Hospitalizations and emergency department visits in heart failure patients after bariatric surgery.
Heart failure is a disease with significant healthcare utilization and a prioritized target for readmission prevention. Although obesity is related to heart failure morbidity, the effects of bariatric surgery in obese patients with heart failure are not well studied. To evaluate the impact of bariatric surgery on hospital-based healthcare utilization for patients with heart failure. Administrative statewide database. The New York Statewide Planning and Research Cooperative System database was used to identify patients with obesity and heart failure who underwent bariatric surgery from 2005 to 2015. Emergency department (ED) visits and hospitalization records from 1 year presurgery and up to 2 years postsurgery were compared. Our study identified 899 patients with heart failure who underwent bariatric surgery. In the year presurgery, 11.48% of patients had any ED visit or hospitalization with a primary diagnosis of heart failure. The rate decreased drastically in the first year after surgery, with only 3.70% of patients having any heart failure-related hospital visits. The rate of heart failure-related visits was also lower in the second year postsurgery (3.44%) compared with the year before surgery. The risk of heart failure-related hospital visits was lower in both the first year (odds ratio [OR], .29; 95% confidence interval [CI], .19-.43) and second year postsurgery (OR, .26; 95% CI, .17-.41; P < .0001) than in the year before surgery. These findings suggest that bariatric interventions might be associated with decreased risks of ED visits or hospitalizations due to heart failure exacerbations in obese patients with preexisting heart failure.


Bone microenvironment-related growth factors, zoledronic acid and dexamethasone differentially modulate PTHrP expression in PC-3 prostate cancer cells.
Bone metastasis microenvironment-related growth factors such as insulin-like growth factor 1 (IGF-1), transforming growth factor beta 1 (TGF-beta1), basic fibroblast growth factor (bFGF) and interleukin 6 (IL-6) show survival factor activity, thereby inhibiting chemotherapy-induced apoptosis of PC-3 prostate cancer cells in vitro. Recently, zoledronic acid has been shown to induce apoptosis in PC-3 prostate cancer cells while overexpression of parathyroid hormone-related protein (PTHrP) inhibits serum deprivation-induced apoptosis in PC-3 cells. Consequently, we have investigated whether IGF-1, TGF-beta1, bFGF, IL-6, zoledronic acid and/or dexamethasone affect the expression of the PTHrP and type I PTH/PTHrP receptor (PTH.1R) in PC-3 prostate cancer cells using relative quantitative PCR and real-time PCR (expression at mRNA level) and immunocytochemical and immunofluorescence analysis (expression at protein level). Our data show that IGF-1, TGF-beta1, bFGF and IL-6 increase PTHrP mRNA expression and its perinuclear localization, while zoledronic acid (50 muM, 100 muM for 24 h and 48 h) and dexamethasone suppress PTHrP expression in PC-3 cells. We did not detect any appreciable change of the PTH.1R expression due to IGF-1, TGF- beta1, bFGF, IL-6, zoledronic acid or dexamethasone in PC-3 cells. Therefore, it is conceivable that bone metastasis microenvironment-related survival factor/anti-apoptotic activity and zoledronic acid anticancer action/pro-apoptotic activity on PC-3 cells is mediated, at least in part, by differential modulation of PTHrP expression.


Methodologic Approaches for Using Electronic Medical Records to Identify Experiences of Violence in Transgender and Cisgender People: Closing the Gap Between Diagnostic Coding and Lived Experiences.
Transgender people experience extreme rates of violence and the electronic medical record (EMR) remains a mostly untapped resource to study the medical sequelae of such experiences. To develop and test a method for identifying experiences of violence using EMR data. Cross-sectional study utilizing EMR data. Transgender and cisgender people seen at a regional referral center in Upstate New York. We tested the utility of keyword searches and structured data queries to identify specific types of violence at various ages and in various contexts among cohorts of transgender and cisgender people. We compared the effectiveness of keyword searches to diagnosis codes and a screening question, "Are you safe at home?" using McNemar's test. We compared the prevalence of various types of violence between transgender and cisgender cohorts using the χ 2 test of independence. Of the transgender cohort, 47% had experienced some type of violence versus 14% of the cisgender cohort (χ 2P value <0.001). Keywords were significantly more effective than structured data at identifying violence among both cohorts (McNemar P values all <0.05). Transgender people experience extreme amounts of violence throughout their lives, which is better identified and studied using keyword searches than structured EMR data. Policies are urgently needed to stop violence against transgender people. Interventions are also needed to ensure safe documentation of violence in EMRs to improve care across settings and aid research to develop and implement effective interventions.


Prognostic value of soluble interleukin 2 receptor levels in Langerhans cell histiocytosis.
We investigated the prognostic significance of soluble interleukin 2 receptor (sIL-2r) levels in the pre- and post-treatment serum of paediatric patients with Langerhans cell histiocytosis (LCH). Serum levels of sIL-2r from 32 LCH patients and 14 healthy controls were determined using enzyme-linked immunosorbent assay. The LCH patients were classified, evaluated and treated according to the Histiocyte Society's protocols. The following clinical stages were considered: single-system disease (A) divided into single-site (A1; n=4), multiple-site (A2; n=9), and multisystem disease (B) without organ dysfunction (B1; n=5) and with organ dysfunction (B2; n=14). Pretreatment concentrations of sIL-2r were markedly increased at diagnosis in LCH patients compared with controls [in pg/ml, median (range) 9200 (1124-40000) versus 610 (343-800)], P < 0.0001. Levels differed significantly between stages A [3250 (1124-11000)] and B [22750 (3400-40000)], P < 0.05, and between substages A2 and B2, P < 0.05. There was a significant correlation between clinical stages and sIL-2r serum levels, r=0.7996 (P < 0.0001). Patients with > or = 17500 pg/ml of sIL-2r had a 30-month survival of 0.417 (SEM: 0.142) compared with those with levels < 17500 pg/ml, who presented a 30-month survival of 0.848 (SEM: 0.100) (log-rank, P < 0.0001). In multivariate analysis, sIL-2r levels > or = 17500 pg/ml were found to have greater predictive strength than other well-known prognostic factors.


Comparison of a Point-of-Care Analyzer With a Chemiluminescent Immunoassay for Serum Progesterone Measurement in Breeding Management of the Bitch.
Accurate serum progesterone measurements for timing bitches during breeding management is critical for reproductive practice, especially as artificial insemination has become routine to facilitate breeding of animals that are geographically or temporally separated. To measure serum progesterone, chemiluminescent immunoassay (CLIA) has replaced radioimmunoassay as the current standard in the bitch due to its high correlation and increased practicality. In January 2019, a colorimetric point-of-care (POC) immunoassay for quantitative in-clinic canine serum progesterone measurements in <30 min was released. This study provides an independent comparison of the POC (Catalyst One, IDEXX) to the current industry standard, CLIA (Immulite-2000, Siemens). To assess inter-assay imprecision of POC and agreement of the POC and CLIA results, 100 canine serum samples were analyzed on three analyzers (POC-1, POC-2, and CLIA), of which, 74 (POC-1) and 75 (POC-2) results were within POCs' reportable range of 0.2-20 ng/mL and included in the study. To assess intra-assay imprecision, pooled canine serum samples at low (L1), intermediate (L2), and high (L3) progesterone concentrations were analyzed ten times each on POC-1 and CLIA. Relative to CLIA, POC values showed good correlation (POC-1, r 2 = 0.9366; POC-2, r 2 = 0.9438, P < 0.0001) and significant positive proportional bias at values >2 ng/mL. The POC inter-assay coefficients of variation (CVs) were 13.2% (0.2-2.9 ng/mL, 0.6-9.2 nmol/L, L1), 10.0% (3.0-9.9 ng/mL, 9.5-31.5 nmol/L, L2), 7.1% (10.0-20.0 ng/mL, 31.8-63.6 nmol/L, L3), and 11.2% (all samples). The intra-assay CVs for POC (L1, 15.3%; L2, 7.0%; L3, 4.7%) were higher than those for CLIA (L1, 5.89%; L2, 4.89%; L3, 3.44%). Based on the more rapid increase in serial serum progesterone concentrations in ovulating bitches and the greater imprecision of the POC, the clinical interpretations of serum progesterone measurements as they relate to canine breeding management should be made with caution.


