest level of total physical activity and indoor physical activity. Additionally, the group with the highest level of total physical activity and indoor physical activity was significantly associated to a lower cardiovascular disease mortality (HR, 0.53; 95% CI, 0.40 to 0.71 and HR, 0.51; 95% CI, 0.39 to 0.67, respectively) compared to the group with the lowest level of total physical activity and indoor physical activity. Our study showed that regular indoor physical activity among elderly Korean women has healthy benefits.


Clinical Outcomes of Switching to Insulin Glargine 300 U/ml from Other Basal Insulins in People with Type 2 Diabetes in Italy: A Real-World Study.
Primary aim was to provide real-world evidence of the outcomes after the switch to glargine 300 U/ml (Gla-300) from other basal insulins (first or second generation) in Italy. Multicenter, observational, retrospective study based on electronic medical records. Overall, 953 T2DM insulin ± OAD treated people switched to Gla-300 or Gla-100 from January 2015 to July 2018. Three clinically relevant cohorts were identified: patients switching to Gla-300 from first-generation basal insulin (cohort 1), patients switching to Gla-300 from degludec-100 (Deg-100) (cohort 2), and those switching to Gla-100 from any basal insulin (cohort 3). The three cohorts differed in terms of age, diabetes duration, and metabolic control. HbA1c changes after 6 months from the switch were - 0.27% (95% CI - 0.38; - 0.16), - 0.06% (95% CI - 0.31; 0.19), and - 0.30% (95% CI - 0.51; - 0.09) in the three cohorts, respectively. FPG significantly decreased in cohort 1 (- 14.07 mg/dl, 95% CI - 20.25; - 7.89), while body weight significantly decreased in cohort 2 (- 1.47 kg, 95% CI - 2.55; - 0.39). Doses of insulin marginally changed during the follow-up (+ 0.89 U in basal insulin daily dose in cohort 1 and + 2.07 U in short-acting insulin daily dose in cohort 2). Switching to Gla-300 from first-generation basal insulin in the real world is associated with improvements in metabolic control despite a suboptimal titration of both basal and short-acting insulins. Inertia in insulin titration documented in the Gla-100 cohort is also observed with the second-generation basal insulin. The switch to Gla-300 from Deg-100 was associated with a decrease in body weight of - 1.47 kg despite a slight increase in short-acting insulin daily doses of about + 2 U.


MSH affects regional perfusion of the brain.
With the single exception of the occipital cortex, the flow of blood to most regions of the brains of conscious, unrestrained rats was reduced within 10 min after intravenous administration of alphaMSH. Though these effects were transitory for most regions of the brain, perfusion of cerebellum, pons and medulla, hippocampus, and parietal cortex was still significantly low by 20 min. Assuming that flow changes reflect functional changes, these early responses to alphaMSH suggest an explanation for the effects of this hormone in which visual learning is improved.


The Effect of Macrophage Migration Inhibitory Factor on Intestinal Permeability: FITC-Dextran Serum Measurement and Transmission Electron Microscopy.
Macrophage migration inhibitory factor (MIF) is a molecule with multiple functions: from enforcing the immune system to fight bacterial infection to the regulation of insulin activity. Also, MIF is expressed by enterocytes that line the intestinal border toward the lumen, and in M cells, where it regulates phagocytosis of antigens from the lumen of the gut and their transport to Peyer's patches. Since there were no data on the role of MIF in the maintenance of the intestinal barrier, we used MIF-deficient mice bred on C57BL/6 background as a model for the investigation of intestinal permeability. The obtained results indicate that the absence of MIF increases intestinal permeability. Here we describe two methods for measuring intestinal permeability in mice: detection of orally delivered FITC-dextran in the serum and transmission electron microscopy used for visualization and measurement of cell-to-cell connections width.


Silver staining the chromosome scaffold.
Cytological silver-staining procedures reveal the presence of a "core" running along the chromatid axes of isolated HeLa mitotic chromosomes. In this communication we examine the relationship between this "core" and the nonhistone chromosome scaffolding, isolated and characterized in previous publications from this laboratory. When chromosomes on coverslips were subjected to the steps used for scaffold isolation in vitro and subsequently stained with silver, the characteristic "core" staining was unaffected. Control experiments suggested that the "core" does not contain large amounts of DNA. When scaffolds were isolated in vitro, centrifuged onto electron microscope grids, and stained with silver, they were found to stain selectively under conditions where specific "core" staining was observed in intact chromosomes. These results suggest that the nonhistone scaffolding is the principal target of the silver stain in chromosomes.