Changes in intestinal morphology, number of mucus-producing cells and expression of coronavirus receptors APN, DPP4, ACE2 and TMPRSS2 in pigs with aging.
Porcine enteric viral infections cause high morbidity and mortality in young piglets (<3 weeks). Later, these rates decrease with age. This age-dependent infectivity remains largely unexplored. This study investigated the changes in intestinal morphology, number of mucus-producing cells and expression level of coronavirus receptors in three age groups of pigs. Villus height and crypt depth increased with age from 3 days to 3 months in duodenum and ileum but not in mid-jejunum, where the villus height decreased from 580 µm at 3 days to 430 µm at 3 months. Enterocyte length-to-width ratio increased from 3 days to 3 months in all intestinal regions. The number of mucus-producing cells increased with age in the intestinal villi and crypts. The Brunner's glands of the duodenum contained the highest concentration of mucus-producing cells. The expression of coronavirus receptor APN was highest in the small intestinal villi at all ages. DPP4 expression slightly decreased over time in jejunum and ileum; it was highest in the ileal villi of 3-day-old piglets (70.2% of cells). ACE2 and TMPRSS2 positive cells increased with age in jejunal and ileal crypts and were particularly dominant in the ileal crypts (> 45% of cells). Except for the expression of DPP4 in the jejunum and ileum of young pigs, the expression pattern of the selected coronavirus receptors was very different and not correlated with the age-dependent susceptibility to viral infections. In contrast, the number of mucus-producing cells increased over time and may play an essential role in protecting enteric mucosae against intestinal viruses.


Binding of the coenzyme and formation of the transketolase active center.
Transketolase (TK) is a homodimer, the simplest representative of thiamine diphosphate (ThDP)-dependent enzymes. It was first ThDP-dependent enzymes the crystal structure of which has been solved and revealed the general fold for this class of enzymes and the interactions of the non-covalently bound coenzyme ThDP with the protein component. Transketolase is a convenient model to study the structure(s) of the active center and the mechanism of action of ThDP-dependent enzymes. This review summarizes the results of studies on the kinetics of the interaction of ThDP with TK from Saccharomyces cerevisiae as well as the generation of the catalytically active form of the coenzyme within the holoenzyme and formation of the enzyme's active center.


Outcomes of treatment of pediatric choroidal neovascularization with intravitreal antiangiogenic agents: the results of the KKESH International Collaborative Retina Study Group.
To evaluate safety and clinical results of intravitreal antiangiogenic agents for choroidal neovascularization in pediatric patients. Retrospective, multicenter, interventional case series. A total of 45 eyes of 39 pediatric patients with choroidal neovascularization of various etiologies were treated with intravitreal injection of antiangiogenic agents (1.25 mg per 0.05 mL of bevacizumab or 0.5 mg per 0.05 mL of ranibizumab). There were 24 girls and 15 boys with group median age of 13 years (range, 3-17 years). Mean follow-up period was 12.8 months (range, 3-60 months). Median visual acuity in terms of logarithm of the minimum angle of resolution at presentation and last follow-up was 0.87 and 0.7, respectively (P = 0.0003). Mean and median number of injections received over the follow-up period was 2.2 and 1, respectively. At the last follow-up, 22 eyes (48%) gained more than 3 lines of vision and 27 eyes (60%) had final visual acuity 20/50 or better. Nine eyes (20%) did not improve and had severe vision loss (20/200 or worse). Intravitreal antiangiogenic therapy for choroidal neovascularization in pediatric patients seems temporarily safe and effective in majority of affected eyes. Because of the rarity and character of this condition, it is unlikely that any clinical trials will soon take place to study this or other treatment option.


State-of-the-art surgery for Crohn's disease: part III-perianal Crohn's disease.
Diagnosis and treatment of perianal Crohn's disease is challenging and requires its own domain of therapy. Different types of perianal disease require a spectrum of treatment strategies. Treatment options range from conservative therapy, including immunosuppressives, biologics, or stem cell therapy, to surgical treatment with specific indications depending on the underlying lesion. This is part III of the series "state-of-the-art surgery for Crohn's disease," focusing on the management of perianal disease. We discuss the definition and diagnosis of perianal Crohn's disease, the treatment of perianal lesions, and specific surgical indications and techniques. Pitfalls and complications play a substantial role in the treatment of perianal Crohn's disease, and surgical therapy may fail. Realistic treatment goals and an individual patient-oriented treatment approach are crucial in the treatment of perianal Crohn's disease.


Antibacterial Mechanism of Liangguoan against Staphylococcus aureus and Escherichia coli.
This study examined the antibacterial activity of the biological pesticide Liangguoan against Staphylococcus aureus and Escherichia coli as a potential replacement for chemical pesticide use in the fruit and vegetable industry. We measured the minimum inhibitory concentration and observed the changes in bacterial morphology, mortality, conductivity, nucleic acid content, and ATP content in response to the bactericide. The minimum inhibitory concentration of Liangguoan was 20 mg/mL for S. aureus and 40 mg/mL for E. coli. After treatment with Liangguoan, the mortality rates of S. aureus and E. coli reached 78.3% and 63.7%, respectively. We observed that the cells were scattered and that the cell morphology was altered in that the cells shortened. The interconnection effect and ATP content decreased, whereas cell conductivity and the nucleic acid content increased. In summary, Liangguoan inhibited S. aureus and E. coli by destroying their cell structure and disrupting their metabolism.


Over 1-year duration and age difference of SARS-CoV-2 antibodies in convalescent COVID-19 patients.
Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglouilin G (IgG) and immunoglouilin M (IgM) antibodies have been widely used to assist clinical diagnosis. Our previous study reported a discrepancy in SARS-CoV-2 antibody response between male and female coronavirus disease 2019 (COVID-19) patients. However, the duration and discrepancy between ages as well as sexes of SARS-CoV-2 antibody in convalescent COVID-19 patients have not been clarified. In this study, a total of 538 health-examination individuals who were confirmed with SARS-CoV-2 infection a year ago were enrolled. Blood samples were collected and detected for IgM and IgG antibodies. Among these convalescent patients, 12.80% were detected positive for IgM antibodies. The positive rates for IgM antibody were close between sexes: for males, this is 9.17% and for females 13.75%. However, the IgG antibody was detected positive in as much as 82.90% convalescent patients and the positive rates were nearly the same between males (82.57%) and females (82.98%). Besides this, the level of IgM and IgG antibodies showed no difference between male and female convalescent patients. The level of IgG antibodies showed a significant difference between ages. The elder patients (over 35 years old) maintained a higher level of IgG antibody than the younger patients (under or equal 35 years old) after recovering for 1 year. In addition, IgG antibody was more vulnerable to disappear in younger patients than in elder patients. Overall, our study identified over 1-year duration of SARS-CoV-2 antibody and age difference of IgG antibody response in convalescent COVID-19 patients. These findings may provide new insights into long-term humoral immune response, vaccines efficacy and age-based personalized vaccination strategies.


Allometric study of renal growth in human fetuses.
Human renal growth was studied in 60 kidneys (30 staged fetuses, ranging in age from 10 to 38 weeks post conception, WPC). The kidneys were measured for greatest length (L) and weight (W) and the data correlated to the gestational age by using the allometric method (Y = bXK). The equations of the growth curves are presented in the text.


Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus identifies germline-somatic interactions with EWSR1-FLI1 binding.
Ewing sarcoma (EwS) is a rare bone and soft tissue malignancy driven by chromosomal translocations encoding chimeric transcription factors, such as EWSR1-FLI1, that bind GGAA motifs forming novel enhancers that alter nearby expression. We propose that germline microsatellite variation at the 6p25.1 EwS susceptibility locus could impact downstream gene expression and EwS biology. We performed targeted long-read sequencing of EwS blood DNA to characterize variation and genomic features important for EWSR1-FLI1 binding. We identified 50 microsatellite alleles at 6p25.1 and observed that EwS-affected individuals had longer alleles (>135 bp) with more GGAA repeats. The 6p25.1 GGAA microsatellite showed chromatin features of an EWSR1-FLI1 enhancer and regulated expression of RREB1, a transcription factor associated with RAS/MAPK signaling. RREB1 knockdown reduced proliferation and clonogenic potential and reduced expression of cell cycle and DNA replication genes. Our integrative analysis at 6p25.1 details increased binding of longer GGAA microsatellite alleles with acquired EWSR-FLI1 to promote Ewing sarcomagenesis by RREB1-mediated proliferation.


Anatomic changes in head and neck intensity-modulated proton therapy: Comparison between robust optimization and online adaptation.
Setup variations and anatomical changes can severely affect the quality of head and neck intensity-modulated proton therapy (IMPT) treatments. The impact of these changes can be alleviated by increasing the plan's robustness a priori, or by adapting the plan online. This work compares these approaches in the context of head and neck IMPT. A representative cohort of 10 head and neck squamous cell carcinoma (HNSCC) patients with daily cone-beam computed tomography (CBCT) was evaluated. For each patient, three IMPT plans were created: 1- a classical robust optimization (cRO) plan optimized on the planning CT, 2- an anatomical robust optimization (aRO) plan additionally including the two first daily CBCTs and 3- a plan optimized without robustness constraints, but online-adapted (OA) daily, using a constrained spot intensity re-optimization technique only. The cumulative dose following OA fulfilled the clinical objective of both the high-risk and low-risk clinical target volumes (CTV) coverage in all 10 patients, compared to 8 for aRO and 4 for cRO. aRO did not significantly increase the dose to most organs at risk compared to cRO, although the integral dose was higher. OA significantly reduced the integral dose to healthy tissues compared to both robust methods, while providing equivalent or superior target coverage. Using a simple spot intensity re-optimization, daily OA can achieve superior target coverage and lower dose to organs at risk than robust optimization methods.


In situ synthesis of biocompatible imidazolium salt hydrogels with antimicrobial activity.
Infection with antibiotic-resistant bacteria is becoming a significant public health risk. In this study, we synthesized a series of imidazolium salt (IMS)-containing polymers and hydrogels and tested their antimicrobial properties against both gram-positive (Staphylococcus aureus and MRSA) and gram-negative (Escherichia coli and PA01) bacteria. IMSs were either grafted as side chains or functionalized in the main chain of linear polymers, which demonstrated antimicrobial properties with minimum inhibitory concentrations as low as 2 μg/mL. Similarly, the optimized IMS-containing hydrogel effectively killed MRSA with a 96.1% killing efficiency and inhibited the growth of PA01. These hydrogels also demonstrated high performance in terms of mechanical property (compressive strength >2 MPa) and were noncytotoxic toward human dermal fibroblasts. STATEMENT OF SIGNIFICANCE: A series of polyimidazolium hydrogels were fabricated with acrylamide monomer and poly(ethylene glycol) dimethacrylate by thermal-initiated polymerization. These hydrogels completely killed methicillin-resistant Staphylococcus aureus and inhibited the growth of Pseudomonas aeruginosa. More importantly, these hydrogels demonstrated adequate mechanical property and biocompatibility. These antimicrobial hydrogels have the potential as biomaterials for preventing infections associated with multidrug-resistant bacteria.


Formation of Okazaki fragments in polyoma DNA synthesis caused by misincorporation of uracil.
When dUTP replaced dTTP during polyoma DNA replication in isolated cell nuclei, radioactivity from labeled deoxynucleoside triphosphates was almost exclusively recovered in very short Okazaki fragments and incorporation ceased after a short time. Addition of uracil, a known inhibitor of the enzyme uracil-DNA glycosidase (Lindahl et al., 1977), increased total synthesis and shifted the incorporation to longer progeny strands. The presence of as little as 2.5% of dUTP in a dTTP-containing system gave a distinct increase in isotope incorporation into Okazaki pieces accompanied by a corresponding decrease in longer strands. This effect was reversed completely by uracil. The short strands formed from dUTP could be chased efficiently into long strands. Our results suggest that dUTP can be incorporated in place of dTTP into polyoma DNA, and that polyoma-infected nuclei, similar to E. coli (Tye et al., 1977), contain an excision-repair system which by removal of uracil causes strand breakage and under certain circumstances may contribute to the formation of Okazaki fragments.


Vitamin D Supplementation Improves Mood in Women with Type 2 Diabetes.
The aim of this study was to determine the effect of vitamin D supplementation on improving mood (depression and anxiety) and health status (mental and physical) in women with type 2 diabetes mellitus (T2DM). Fifty women with T2DM and significant depressive symptomology were enrolled into the "Sunshine Study," where weekly vitamin D supplementation (ergocalciferol, 50,000 IU) was given to all participants for six months. The main outcomes included (1) depression (Center for Epidemiologic Studies Depression, CES-D, and Patient Health Questionnaire, PHQ-9), (2) anxiety (State-Trait Anxiety), and (3) health status (Short Form, SF-12). Forty-six women (92%) completed all visits. There was a significant decrease in depression (CES-D and PHQ-9, p < 0.001) and anxiety (state and trait, p < 0.001). An improvement in mental health status (SF-12, p < 0.001) was also found. After controlling for covariates (race, season of enrollment, baseline vitamin D, baseline depression (PHQ-9), and body mass index), the decline in depression remained significant (CES-D, p < 0.001). There was a trend for a better response to supplementation for women who were not taking medications for mood (antidepressants or anxiolytics) (p = 0.07). Randomized trials to confirm that vitamin D supplementation can improve mood and health status in T2DM women are needed.


SUMO-Chain-Regulated Proteasomal Degradation Timing Exemplified in DNA Replication Initiation.
Similar to ubiquitin, SUMO forms chains, but the identity of SUMO-chain-modified factors and the purpose of this modification remain largely unknown. Here, we identify the budding yeast SUMO protease Ulp2, able to disassemble SUMO chains, as a DDK interactor enriched at replication origins that promotes DNA replication initiation. Replication-engaged DDK is SUMOylated on chromatin, becoming a degradation-prone substrate when Ulp2 no longer protects it against SUMO chain assembly. Specifically, SUMO chains channel DDK for SUMO-targeted ubiquitin ligase Slx5/Slx8-mediated and Cdc48 segregase-assisted proteasomal degradation. Importantly, the SUMOylation-defective ddk-KR mutant rescues inefficient replication onset and MCM activation in cells lacking Ulp2, suggesting that SUMO chains time DDK degradation. Using two unbiased proteomic approaches, we further identify subunits of the MCM helicase and other factors as SUMO-chain-modified degradation-prone substrates of Ulp2 and Slx5/Slx8. We thus propose SUMO-chain/Ulp2-protease-regulated proteasomal degradation as a mechanism that times the availability of functionally engaged SUMO-modified protein pools during replication and beyond.


Immunotherapy in Solid Tumors and Gut Microbiota: The Correlation-A Special Reference to Colorectal Cancer.
Over the last few years, immunotherapy has been considered as a key player in the treatment of solid tumors. Immune checkpoint inhibitors (ICIs) have become the breakthrough treatment, with prolonged responses and improved survival results. ICIs use the immune system to defeat cancer by breaking the axes that allow tumors to escape immune surveillance. Innate and adaptive immunity are involved in mechanisms against tumor growth. The gut microbiome and its role in such mechanisms is a relatively new study field. The presence of a high microbial variation in the gut seems to be remarkably important for the efficacy of immunotherapy, interfering with innate immunity. Metabolic and immunity pathways are related with specific gut microbiota composition. Various studies have explored the composition of gut microbiota in correlation with the effectiveness of immunotherapy. Colorectal cancer (CRC) patients have gained little benefit from immunotherapy until now. Only mismatch repair-deficient/microsatellite-unstable tumors seem to respond positively to immunotherapy. However, gut microbiota could be the key to expanding the use of immunotherapy to a greater range of CRC patients.


Independent no-reflow predictors in female patients with ST-elevation acute myocardial infarction treated with primary percutaneous coronary intervention.
Independent no-reflow predictors should be evaluated in female patients with ST-segment elevation acute myocardial infarction (STEMI) and successfully treated with primary percutaneous coronary intervention (PPCI) in the current interventional equipment and techniques, thus to be constructed a no-reflow predicting model. In this study, 320 female patients with STEMI were successfully treated with PPCI within 12 h after the onset of AMI from 2007 to 2010. All clinical, angiographic, and procedural data were collected. Multiple logistic regression analysis was used to identify independent no-reflow predictors. The no-reflow was found in 81 (25.3%) of 320 female patients. Univariate and multivariate stepwise logistic regression analysis identified that low SBP on admission <100 mmHg (OR 1.991, 95% CI 1.018-3.896; p = 0.004), target lesion length >20 mm (OR 1.948, 95% CI 1.908-1.990; p = 0.016), collateral circulation 0-1 (OR 1.952, 95% CI 1.914-1.992; p = 0.019), pre-PCI thrombus score ≥ 4 (OR 4.184, 95% CI 1.482-11.813; p = 0.007), and IABP use before PCI (OR 1.949, 95% CI 1.168-3.253; p = 0.011) were independent no-reflow predictors. The no-reflow incidence significantly increased as the numbers of independent predictors increased [0% (0/2), 10.8% (9/84), 14.5% (17/117), 37.7% (29/77), 56.7% (17/30), and 81.8% (9/11) in female patients with 0, 1, 2, 3, 4, and 5 independent predictors, respectively; p < 0.0001]. The five no-reflow predicting variables were admission SBP <100 mmHg, target lesion length >20 mm, collateral circulation 0-1, pre-PCI thrombus score ≥ 4, and IABP use before PCI in female patients with STEMI treated with PPCI.