Esophago-pleuro-cutaneous fistula. A case report.
In a sixty-three year old Japanese man with a history of long standing pulmonary tuberculosis, an unusual esophago-cutaneous fistula developed. The possibility of esophago-pleuro-cutaneous fistula was considered, because there was an old tuberculosis causing lung abscess of hilar lymph node adenopathy and which facilitated development of an extensive fistulous tract. The patient was effectively treated by palliative surgical procedure. This may be the first report of a benign esophago-pleuro-cutaneous fistula.


Association between depression and rheumatoid arthritis: two longitudinal follow-up studies using a national sample cohort.
To investigate the bidirectional relation between RA and depression. Data from the Korean Health Insurance Review and Assessment Service - National Sample Cohort from 2002 to 2013 were analysed. Patients ≥20 years of age were included. Study I was conducted with 38 087 depression patients and 152 348 matched control participants. Study II was conducted with 7385 RA patients and 29 540 matched control participants. Stratified Cox proportional hazards models were used to analyse the hazard ratios (HRs) for depression and RA (study I) and for RA and depression (study II). The data were adjusted by the Charlson comorbidity index; rheumatic disease was excluded. Subgroups were also analysed according to age and sex. A total of 0.7% (1260/38 087) of the depression group and 0.6% (883/152 348) of the control I group had RA (P = 0.02). The HR for RA in the depression group was not significantly higher than that in control I group. In study II, 5.5% (408/7385) of the RA group and 4.3% (1246/29 540) of the control II group presented with depression (P < 0.001). The RA patients showed an adjusted depression HR that was 1.20 times higher (95% CI 1.07, 1.34; P = 0.002) than that of the control group. The >30-years-old and women subgroups of RA patients showed higher depression HRs than the control subgroups. RA increased the risk of depression; however, depression did not increase the risk of RA in the Korean adult population.


P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) restrict brain accumulation of the active sunitinib metabolite N-desethyl sunitinib.
N-desethyl sunitinib is a major and pharmacologically active metabolite of the tyrosine kinase inhibitor and anticancer drug sunitinib. Because the combination of N-desethyl sunitinib and sunitinib represents total active drug exposure, we investigated the impact of several multidrug efflux transporters on plasma pharmacokinetics and brain accumulation of N-desethyl sunitinib after sunitinib administration to wild-type and transporter knockout mice. In vitro, N-desethyl sunitinib was a good transport substrate of human ABCB1 and ABCG2 and murine Abcg2, but not ABCC2 or Abcc2. At 5 μM, ABCB1 and ABCG2 contributed almost equally to N-desethyl sunitinib transport. In vivo, the systemic exposure of N-desethyl sunitinib after oral dosing of sunitinib malate (10 mg/kg) was unchanged when Abcb1 and/or Abcg2 were absent. However, brain accumulation of N-desethyl sunitinib was markedly increased (13.7-fold) in Abcb1a/1b(-/-)/Abcg2(-/-) mice, but not in Abcb1a/1b(-/-) or Abcg2(-/-) mice. In the absence of the ABCB1 and ABCG2 inhibitor elacridar, brain concentrations of N-desethyl sunitinib were detectable only in Abcb1a/1b(-/-)/Abcg2(-/-) mice after sunitinib administration. Combined elacridar plus N-desethyl sunitinib treatment increased N-desethyl sunitinib plasma and brain exposures, but not brain-to-plasma ratios in wild-type mice. In conclusion, brain accumulation of N-desethyl sunitinib is effectively restricted by both Abcb1 and Abcg2. The effect of elacridar treatment in improving brain accumulation of N-desethyl sunitinib in wild-type mice was limited compared with its effect on sunitinib brain accumulation.


Horizontal Gene Transfer of the Non-ribosomal Peptide Synthetase Gene Among Endophytic and Epiphytic Bacteria Associated with Ethnomedicinal Plants.
This study genetically screened endophytic and epiphytic bacteria associated with ethnomedicinal plants for the presence of the non-ribosomal peptide synthetase (NRPS) gene and identified horizontal gene transfer (HGT) of the NRPS gene between the bacterial species. NRPSs are large multimodular enzymes that synthesize a wide range of biologically active natural compounds that are pharmacologically important. Twenty-nine plant-associated culturable bacteria were screened for the presence of the NRPS gene, of which seven bacterial NRPS gene fragments were successfully detected. According to our findings the presence of NRPS gene among the isolates does not always equate to their antagonistic ability. Phylogenetic analysis of the NRPS and 16S rRNA-encoding genes was used to predict HGT that may have occurred during gene evolution. The occurrence of HGT was demonstrated in the isolates (one inter-phylum and four intra-phyla) and was supported by phylogenetic analysis, mol% G+C content, and tetranucleotide usage pattern and codon usage frequency. Among the four intra-phyla HGT, one isolate showed inter-class HGT and three other isolates showed intra-class HGT.