Implication of inflammatory cytokines in the aqueous humour for management of macular diseases.
To characterize profile of cytokines in aqueous humour of common macular diseases during intravitreal anti-VEGF therapy. Aqueous humour from eyes with central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), diabetic macular oedema (DME), neovascular age-related macular degeneration (nAMD) or pathologic myopia associated choroidal neovascularization (pmCNV) was sampled prior to 1st (n = 144) and 2nd (n = 48) intravitreal anti-VEGF therapy. Cytokines including vascular endothelium growth factor (VEGF), intercellular adhesion molecule 1 (ICAM-1) and interleukin 6 (IL-6) were quantitated and analysed along with retinal thickness data by optical coherence tomography (OCT) across two intravitreal injections and five macular disease types. ICAM-1, IL-6 and VEGF are positively associated in the aqueous humour of naive eyes (r = 0.39-0.77, p = 0.018 to <0.0001). ICAM-1, VEGF and IL-6 were significantly higher in CRVO and DME while lowest in pmCNV (p < 0.0001). Reduction of central retinal thickness (CRT) as a favourable response to anti-VEGF therapy was in the order of CRVO, BRVO, DME and nAMD/pmCNV (p < 0.0001). The strongest predictor for favourable CRT reduction was baseline CRT (p < 0.0001) followed by baseline ICAM-1 (p = 0.04). After the 1st intravitreal anti-VEGF therapy, VEGF in aqueous humour lowered significantly but ICAM-1 and IL-6 levels remained unchanged. ICAM-1 was not predictive for CRT reduction following 2nd anti-VEGF therapy. Rate of cytokine production is disease-dependent and higher in CRVO and DME. Anatomical response to intravitreal anti-VEGF therapy is disease-specific and best in RVO patients. A combination therapy using both anti-VEGF and anti-inflammatory therapeutics may be superior to single anti-VEGF therapy, at least for RVO and DME.


Apoptosis signal-regulating kinase 1 inhibits hepatocarcinogenesis by controlling the tumor-suppressing function of stress-activated mitogen-activated protein kinase.
The stress-activated mitogen-activated protein kinases (MAPKs), c-Jun NH2-terminal kinase (JNK), and p38 have been implicated in hepatocarcinogenesis. Although the many interrelated functions of JNK and p38 are precisely regulated by upstream signaling molecules, little is known about upstream regulators. We investigated the role of apoptosis signal-regulating kinase 1 (ASK1), a major player in the regulation of JNK and p38 activities, in hepatocarcinogenesis using a mouse hepatocellular carcinoma (HCC) model. ASK1-deficient (ASK1(-/-) ) and wildtype (WT) mice were treated with diethylnitrosamine on postnatal day 14. Strikingly, after 7 months, approximately three times as many tumors developed in ASK1(-/-) mice as in WT mice. Although JNK and p38 activation were attenuated in ASK1(-/-) HCCs relative to WT HCCs, cell proliferation was comparable in HCCs from both types of mice. On the other hand, both cancer cell apoptosis and hyperphosphorylation of BimEL, a proapoptotic Bcl-2 family member, were suppressed in the ASK1(-/-) HCCs. ASK1(-/-) mice showed remarkable resistance to Fas-induced hepatocyte apoptosis in vivo, probably because of attenuated JNK-mediated BimEL phosphorylation and mitochondrial apoptotic pathway activation. The reintroduction of ASK1 to ASK1(-/-) mouse liver using an adenoviral vector restored Fas-induced hepatocyte death and phosphorylation of JNK and BimEL. Similar findings were obtained in tumor necrosis factor alpha-induced hepatocyte apoptosis. Furthermore, ASK1 was involved in DNA damage-induced p21 up-regulation through a p38 pathway. ASK1 is involved in death receptor-mediated apoptosis and DNA-damage response by way of stress-activated MAPK in the liver, and thus acts as a tumor suppressor in hepatocarcinogenesis. This study provides new insight into the regulation of stress- activated MAPK signaling in hepatocarcinogenesis.


Behavioral effects of toluene in rats selectively bred for infantile vocalization rate.
Glue sniffing is epidemic among children living in poverty in Latin America. Previous research has shown that abused inhalants such as toluene share pharmacological properties with anxiolytic drugs, and that personality factors such as degree of anxiety have been proposed to modulate the effects of these drugs. To study this interaction in an animal model, rats selectively bred for high (High) or low (Low) rates of distress calls after maternal separation (ultrasonic vocalizations, USVs) were used to investigate toluene's acute and long-term effects on two measures of anxiety behavior. At ten days of age, neonatal subjects were administered toluene (1 g/kg i.p.) and USVs were recorded. The subjects were retested as juveniles on an elevated plus maze to examine sequela of earlier toluene exposure. Acute toluene administration reduced USVs relative to control groups in neonates of both lines, indicating anxiolysis. As expected, Lows had reduced USVs relative to Highs. At 28 days of age, Highs spent more time in the open arms of the elevated plus maze than Lows. However, prior neonatal toluene exposure blocked this reversal of behavioral phenotype. This suggests that early toluene exposure compromised a compensatory process occurring during this developmental period, which may have been maternally mediated. These results have implications for the effects of early drug exposure on plasticity in the developing nervous system.


Retinal hemangioblastoma vascular detail elucidated on swept source optical coherence tomography angiography.
To report the distinct vascular pattern of a treatment-naïve retinal hemangioblastoma imaged on swept source optical coherence tomography angiography (SS-OCTA). A 33-year-old female with a history of Von Hippel-Lindau disease presented for follow-up of bilateral retinal hemangioblastomas. Ultra-widefield fundus photography of the left eye revealed a small, juxtapapillary lesion. SS-OCTA imaging centered at the lesion identified two distinct vascular foci. Centrally, the lesion was composed of a dense capillary meshwork. Peripherally, a pattern of branching vessels with terminal budding was identified. The patient was diagnosed with a new juxtapapillary retinal hemangioblastoma. SS-OCTA can visualize the in-vivo vascular structure of retinal hemangioblastomas. Early lesion identification can help in prompt diagnosis and monitoring. Further investigation is needed to assert if the branching and budding pattern described in this case report is broadly characteristic of this tumor entity.


Electromagnetic nondiffracting pulses in lossless isotropic plasmalike media.
We introduce a scheme for describing electromagnetic nondiffracting pulses propagating in isotropic and lossless media characterized by a plasma-like refractive index. A family of nondiffracting waves in a dispersive medium is analytically derived in the form of a generalization of X waves propagating in vacuum. It is also shown how the ratio between pulse width and plasma length has a crucial effect on the pulse dynamics.


The national perinatal mortality rate in the State of Qatar during 2011; trends since 1990 and comparative analysis with selected high-income countries: the PEARL study project.
To prospectively ascertain Qatar's national perinatal mortality rate (PMR) during 2011, compare it with recent data from selected high-income countries, and analyze trends in Qatar's PMR between 1990 and 2011 using historical data. A national prospective cohort study. National data on live births, stillbirths, and early neonatal mortality (day 0–6) were collected from all public and private maternity units in Qatar (1st January–December 31st 2011) and compared with historical perinatal mortality data (1990–2010) ascertained from the database of maternity and neonatal units of Women's Hospital and annual reports of Hamad Medical Corporation (HMC). For inter-country comparison, country data were extracted from the World Health Statistics published by WHO in 2011 and from the European Perinatal Health Report published by the Europeristat project in 2008. A total of 20,725 births (20,583 live births plus 142 stillbirths) were recorded during the study period. Qatar's national PMR during 2011 was 9.55 [early neonatal mortality rate (ENMR) 2.7 and stillbirth rate (SBR) 6.85], which was a significant improvement from a PMR of 13.2 in 1990 [risk ratio (RR) 0.72, 95% confidence interval 0.58–0.89, P=0.002]. This improvement in PMR was more significant in ENMR (P<0.001) than in SBR (P=0.019). The stillbirths constituted 55% of PMR in 1990, which increased to 71.72% of PMR during 2011. The RR of PMR had a significant downwards trend between 1990 and 2011 (P=0.016). Qatar's 2011 PMR, SBR, and ENMR are comparable to those of selected high-income counties. Qatar's PMR, ENMR, and SBR have significantly improved between 1990 and 2011, and are currently comparable to those of selected high-income countries. An in-depth research to assess the correlates and determinants of stillbirth and perinatal mortality in Qatar is indicated.