The use of high-performance liquid chromatography for sample clean-up in mass fragmentographic assays.
A novel high-performance liquid chromatography (HPLC) sample clean-up procedure for use in mass fragmentographic assays of (sub)-nanogram amounts of drugs in human plasma is described and compared with a conventional extraction sequence for sample purificaiton. With the assay of the new antidepressant drug mianserin hydrochloride (Org GB 94) as an example, the HPLC procedure is discussed with respect to retention time, recovery, purification, colum deterioration and convenience. It is demonstrated that HPLC sample clean-up is a useful and time-saving procedure for routine clinical analyses.


STREPTOCOCCUS SUIS ENDOGENOUS ENDOPHTHALMITIS IN A PATIENT WITH MENINGITIS.
Streptococcus suis is a major porcine pathogen that can cause severe systemic infection in humans. The common clinical features include meningitis, septicemia, purulent arthritis, and oftentimes deafness. However, ocular inflammation is very rare. We report the case of endogenous endophthalmitis, meningitis, and septicemia caused by S. suis. The patient received 2 months of systemic antibiotics therapy, intravitreal vancomycin, and vitrectomy combining phacoemulsification with intraocular lens without silicone oil-filled. The result with the best-corrected visual acuity was 20/40 on the left eye and 20/25 on the right eye. This case illustrates the rare presentation of endogenous endophthalmitis in a patient with meningitis due to S. suis. In patients presenting with endophthalmitis and meningitis, S. suis should be considered, especially if prominent and early visual acuity impairment is present.


Crystallographic structure and quantum chemical computations of 1-(3,4-dimethylphenyl)-3-phenyl-5-(4-methoxyphenyl)-2-pyrazoline.
In this study the experimental crystallographic structure and the calculated optimized geometric parameters, vibrational wavenumbers, (1)H NMR and (13)C NMR chemical shift values, electronic absorption maximum wavelength values, HOMO-LUMO analysis, and molecular electrostatic potential (MEP) of 1-(3,4-dimethylphenyl)-3-phenyl-5-(4-methoxyphenyl)-2-pyrazoline (in abbreviated 1h), molecule, (C24H24N2O), by using density functional theory (DFT/B3LYP) method with 6-311++G(d,p) basis set in the ground state have been reported for the first time. Furthermore the IR and Raman spectra of title molecule were simulated by using calculated vibrational results. Geometric parameters (bond lengths and bond angles) vibrational wavenumbers and (13)C &(1)H NMR chemical shift values for the mentioned compound calculated at B3LYP/6-311++G(d,p) level are in good agreement with the experimental data.


Cranioplasty Complications and Costs: A National Population-Level Analysis Using the MarketScan Longitudinal Database.
To characterize cranioplasty complications and costs at a population level using a longitudinal national claims database. We identified patients undergoing cranioplasty between 2007 and 2014 in the MarketScan national database. We evaluated age, autograft usage, cranioplasty size, and cranioplasty timing stratified by postoperative outcomes. We further analyzed associated costs. A subset analysis of adult patients with emergent indications, including stroke and trauma, was performed. We identified 8275 patients (mean age 44.0 years ± 20.0, 45.2% male), including 13.8% children (<18 years old), 76.0% adults (18-64 years old), and 10.2% elderly adults (≥65 years old). Overall complication rate was 36.6%, mortality rate was 0.5%, and 30-day readmission rate was 12.0%. Elderly patients had the highest complication rate (P < 0.0001). Large cranioplasties (>5 cm) had higher complication rates than small cranioplasties (≤5 cm; P = 0.047). In patients with emergent indications (n = 1282), size did not influence complications, although large cranioplasties showed higher infection risk (P = 0.02). Autograft use did not affect outcomes but was associated with higher complication risk, including infections, in the subset with emergent indications (P < 0.001, P = 0.001). Late (>90 days) cranioplasty timing had higher complication rates in the overall cohort and the subset with emergent indications (P < 0.001, P < 0.001). Index costs of care were mainly driven by hospital payments in both the overall cohort and the cohort with emergent indications. A high complication rate is associated with cranioplasty in the United States. Older age, large cranioplasties, and delayed cranioplasties increased complication risk overall. Among patients with emergent indications, complications were associated with delayed time to cranioplasty and autograft usage.


Effect of phytoestrogens on gene expression of carbonic anhydrase II in rat uterus and liver.
The aim of this study was to characterize carbonic anhydrase II (CA2), as novel estrogen responsive gene, towards its usefulness to elucidate the molecular mechanisms of phytoestrogen action. Effects of estradiol-17beta (E2), and the phytoestrogens genistein (Gen), daidzein (Dai), as well as 8-prenylnaringenin (8PN) on CA2 mRNA expression were investigated in vivo in the uterus and liver of Wistar rats, and in vitro in Fe33 hepatoma cells. Relative amounts of mRNA levels of CA2 were measured by real-time RT-PCR. In vivo CA2 expression in uterus and liver is down-regulated by estrogen in time dependent manner with the most pronounced effect detectable 72 h after treatment. Treatment with Gen results in a slight down-regulation of CA2 expression in the uterus. In liver a response to Gen is detectable only after 7 h, where the expression of the gene is down-regulated to 60%. Treatment with Dai and 8PN for 72 h results in a slight down-regulation of CA2 in both tissues. In contrast in Fe 33 cells CA2 gene expression was up-regulated in response to the treatment with E2 for 7 h. In summary, we could demonstrate that the modulation of CA2 gene expression following treatment with E2 and Gen in rat uterus is comparable to the uterotrophic response of these substances, but with an inverted pattern. Remarkably, of all phytoestrogens 8PN exhibited the strongest uterotrophic response but only induced a very faint decrease of CA2 expression. In addition, we provide the first pieces of evidence that 8PN, like Gen and Dai, cannot be considered as a pure agonist. In conclusion, CA2 shows estrogen sensitivity not only in both tissues studied, but also in many others. Further, it exhibits a differential sensitivity thereby being capable to discriminate between different molecular qualities of phytoestrogens, like demonstrated for Gen and 8PN.


Influence of storage on the quality of conventional CT and µCT-imaging for the middle and inner cat ear.
The aim of this study was to analyze whether different fixation methods such as freezing or formaldehyde storage for different periods of time have an influence on the recognition of anatomical relevant structures in the middle and inner ear of the cat with conventional computed tomography (cCT) and micro-computed tomography (µCT). Besides, effects of freeze-thaw cycles on determined structures of the ear were investigated by means of histological slices. Three veterinarians with different radiologic expertise evaluated the scans of 30 dissected cat ears anonymously and scored predefined structures in a five-point scale with reference to visually sharp reproducibility and perfect image quality. The total scores of the different fixation groups as well as the ears within a group were compared with each other. Furthermore, an intra-reader examination including an evaluation of the identifiability of specified structures was performed for both imaging methods. cCT as well as µCT-scans have a very low variation coefficient of 1.6% and 2.3%, respectively. The results for the alterations between the different fixation methods show that the changes for cCT-scans are negligible, as the percentage alteration compared to fresh samples ranges in a very small interval with values from 1.0% better to 1.2% worse. µCT-scans are more influenced by the fixation method with a range from 1.3% better to 6.9% worse values. The scans mostly deteriorated after two freeze-thaw cycles (1.8% worse) and after storing the samples for 1 (2.4% worse), respectively, and 3 weeks in formaldehyde (6.9% worse).


Scientific considerations in the regulatory approval of generic (or biosimilar) version of enoxaparin sodium - A lifesaving carbohydrate polymer.
Enoxaparin sodium (Clexane®/Klexane®/Lovenox®) is one amongst the few drugs that have assumed a central role as drug of treatment and/or prevention against thromboembolic complications during COVID-19. The increase in demand resulting in many generic (or biosimilar) versions entering the market has increased the risks of quality and safety (including immunogenicity) related issues. Under the circumstances, development of stringent regulatory approaches has received much attention as investigation of new drug delivery systems for improved therapeutic activity. As one of the measures to increase quality testing and ensure uninterrupted supply of this life-saving drug globally, determination of enoxaparin molecular weight (MW) has been added in the United States Pharmacopoeia (USP) monograph for enoxaparin sodium. In addition, the presence of a unique 1,6-anhydro-ring structure at the reducing end of about 15-25% of the poly (oligo) saccharide chains of the generic (or biosimilar) product has been set as a mandatory requirement. This article presents an overview of the scientific considerations in the quality manufacturing and testing of the generic (or biosimilar) enoxaparin for regulatory review and approval. In certain cases of strong analytical similarity (structural and functional), abandonment of in vivo testing in animals and humans represents a major advancement in the approval of generic (or biosimilar) version of innovator enoxaparin sodium (lovenox®, injections).