Phase angle and mortality: a systematic review.
The phase angle, expressed through bioelectrical impedance, has been studied as a prognostic marker in several health conditions. As this issue is still conflicting, the question whether this parameter correlates with mortality in the most diverse clinical situations remains. Therefore, this study aimed to evaluate the relationship between phase angle and mortality through a systematic review of the literature. This research was conducted in electronic databases (Pubmed, Embase, Cochrane, Lilacs, Scielo, e Scopus), and included studies that had phase angle as a variable of interest and mortality/survival as an outcome. Data were extracted independently by two reviewers and disagreements were assessed by a third reviewer. Forty-eight of 455 papers were assessed and an amount of 42 showed a correlation between phase angle and mortality. Phase angle seems to be a good indicator for mortality in many clinical situations and can be used in screening individuals prone to this outcome.


Angiosarcoma of the scalp. A case with a particularly aggressive evolution.
A 80-year-old woman presented with a spontaneously bleeding wound on her scalp. The diagnosis of angiosarcoma was made based on histopathological examination of the second biopsy 1 month later. At that time, a large hematoma was present on the scalp and forehead with two bleeding erosions and numerous small blue-black nodules as well as a right cervical lymphadenopathy. The patient was treated by wide-field electron-beam radiotherapy, which showed no effect. The particularly aggressive evolution of this angiosarcoma led to death within less than 2 months.


Exploration of invasive mechanisms via global ncRNA-associated virus-host crosstalk.
Viral infection is a complex pathogenesis and the underlying molecular mechanisms remain poorly understood. In this study, an integrated multiple resources analysis was performed and showed that the cellular ncRNAs and proteins targeted by viruses were primarily "hubs" and "bottlenecks" in the human ncRNA/protein-protein interaction. The common proteins targeted by both viral ncRNAs and proteins tended to skew toward higher degrees and betweenness compared with other proteins, showed significant enrichment in the cell death process. Specifically, >800 pairs of human cellular ncRNAs and viral ncRNAs that exhibited a high degree of functional homology were identified, representing potential ncRNA-mediated co-regulation patterns of viral invasion. Additionally, clustering analysis further revealed several distinct viral clusters with obvious functional divergence. Overall, this is the first attempt to systematically explore the invasive mechanism via global ncRNA-associated virus-host crosstalk. Our results provide useful information in comprehensively understanding the viral invasive mechanism.


Mesenchymal stromal cells: a novel and effective strategy for facilitating engraftment and accelerating hematopoietic recovery after transplantation?
MSCs are multipotent cells that can be isolated from several human tissues and expanded ex vivo for clinical use. They comprise a heterogeneous population of cells, which, through production of growth factors, cell-to-cell interactions and secretion of matrix proteins, has a role in the regulation of hematopoiesis. In recent years, several experimental studies have shown that MSCs are endowed with immunomodulatory properties and with the capacity to promote graft survival in animal models. In view of these properties, MSCs have been tested in pilot studies aimed at preventing/treating graft rejection and at accelerating recovery after hematopoietic cell transplantation (HCT). The available clinical evidence deriving from these studies indicates that MSC infusion is safe and promising in terms of capacity of preventing graft failure. More debated is the effect of MSCs for what concerns their capacity of accelerating hematopoietic reconstitution after HCT. Whether the favorable effect of MSCs largely depends on the type of transplantation remains also a field of future investigation. Moreover, future researches should be oriented to gain more insights on MSC biological and functional mechanisms relevant for exploiting their use in the modulation of alloreactivity and in the promotion of hematopoietic reconstitution.


Longitudinal health utility and symptom-toxicity trajectories in patients with head and neck cancers.
This study examined long-term health utility and symptom-toxicity trajectories among patients with head and neck cancer (HNC). For patients diagnosed with HNC (2014-2019), Health Utility Index 3 (HUI-3), Edmonton Symptom Assessment Scale (ESAS), and MD Anderson Symptom Inventory (MDASI) surveys (including both the core and head and neck cancer modules) were prospectively collected at multiple time points (at the baseline, after surgery, during radiotherapy, and 3, 6, 12, and 24 months after treatment). Locally estimated scatterplot smoothing plots were generated to describe HUI-3, ESAS, and MDASI trajectories over time by clinicodemographic factors, treatment modality, and tumor subsite. Contributions of clinical factors were assessed with univariable and multivariable analyses. In 800 patients, the treatment modality and the tumor subsite produced unique HUI-3, ESAS, and MDASI trajectories. Patients treated with surgery alone experienced rapid improvements in HUI-3, ESAS, and MDASI scores postoperatively. Among patients treated with chemoradiotherapy, patients with nasopharyngeal carcinoma had greater declines in HUI-3 during treatment in comparison with patients with oropharyngeal carcinoma, but they had similar ESAS/MDASI scores. Among patients treated with radiotherapy, patients with laryngeal carcinoma had better HUI-3/ESAS/MDASI scores than those with oropharyngeal carcinoma during treatment, but they slowly converged after treatment. Female sex, an age > 75 years, a household income < $40,000, a Charlson comorbidity score > 1, an Eastern Cooperative Oncology Group performance status > 0 (at the baseline), and current smoking were independently associated with worse HUI-3 trajectories. HUI-3 had mild to moderate correlations (ρ = 0.2-0.5) with individual symptom-toxicity trajectories. Long-term HUI-3 trajectories are associated with tumor subsite, clinicodemographic, and treatment factors, and this may be partly explained by relationships with symptoms/toxicities. Separate evaluations by subsite and treatment should occur in health utility and symptom-toxicity studies of HNC. This study indicates that the long-term health utility and symptoms/toxicities of patients with the most common head and neck cancers (ie, squamous cell carcinomas and nasopharyngeal carcinomas) differ over time with a variety of factors, including the tumor anatomic site, treatment volume, clinicodemographic characteristics (eg, age, human papillomavirus status, tumor stage, gender, smoking status, alcohol status, education, and comorbidities), and treatment modalities. Generalizations across all head and neck cancers should be strongly discouraged. Future studies should evaluate health utility, symptoms and toxicities, and patient need assessments separately for each anatomic site and treatment modality.


Behaviour in aggregates of irradiated imaginal disk cells ofDrosophila.
The ability of dissociated cells to reaggregate, grow in culture (in vivo) and differentiate cuticular structures following increasing doses of X-ray radiation has been studied.At low doses (up to 5 Kr) reaggregation, but not cell viability, is affected. The reaggregation ability of irradiated cells is improved with increasing time between irradiation and aggregation and can be rescued by mixing irradiated and non-irradiated cells.On the contrary, growth and cell differentiation seem to be cell autonomous events. At doses between 5 Kr and 8 Kr cell proliferation is impaired, and after doses over 10 Kr reaggregates show a "negative growth." The differentiation of cuticular structures, such as chaetes and trichomes, show a different X-ray sensitivity.A unifying interpretation of these results is outlined in the discussion.


A modified immune tolerant mouse model to study the immunogenicity of recombinant human interferon beta.
Interferon beta may induce antibodies in multiple sclerosis patients and the incidence of immunogenicity depends on the type of product. These antibodies can reduce the efficacy of interferon beta. Two transgenic immune tolerant mouse models for human interferon beta (hIFNβ) (C57Bl/6, and C57Bl/6×FVB/N F1 hybrid mice) have been developed previously for studying immunogenicity. These models, however, may not be used for every interferon beta product because of the lack of immunogenicity in the wildtype genetic background. We therefore developed a modified transgenic mouse model by backcrossing the F1 hybrid C57Bl/6×FVB/N transgenic mice with wildtype FVB/N for 10 generations. These F10 offspring (referred to hear as FVB/N) have a genetic background consisting of mostly FVB/N (99.9%) and very little C57Bl/6 (0.1%), and are expected to have the more sensitive antibody producing phenotype of the parental FVB/N strain. The newly generated "FVB/N" strain was assessed for antibody formation against different rhIFNβ formulations compared to the C57Bl/6, and C57Bl/6×FVB/N transgenic mouse models. The new FVB/N transgenic mouse model was more sensitive for all tested rhIFNβ products, and the difference in antibody titers between the transgenic and non-transgenic mice of the FVB/N strain was much bigger compared to the antibody levels of the C57Bl/6, and C57Bl/6×FVB/N strains.