Addressing a Key Leadership Challenge: Workplace Violence.
Workplace violence is a growing concern among health care workers, especially staff working in emergency departments. Emergency department leaders have oversight accountability that includes mitigation of workplace violence risks and staff education related to workplace violence prevention. Challenges associated with workplace violence events include disruption of safe patient care, decreased staff job satisfaction, and increased turnover. Improving safety for staff, patients, and visitors requires a culture focused on safety. A summary of current regulations, standards, and resources available to date is provided, including a list of mitigation strategies that can be easily translated into practice by emergency nurse leaders.


Lipophilicity and brain disposition of clonidine and structurally related imidazolidines.
The apparent partition coefficients (P') of clonidine and 27 of its structurally related imidazolidines were determined in the octanol/buffer (pH = 7.4) system as a measure of lipophilic behaviour. Lipophilicity of the imidazolidines is limited to the free bases and the principle of additivity is valid for this series of structurally similar compounds. Brain concentrations of clonidine and a number of its derivatives, achieved at the moment of maximal decrease in blood pressure, were determined following intravenous administration of anaesthetized rats. These brain concentrations represent the maximally attainable values. The ratio of log brain concentration/dose administered intravenously, log (Cbrain/Ci.v.), was employed as a measure of the penetration ability of the imidazolidines into the brain. The octanol/buffer (pH = 7.4) system proved a satisfactory reference model in order to describe the transport process of the present imidazolidines from the blood to the brain. The penetration ability of these compounds into the brain could be expressed mathematically by a highly significant, parabolic relationship in log P'. Ideal lipophilic character for optimal brain concentrations is connected with a log P' value of 2.16.


Translatome and transcriptome analysis of TMA20 (MCT-1) and TMA64 (eIF2D) knockout yeast strains.
TMA20 (MCT-1), TMA22 (DENR) and TMA64 (eIF2D) are eukaryotic translation factors involved in ribosome recycling and re-initiation. They operate with P-site bound tRNA in post-termination or (re-)initiation translation complexes, thus participating in the removal of 40S ribosomal subunit from mRNA stop codons after termination and controlling translation re-initiation on mRNAs with upstream open reading frames (uORFs), as well as de novo initiation on some specific mRNAs. Here we report ribosomal profiling data of S.cerevisiae strains with individual deletions of TMA20, TMA64 or both TMA20 and TMA64 genes. We provide RNA-Seq and Ribo-Seq data from yeast strains grown in the rich YPD or minimal SD medium. We illustrate our data by plotting differential distribution of ribosomal-bound mRNA fragments throughout uORFs in 5'-untranslated region (5' UTR) of GCN4 mRNA and on mRNA transcripts encoded in MAT locus in the mutant and wild-type strains, thus providing a basis for investigation of the role of these factors in the stress response, mating and sporulation. We also document a shift of transcription start site of the APC4 gene which occurs when the neighboring TMA64 gene is replaced by the standard G418-resistance cassette used for the creation of the Yeast Deletion Library. This shift results in dramatic deregulation of the APC4 gene expression, as revealed by our Ribo-Seq data, which can be probably used to explain strong genetic interactions of TMA64 with genes involved in the cell cycle and mitotic checkpoints. Raw RNA-Seq and Ribo-Seq data as well as all gene counts are available in NCBI Gene Expression Omnibus (GEO) repository under GEO accession GSE122039 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE122039).


Miltefosine as a PPM1A activator improves AD-like pathology in mice by alleviating tauopathy via microglia/neurons crosstalk.
Alzheimer's disease (AD) is a progressively neurodegenerative disease without effective treatment. Here, we reported that the levels of expression and enzymatic activity of phosphatase magnesium-dependent 1A (PPM1A) were both repressed in brains of AD patient postmortems and 3 × Tg-AD mice, and treatment of adeno-associated virus (AAV)-ePHP-overexpression (OE)-PPM1A for brain-specific PPM1A overexpression or the new discovered PPM1A activator Miltefosine (MF, FDA approved oral anti-leishmanial drug) for PPM1A enzymatic activation improved the AD-like pathology in 3 × Tg-AD mice. The mechanism was intensively investigated by assay against the 3 × Tg-AD mice with brain-specific PPM1A knockdown (KD) through AAV-ePHP-KD-PPM1A injection. MF alleviated neuronal tauopathy involving microglia/neurons crosstalk by both promoting microglial phagocytosis of tau oligomers via PPM1A/Nuclear factor-κb (NF-κB)/C-X3-C Motif Chemokine Receptor 1 (CX3CR1) signaling and inhibiting neuronal tau hyperphosphorylation via PPM1A/NLR Family Pyrin Domain Containing 3 (NLRP3)/tau axis. MF suppressed microglial NLRP3 inflammasome activation by both inhibiting NLRP3 transcription via PPM1A/NF-κB/NLRP3 pathway in priming step and promoting PPM1A binding to NLRP3 to interfere NLRP3 inflammasome assembly in assembly step. Our results have highly addressed that PPM1A activation shows promise as a therapeutic strategy for AD and highlighted the potential of MF in treating this disease.


A reliable tool for detecting 7-dehydrocholesterol and cholesterol in human plasma and its use in diagnosis of Smith-Lemli-Opitz syndrome.
Smith-Lemli-Opitz syndrome is a birth defect caused by the deficiency of 7-dehydrocholesterol reductase in cholesterol biosynthesis pathway, which leads to accumulation of 7-dehydrocholesterol and reduction of cholesterol in body fluids. To effectively diagnose Smith-Lemli-Opitz syndrome and monitor therapy, a reliable method for simultaneous detection of 7-dehydrocholesterol and cholesterol is needed. In the presence of antioxidants (2,6-ditert-butyl-4-methylphenol and triphenylphosphine), 50 μL of human plasma were hydrolyzed at 70℃ for 40 min with 1 M potassium hydroxide in 90% ethanol, and then 7-dehydrocholesterol and cholesterol were extracted by 600 μL of n-hexane for three times. After microwave-assisted derivatization with 70 μL of N,O-bis(trimethylsilyl)trifluoroacetamide at 460 W for 3 min, the analytes were measured by gas chromatography-mass spectrometry. The limits of detection were 100 ng/mL for 7-dehydrocholesterol and 300 ng/mL for cholesterol. Good linearity was obtained in the range of 1-600 μg/mL for 7-dehydrocholesterol and 10-600 μg/mL for cholesterol, which completely covered the biochemical levels of Smith-Lemli-Opitz syndrome patients that have been reported. A time-saving and accurate gas chromatography with mass spectrometry based method was developed for the determination of 7-dehydrocholesterol and cholesterol in human plasma, which also serves as a useful tool for Smith-Lemli-Opitz syndrome diagnosis, treatment, and research.


Toxic ligand conjugates as tools in the study of receptor-ligand interactions.
We have constructed hybrid proteins in which the toxic A chains of ricin or diptheria toxin have been linked to either asialofetuin, fetuin, or epidermal growth factor (EGF). Both ASF-RTA and ASF-DTA are potent toxins on cultured rat hepatocytes, cells that display the asialoglycoprotein receptor. Toxicity of these two compounds is restricted to hepatocytes and can be blocked by asialoglycoproteins but not the native glycoproteins or asialoagalactoglycoprotein derivatives, indicating that the toxicity of the conjugates is mediated by the hepatic asialoglycoprotein receptor. The EGF-RTA conjugate is an extremely potent toxin on cells that can bind the hormone, but is only poorly effective on cells that are unable to bind EGF. The EGF-DTA conjugate, in contrast, is unable to kill 3T3 cells and is at least two orders of magnitude less effective than EGF-RTA on A431 cells, a cell line with 1-2 X 10(6) EGF receptors per cell. However, when EGF-RTA and EGF-DTA were tested on primary liver hepatocyte cultures, which were susceptible to both ASF-RTA and ASF-DTA, both EGF conjugates were potent toxins. Sensitivity of the hepatocyte cultures to ricin toxicity increases slightly during a 52-hr culture period. In contrast, sensitivity to EGF-RTA and ASF-RTA decline dramatically during this period. Receptors for both ligands remain plentiful on the cell surface during this time.