Descemet membrane endothelial keratoplasty in vitrectomized eyes: a case series of outcomes and complications.
The aim of this study was to evaluate the clinical outcomes of Descemet membrane endothelial keratoplasty (DMEK) in vitrectomized eyes. A multi-surgeon, retrospective case series of previously vitrectomized eyes that underwent DMEK between 2013 and 2018 at Moorfields Eye Hospital. Patients' demographics, preoperative, intraoperative and postoperative data were collected. In total, 14 eyes of 13 patients, aged 63 ± 14.6 years were included. Three eyes had intraoperative posterior dislocation of the DMEK graft into the vitreous cavity, two of these were aphakic and one had an unstable PCIOL. Postoperatively, one graft had a total detachment and required repeat keratoplasty for primary failure, two grafts had visually significant partial detachment and needed rebubbling. Three patients developed high intraocular pressure (IOP) and one required an urgent glaucoma drainage device 1-month post-DMEK. The mean corrected distance visual acuity was 0.81 ± 0.42 logMAR preoperatively, and postoperatively was 0.6 ± 0.51 at 3 months (p = 0.414); 0.69 ± 0.81 at 6 months (p = 0.684); and 0.7 ± 0.8 at 12 months (p = 0.658). DMEK in vitrectomized eyes has unique challenges that necessitate careful preoperative planning. We observed a significant proportion of dislocated grafts in vitrectomized eyes with either unstable IOL or aphakic. Moreover, vitrectomized eyes with secondary glaucoma may be particularly vulnerable to uncontrolled IOP postoperatively and close monitoring is essential to prevent worsening of visual acuity. We recommend that DMEK may not be a feasible option in eyes that are prone to collapse, in particular aphakic vitrectomized eyes, as opposed to DSAEK or penetrating keratoplasty.


Endothelin(B) receptor blocker inhibits high glucose-induced synthesis of fibronectin in human peritoneal mesothelial cells.
Long-term peritoneal dialysis using glucose-based dialysates is associated with peritoneal fibrosis. The object of this study was to investigate the hypothesis that endothelin (ET)-1, which is known to play an important role in various fibrotic diseases, may also be involved in peritoneal fibrosis using human peritoneal mesothelial cells (HPMC). HPMC were cultured with 4% D- or L-glucose, or loaded with 10 nmol/L ET-1. In some experiments, the ETA receptor antagonist BQ-123, the ETB receptor antagonist BQ-788, and antioxidants 4-hydroxy-2,2,6,6-tetramethyl-piperidine 1-oxyl (TEMPOL) and diphenyleneiodium chloride (DPI) were used. mRNA expression of ET-1, ETA receptor, ETB receptor, and fibronectin (FN) was analyzed by real-time polymerase chain reaction (real-time PCR). The protein levels for FN and ET-1 were measured by ELISA. CM-H2DCFDA-sensitive reactive oxygen species (ROS) were evaluated by flow cytometry. D-Glucose significantly induced mRNA expression of ET-1 and the ETB receptor but not the ETA receptor. FN production under high glucose conditions was inhibited by BQ-788. ET-1 directly stimulated H PMC to increase mRNA expression of FN and CM-H2DCFDA-sensitive ROS production. BQ-788, TEMPOL, and DPI inhibited mRNA expression of FN induced by ET-1. The present study suggests that high-glucose-induced FN synthesis is mediated by the ET-1/ETB receptor pathway and, therefore, an ETB receptor antagonist may be usefulin preventing FN production in HPMC.


Prostate-specific antigen in mass screening for carcinoma of the prostate.
Prostate-specific antigen (PSA) has various advantages over prostatic acid phosphatase (PAP) as a marker for prostate cancer, but its role in prostate cancer mass screening remains controversial. We measured serum PSA in addition to serum PAP determination and digital rectal examination (DRE) in our mass screening program to assess the usefulness of PSA for prostate cancer mass screening. Serum PSA and PAP measurements and DRE were performed in 1249 patients in mass screening for carcinoma of the prostate in 1989 and 1990. Thirteen cancers were diagnosed. We calculated the mean plus standard deviations (2SD) of the PSA and PAP values of men without cancer, and assessed the usefulness of PSA for prostate cancer screening by using these figures as the upper limit of normal. The number positive for PSA, PAP and DRE were 39, 36 and 48, respectively. If our screening had been performed without DRE, three cancers would have remained undetected, and the number would have been the same if performed without PSA. If the screening had been performed without PAP, on the other hand, no cancers would have remained undetected. The sensitivities of PSA and PAP were 54% and 23%, respectively. The screening detection rate with DRE and PSA was 0.88%, and with DRE and PAP was 0.64%. Measurement of serum PSA values with adjustment of the cut-off value was considered more useful than PAP in mass screening for prostate cancer.


Anesthetic management of a pregnant patient with an automatic implantable cardioverter-defibrillator: a case report.
There is little data currently available for the obstetric anesthetist to use as a reference for the anesthetic management of laboring women with automatic implantable cardioverter-defibrillators (AICDs). This case report involves a parturient with an AICD and a history of serious cardiac events. The information contained in this case report may be used by anesthesia providers in the obstetric suite confronted with this unique subset of patients that require in-depth anesthetic management. The parturient presented to our labor suite in active labor. The choice of anesthetics used to provide her with analgesia for labor is described, including the rationale for this anesthetic plan. A review of the literature that contains information on safe and effective anesthesia used for laboring women with AICDs is described.


Growth performance, carcass characteristics and meat sensory evaluation of West African dwarf sheep fed varying levels of maize and cassava hay.
A study was conducted to determine the growth performance and meat yield and quality of West African dwarf sheep. Twenty rams weighing an average of 15.3 ± 0.79 kg live weight and with an average age of 18 months were allotted at random to five dietary treatments of 0%, 25%, 50%, 75% and 100% maize hay (MH) for a period of 105 days. Dry matter (DM) intake and growth rate of the rams were improved as the level of cassava hay (CH) increased in the diets. Live weight gain varied significantly (P < 0.05) across the treatments, ranging from 38.8 to 47.9 g/day. The carcass weight of the rams fed 100% MH was significantly (P < 0.05) lower compared with the other treatments. Dressing percentage ranged from 56.5% to 61.0% with no significant (P > 0.05) difference observed across the treatments, while the distribution of the slaughtered parts was similar (P > 0.05) regardless of the dietary treatment. Proximate composition of the meat from the loin indicated that the DM, crude protein, fat and ash contents were not influenced (P > 0.05) by the dietary treatments. Panellists rated the meat to be similar (P > 0.05) in flavour, juiciness, tenderness and overall acceptability while colour and texture varied significantly (P < 0.05) across the treatments. In conclusion, this study indicated that better growth performance and meat production in West African dwarf sheep can be improved in form of body weight and carcass production when fed 25%MH and 75% CH diet.


[Quantitative determination of the gingival sulcus fluid by means of microcapillaries].
Evaluation of the quantity and quality of crevicular fluid has become increasingly important in the past few years. Amount and composition of the gingival exudate reflects the physical condition of the gingival margin. For drawing off the gingival fluid primarily filter paper stripes are recommended. Some authors use microcapillaries made of glass. For facilitating measurements on the fluid a special method is described using standardized glass pipettes for collecting the gingival exudate.


History and rationale of genetic toxicity testing: an impersonal, and sometimes personal, view.
Genetic toxicity testing is a necessary and pivotal component of product development and registration. This article traces the historical development and evolution of genetic toxicity testing, and the rationale for such testing, and identifies some of the individuals who played key roles in this process. The evolution of the present test batteries and some of the research and rationales behind the decisions to accept or reject tests are described.


Mitochondrial genomes of Trichinella species and genotypes – a basis for diagnosis, and systematic and epidemiological explorations.
In the present study we sequenced or re-sequenced, assembled and annotated 15 mitochondrial genomes representing the 12 currently recognised taxa of Trichinella using a deep sequencing-coupled approach. We then defined and compared the gene order in individual mitochondrial genomes (14 to 17.7 kb), evaluated genetic differences among species/genotypes and re-assessed the relationships among these taxa using the mitochondrial nucleic acid or amino acid sequence data sets. In addition, a rich source of mitochondrial genetic markers was defined that could be used in future systematic, epidemiological and population genetic studies of Trichinella. The sequencing-bioinformatic approach employed herein should be applicable to a wide range of eukaryotic parasites.


CADASIL: yesterday, today, tomorrow.
In 2019, the Brain Prize crowned the discovery of CADASIL in the 1990s and research efforts on this archetypal small vessel disease of the brain over 40 years. The hereditary origin of this arteriolopathy was discovered from a first clinical case and detailed observation of the patient's family. Thereafter, the role of causative mutations within the NOTCH3 gene were identified, allowing the development of a genetic test and then of an animal model of the disease. These crucial steps led to the discovery progressively that CADASIL is the most common genetic cerebral small vessel disease, to describing for the first time the natural history of a cerebral ischaemic small vessel disease from silent cerebral tissue lesions up to severe motor disability and dementia at the end stage, to demonstrating the central role of matrix proteins in its pathophysiology and to opening the door to the discovery of several other genes involved in monogenic cerebral small vessel diseases. Today, CADASIL is known to every neurologist, but the disease has not yet revealed all its secrets. A lot of effort is still needed to understand the intimate mechanisms of the disease and the most efficient targets or approaches for the development of efficient therapeutics. The history of CADASIL will be further enriched by multiple ongoing research projects worldwide, at clinical and preclinical level, and will continue to enlighten research in the field of cerebral small vessel disorders.


Tubocurarine suppresses slow calcium-dependent after-hyperpolarization in guinea-pig inferior mesenteric ganglion cells.
Intracellular recordings were made from neurones of the isolated guinea-pig inferior mesenteric ganglia. Single-spike potentials evoked by either depolarizing current pulses applied through the recording micro-electrode or stimulation of the hypogastric nerves were followed by an after-hyperpolarization (a.h.). The spike a.h. in 40% of the neurones, referred to herein as type I, had a relatively short duration (less than 50 ms) and exhibited a monophasic decay with a mean time constant (tau) of 11.4 ms. In the remaining cells (type II), the spike was followed by a long a.h. (greater than 100 ms) having a double-exponential decay; the fast and slow components of the a.h. are termed a.h.f and a.h.s, respectively, and they had mean tau values of 11.4 and 74 ms, respectively. A.h.f and a.h.s of type II neurones were reduced by membrane hyperpolarization and reversed their polarities between -80 and -90 mV. The reversal potentials shifted in a manner closely predicted by the Nernst equation as external K+ concentration was increased. Superfusion of low-Ca2+ high-Mg2+ solution to type II neurones reduced the a.h.f and a.h.s by 32 and 82%, respectively, indicating that a.h.s is largely Ca2+-dependent. Application of (+)-tubocurarine (10-100 microM) reversibly suppressed the a.h.s without affecting a.h.f in a concentration-dependent manner. Following a short train of action potentials evoked from type II neurones, the post-tetanic hyperpolarization (p.t.h.) was similarly depressed by (+)-tubocurarine in a dose-dependent manner. (+)-tubocurarine did not significantly change the amplitude of Ca2+-dependent spike potentials evoked in neurones bathed in Na+-free high-Ca2+ plus tetraethylammonium (5-10 mM) solution. The results indicate that (+)-tubocurarine selectively suppresses a.h.s, a slow Ca2+-dependent a.h., the consequence of which is a facilitation of repetitive discharges of the cells.


Photocontrolled miR-148b nanoparticles cause apoptosis, inflammation and regression of Ras induced epidermal squamous cell carcinomas in mice.
Despite evidence that microRNAs (miRNAs) are essential in modulating tumorigenesis, a major challenge in cancer treatment is to achieve tumor-specific selectivity and efficient yet safe delivery of miRNAs in vivo. In this study, we have developed a light-inducible silver nanoparticle nucleic acid delivery system that demonstrates precise spatiotemporal control, high cellular uptake, low cytotoxicity, escape from endosomes and release of functional miRNA into the cytosol. Using this approach, we delivered exogenous miR-148b to induce apoptosis in Ras-expressing keratinocytes and murine squamous cell carcinoma cells while avoiding cytotoxicity in untransformed keratinocytes. When administered to transgenic mice with HRasG12V-driven skin tumors, a single dose of silver nanoparticle conjugates followed by 415 nm LED irradiation at the tumor site caused a rapid and sustained reduction in tumor volume by 92.8%, recruited T cells to the tumor site, and acted as a potent immunomodulator by polarizing the cytokine balance toward Th1 both locally and systemically. In summary, our results demonstrate that spatiotemporal controlled miR-148b mimic delivery can promote tumor regression efficiently and safely.


CYP3A5*3 polymorphism and age affect tacrolimus blood trough concentration in myasthenia gravis patients.
The study aims to identify clinical factors affecting tacrolimus blood trough concentration (C0) in myasthenia gravis (MG) patients and to optimize the initial dose of tacrolimus in MG treatment. A total of 103 MG patients participated in this study, and their clinical factors, medication regimens, C0 values and CYP3A5*3 polymorphisms were collected in detail. We used a linear mixed model to analyze the effect of multiple factors on the dosage-weighted C0 (C0:D) and performed subgroup analyses to investigate the consistency of correlations between influencing factors and the C0:D ratios. Among all factors, CYP3A5*3 polymorphism and age showed a strong positive correlation with C0:D ratios. The C0:D ratios (ng/ml·mg-1) were higher for CYP3A5*3/*3 than for CYP3A5*1 (mean difference: 1.038, 95% confidence interval [CI]: 0.820-1.256, P-value <0.001), and for age in the range of 45-64 and ≥ 65 years than for age < 45 years (mean difference [95% CI] and P-value: 0.531[0.257-0.805] and P-value <0.001, 0.703 [0.377-1.029] and P-value <0.001, respectively). The C0:D ratios were not related to corticosteroid dosage, body weight, sex, hematocrit or the concomitant use of calcium channel blockers. The consistencies of the correlations between C0:D ratios and CYP3A5*3 polymorphism or age were confirmed by subgroup analyses. Thus, CYP3A5*3 polymorphism and age should be considered in optimizing the initial dose of tacrolimus for MG treatment.


In reply to the letter to the editor regarding "TGM6 variants in Parkinson's disease: clinical findings and functional evidence".
No abstract present.


Failure of captopril to lower blood pressure in spontaneously hypertensive rats offered water and saline to drink.
The hypotensive action of chronic oral captopril treatment (50 mg/kg per day) was examined in two groups of male spontaneously hypertensive rats (SHR) of the Okamoto strain, one group offered a choice of water and 0.9% saline as drinking fluid, the other offered water alone, a third group of SHR, offered a choice of water and 0.9% saline, were treated with vehicle (0.9% saline, 2 ml/kg per day). Captopril treatment, over ten days, significantly lowered blood pressure in the group drinking water only but failed to significantly alter the blood pressure of SHR drinking a choice of water and 0.9% saline. Vehicle treatment did not alter the blood pressure of SHR drinking a choice of saline and water. In an identical experiment using male, genetically hypertensive rats (GHR) of the Smirk strain, captopril lowered blood pressure to the same extent in GHR drinking either a choice of water and 0.9% saline or water alone. In conclusion, the reported exaggerated saline preference of the spontaneously hypertensive rat appears to antagonize the hypotensive action of captopril.


Resting-State functional networks of different topographic representations in the somatosensory cortex of macaque monkeys and humans.
Information processing in the brain is mediated through a complex functional network architecture whose comprising nodes integrate and segregate themselves on different timescales. To gain an understanding of the network function it is imperative to identify and understand the network structure with respect to the underlying anatomical connectivity and the topographic organization. Here we show that the previously described resting-state network for the somatosensory area 3b comprises of distinct networks that are characteristic for different topographic representations. Seed-based resting-state functional connectivity analysis in macaque monkeys and humans using BOLD-fMRI signals from the face, the hand and rest of the medial somatosensory representations of area 3b revealed different correlation patterns. Both monkeys and humans have many similarities in the connectivity networks, although the networks are more complex in humans with many more nodes. In both the species face area network has the highest ipsilateral and contralateral connectivity, which included areas 3b and 4, and ventral premotor area. The area 3b hand network included ipsilateral hand representation in area 4. The emergent functional network structures largely reflect the known anatomical connectivity. Our results show that different body part representations in area 3b have independent functional networks perhaps reflecting differences in the behavioral use of different body parts. The results also show that large cortical areas if considered together, do not give a complete and accurate picture of the network architecture.