Cross-sensitivity between paclitaxel and docetaxel in a women's cancers program.
With the use of steroid premedication, the incidence of severe hypersensitivity reactions (S-HSR) to paclitaxel is estimated to be 2%. For those who develop a S-HSR to paclitaxel, docetaxel has been employed as an alternative agent though the presence of cross-sensitivity has not been established. We sought to define the incidence of S-HSR to docetaxel following a paclitaxel S-HSR in an academic women's cancer program. Patients treated with either paclitaxel (P) or docetaxel (D) between 11/1999 and 8/2004 were identified through our pharmacy database. Records were reviewed and data collected on those patients who had a S-HSR, defined as symptoms for which drug was discontinued, to P, D, or both. 718 patients received P and 93 received D. 59 received D following treatment with P. The presence of S-HSR for P was 2.2% (16/718 patients) and for D was 9.7% (9/93 patients). 10 patients with S-HSR to P crossed over to D and all nine patients reacting to D had a prior reaction to T for a cross-sensitivity rate of 90% (9/10 patients). Cross-sensitivity of D after P was 90% at our institution. Given the different vehicles used in P and D, it is likely attributed to the taxane moiety. Caution is required with re-challenge of patients with docetaxel if they have previously reacted to paclitaxel.


Defining A-Kinase Anchoring Protein (AKAP) Specificity for the Protein Kinase A Subunit RI (PKA-RI).
A-Kinase anchoring proteins (AKAPs) act as spatial and temporal regulators of protein kinase A (PKA) by localizing PKA along with multiple proteins into discrete signaling complexes. AKAPs interact with the PKA holoenzyme through an α-helix that docks into a groove formed on the dimerization/docking domain of PKA-R in an isoform-dependent fashion. In an effort to understand isoform selectivity at the molecular level, a library of protein-protein interaction (PPI) disruptors was designed to systematically probe the significance of an aromatic residue on the AKAP docking sequence for RI selectivity. The stapled peptide library was designed based on a high affinity, RI-selective disruptor of AKAP binding, RI-STAD-2. Phe, Trp and Leu were all found to maintain RI selectivity, whereas multiple intermediate-sized hydrophobic substitutions at this position either resulted in loss of isoform selectivity (Ile) or a reversal of selectivity (Val). As a limited number of RI-selective sequences are currently known, this study aids in our understanding of isoform selectivity and establishing parameters for discovering additional RI-selective AKAPs.


The impact of clinical data on interpretation of thallium scintigrams.
The availability of clinical information often influences the interpretation of diagnostic imaging information. In this study we examined the impact of such data on interpretation of exercise thallium scans and the differences in analysis of such information between radiologists and clinicians. Two hundred thirty-seven exercise tolerance test-thallium scans (122 in patients with suspected coronary disease and 115 in patients with documented coronary disease) were read prospectively, first without and then with the knowledge of clinical information. Test scores, the readers' and clinicians' interpretations of historic data, and any changes in readings or interpretation of scintigraphic data were recorded. We found that the addition of clinical information resulted in changes in interpretation of 63 test results (27%), 20 (8%) of them major. Furthermore, clinical data significantly affected final test scores in 26 patients (11%), potentially affecting clinical management in this group. The changes in test scores were triggered predominantly by differences in interpretation of perfusion abnormalities rather than thallium lung uptake or left ventricular dilation with exercise. The impact of clinical data on overall test scores was greater in patients with suspected than documented coronary disease (p < 0.05). There was good agreement in assessment of clinical information between scan readers and a clinician in tests done in patients with suspected coronary artery disease but not in patients with known coronary disease. We conclude that clinical information has major influences on the interpretation of thallium scans, and interpretation of data can vary significantly between cardiologists and radiologists depending on the nature of the clinical data.


Autoimmune haemolytic anaemia triggered by Bartonella henselae infection: a case report.
Bartonella henselae is a hitherto unidentified cause of autoimmune haemolytic anaemia. Here we report a case of Coombs-negative autoimmune haemolytic anaemia. The episode was preceded by exposure to a cat and a non-specific infectious syndrome. Concomitant serum titres of B. henselae antibodies were indicative of a recent infection. The case report suggests that B. henselae infection can trigger secondary autoimmune haemolytic anaemia.


The value of intramural vascular invasion in colorectal cancer - a systematic review and meta-analysis.
Extramural venous invasion (EMVI) is a well-known prognostic factor in colorectal cancer (CRC). Vascular invasion within the bowel wall, intramural vascular invasion (IMVI), has received less attention and its incidence and prognostic importance in CRC is not completely known. A systematic literature search was performed focusing on the impact of IMVI in CRC. Data were analysed using Review Manager version 5.3 on incidence and clinical endpoints local recurrence, 5-year cancer-specific survival (CSS) and 5-year overall survival (OS). Meta-analysis was performed in terms of risk ratios (RR) and hazard ratios (HR) with 95% confidence interval (95% CI). Of the initial 1199 papers identified by our search strategy, 20 were included in this meta-analysis. Of the 8078 included patients, 1008 patients had IMVI (12.5%). Studies that re-examined histological slides showed a higher incidence of IMVI compared to studies extracting IMVI from pathology reports (17.6 versus 7.7%, P < 0.001). Detection of IMVI increased significantly with the use of additional staining (22.9 versus 12.3%, P < 0.001). IMVI was associated with a decreased CSS HR: 1.6, 95% CI 1.2-2.2 in multivariate analysis). A borderline significant effect was observed for IMVI on local recurrence (RR: 1.5, 95% CI: 0.98-2.3) and OS (RR: 1.2, 95% CI: 1.0-1.4). In conclusion, despite the limited number of studies, there is a clear association with outcome in the presence of IMVI. This warrants more attention to this under-reported prognostic factor.


Does the duration of symptoms influence outcome in patients with sciatica undergoing micro-discectomy and decompressions?
Early surgical treatment for back and leg pain secondary to disc herniation has been associated with very good outcomes. However, there are conflicting data on the role of surgical treatment in case of prolonged radicular symptomatology. We aimed to evaluate whether the duration of symptoms at presentation affects the subjective outcome. This is a retrospective review of prospectively collected data from a single surgeon including micro-discectomies and lateral recess decompressions in patients younger than 60 years old using patient medical notes, radiology imaging, operation notes, and Patient Reported Outcome Measures (PROMS) including Oswestry Disability Index (ODI), visual analogue scale for back pain and leg pain (VAS-BP and VAS-LP). The final follow-up was carried out through postal questionnaire or telephone consultation. Demographic information, duration of symptoms, type and incidence of complications, length of hospital stay, and follow-up were analyzed. Data were categorized into four subgroups: symptoms 0≥6 months, 6 months≥1 year, 1 year≥2 years, and >2 years. A clinically significant result was an average improvement of 2 or more points in the VAS and of 20% and over in the ODI. The level of statistical significance was <0.05%. A total number of 107 patients who underwent 109 operations were included. The level of surgery was L5/S1 (50), L4/L5 (43), L3/L4 (3), L2/L3 (2), and two levels (11). The mean improvement was from 0 to ≤6 months (VAS-LP 5.21±2.81, VAS-BP 3.04±3.15, ODI 35.26±19.25), 6 months to ≤1 year (VAS-LP 4.73±2.61, VAS-BP 3.30±3.05, ODI 26.92±19.49), 1 year to ≤2 years (VAS-LP 3.78±3.68, VAS-BP 3.00±2.78, ODI 19.03±20.24), and >2 years (VAS-LP 4.77±3.61, VAS-BP 3.54±3.43, ODI 28.36±20.93). The length of hospital stay and complication rate was comparable between groups. Average follow-up was 15.69 months. Our study showed significant improvement in patients with symptoms beyond 1 as well as 2 years since onset, and surgery is a viable option in selected patients.


Ethnic differences in bullying victimization and psychological distress: A test of an ecological model.
This study examines ethnic differences in the prevalence of bullying victimization by peers as well as the associations between bullying victimization and psychological distress with relevant ecological factors including parental supervision, school support, and community safety. The study utilized the 2011-2012 California Health Interview Survey (CHIS) Adolescents Data, which was collected in the United States using a multi-stage stratified sampling design with a Random Digit-Dial method. The final study sample contained a total of 2367 adolescents, comprised of 48.7% Whites, followed by 35.8% Latinos, 11.1% Asians, and 4.4% African Americans. About 49.3% were males with an overall mean age of 14.6 (sd = 1.7). Results showed that there were significant differences in rates of bullying victimization among the four surveyed ethnic subgroups of adolescents. Black adolescents reported the highest and Asian adolescents the lowest level of victimization. The results of the SEM test using the calibration sample revealed an adequate fit to the data (CFI = 0.95, RMSEA = 0.04, Δχ2/Δdf = 2.99). Separate model tests with the four subgroups of adolescents revealed good fits with the subsample data with the exception of the subsample of African Americans. Additionally, results show that factors associated with psychological distress vary widely among the White, Latino and Asian subgroups.