Repair of UV-induced DNA damage in recombination-deficient strains of Bacillus subtilis.
To clarify the role of gene products for genetic recombination which might be concerned in excision repair, the repair of DNA lesions induced by ultraviolet (UV) irradiation was examined under non-growing conditions with a variety of recombination deficient (Rec-) mutants of Bacillus subtilis. The extent of repair was estimated by the recovery of transforming activity of DNA extracted from the cells during the post-irradiation incubation period (the assay method was termed as marker-repair experiment). The marker repair seemed to be accomplished by the excision repair as assumed from the effects of inhibitors. Among Rec- mutants tested, a mutant strain UVS80TH (rec-80) exhibited a normal level of marker repair activity, whereas strains GSY1025 (recA1), GSY1028 (recB2) and GSY908 (rec-4) exhibited reduced marker repair activities. These results and the data on UV sensitivity of the mutants indicate that (1) the products of all these Rec genes are related to UV resistance of the cell viability and are factors functioning through mechanisms other than excision repair, (2) the products of recA, recB and rec-4 genes display some roles in maintenance of a level of excision repair activity, and (3) the product of the rec-80 gene does not participate at all in excision repair.


Right sided transmesentric hernia: A rare cause of acute abdomen in adults.
Transmesenteric mesocolic hernias are a rare cause of acute abdomen in adults with few reported cases in published literature. We report a rare case of a 30-year-old male with right-sided transmesenteric hernia of ileum due to a congenital mesocolic defect resulting in acute abdomen, presenting as acute abdomen. The hernia was reduced, small bowel inspected for gangrene and mesenteric hernia repaired, following which the patient made a good recovery and was discharged 5 days later. The insidious onset of transmesenteric herniae and lack of specific radiological or laboratory investigations reaffirms the importance of surgeons maintaining a high index of suspicion for this surgical emergency. Transmesentric hernia though rare can present as a case of acute abdomen in an emergency. The diagnosis is purely by a CT scan and close monitoring of the patient's general condition in cases of non-specific abdominal pain is essential to identify the rare deteriorating patient for early surgical intervention and optimal outcome.


miR-212 promotes pancreatic cancer cell growth and invasion by targeting the hedgehog signaling pathway receptor patched-1.
microRNAs (miRNAs) are a class of small non-coding RNAs that play important roles in carcinogenesis. In the present study, we investigated the effect of miR-212 on pancreatic ductal adenocarcinoma (PDAC) and its target protein. Quantitative real-time PCR(qRT-PCR) was performed to detect the expression of miR-212 in PDAC tissues and pancreatic cancer cell lines. miR-212 mimic, miR-212 inhibitor and negative control were transfected into pancreatic cancer cells and the effect of miR-212 up-regulation and down-regulation on the proliferation, migration and invasion of cells were investigated. Furthermore, the mRNA and protein levels of Patched-1(PTCH1) were measured. Meanwhile, luciferase assays were performed to validate PTCH1 as miR-212 target in PDAC. miR-212 was up-regulated in PDAC tissues and cells.Using both gain-of function and loss-of function experiments, a pro-oncogenic function of miR-212 was demonstrated in PDAC. Moreover, up-regulated of PTCH1 could attenuate the effect induced by miR-212. These data suggest that miR-212 could facilitate PDAC progression and metastasis through targeting PTCH1, implicating a novel mechanism for the progression of PDAC.


Homicidal poisoning series in a nursing home: retrospective toxicological investigations in bone marrow and hair.
Homicidal poisonings remain rare and can be difficult to detect, especially in the elderly or in medical settings. In this atypical poisoning series, a young nursing assistant purposely poisoned thirteen residents of a nursing home and killed ten of them. The medications used were a mix of psychotropic medications (cyamemazine, loxapine, tiapride, risperidone, and mirtazapine), under liquid formulation, which were inducing malaise and coma. The forensic investigation included analysis of blood, urine, hair, and bone marrow and exhumations of seven corpses up to 3 years after the inhumation. Hair collected from a hairbrush of a cremated victim have been analyzed. Bone marrow sample preparation was based on a liquid/liquid triple extraction. Hair were incubated after decontamination overnight at 55 °C in methanol. Segmentation was possible for seven samples, except for delayed exhumation samples (n = 4) and hairbrush hair sample (n = 1). The extracts were then analyzed using gas chromatography coupled with mass spectrometry (GC-MS) for unknown screening and using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) for a targeted screening and quantification. Screenings revealed the presence of the same mix of psychotropic medications. Cyamemazine, mirtazapine, loxapine, tiapride, and risperidone hair concentrations were 6-17,458 pg/mg, 74-1271 pg/mg, 9-1346 pg/mg, 13-148 pg/mg, and 3-5 pg/mg, respectively. Cyamemazine bone marrow concentrations were 229 and 681 ng/g and 152-717 ng/mL in blood. Patients' medications were also identified and quantified. This poisoning series provide analytical data that could support subsequent toxicological result interpretation in similar forensic cases.


Determinants of physical activity among people with spinal cord injury: a test of social cognitive theory.
Little theory-based research has focused on understanding and increasing physical activity among people with physical disabilities. Testing a social cognitive theory-based model of determinants is important for identifying variables to target in physical activity-enhancing interventions. The aim of this study is to examine Social Cognitive Theory variables as predictors of physical activity among people living with spinal cord injury. Structural equation modeling was used to test a model of Social Cognitive Theory predictors of physical activity (n=160). The model explained 39% of the variance in physical activity. Self-regulation was the only significant, direct predictor. Self-regulatory efficacy and outcome expectations had indirect effects, mediated by self-regulation. Social Cognitive Theory is useful for predicting physical activity in people with spinal cord injury. Self-regulation is the most potent Social Cognitive Theory predictor of physical activity in people with spinal cord injury. Self-regulation and its determinants should be targeted in physical activity-enhancing interventions.


Significant bacterial contamination risk reduction with the use of diversion pouch.
Significant efforts have been made towards bacterial risk minimization by limiting the chance of bacteria entering into collected blood, detecting its presence and eliminating them by pathogen reduction technology. Improved skin disinfection and the use of diversion pouch are effective upstream measures to reduce the risk of bacterial sepsis. Here we report on our experience with the use of blood bags with diversion pouch. An observational study was performed to compare the bacterial contamination rate for two periods of time, i.e. before and after introduction of diversion pouch into blood bags. The incidence of bacterial contamination was monitored by the existing bacterial surveillance programme using pooled samples from 5 units of random donor platelets underwent aerobic culture in the BacT/ALERT 3D system. Between 1 June 2004 and 31 May 2006 (blood bag without diversion pouch), 50 (0·0213%) out of 234,252 units of random donor platelets were found to have bacteria on culture whereas 15 (0·0057%) isolates out of 262,156 units were found from 1 June 2007 to 31 May 2009 (after diversion pouch was introduced). Overall, there was an 85% reduction in bacterial contaminated risk due to skin flora (P < 0·0001) but an increasing trend of detection of non skin flora such as Streptococcus bovis was noted. Integration of diversion pouch into blood bags to divert the first 30 mL blood during blood collection on top of the current skin disinfection protocol can significantly reduce the risk of bacterial contamination.


Anti-BCMA CAR-T Cell Therapy in Relapsed or Refractory Multiple Myeloma Patients with Impaired Renal Function.
Anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy is effective and well-tolerated for refractory or relapsed multiple myeloma (RRMM). The purpose of the present study was to analyze efficacy in RRMM patients with renal impairment treated by anti-BCMA CAR-T cell therapy. A total of 59 RRMM patients were selected, and divided into impaired renal function (IRF) group [baseline estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 (n=18)] and normal renal function (NRF) group (baseline eGFR ≥ 90 mL/min/1.73 m2, n=41). For patients with IRF, eGFR at the 6th month post-CAR-T cells infusion was significantly higher than the baseline (P<0.05). The multivariate analysis showed that light chain type and beta-2 micro-globulin (beta-2M) were associated factors with the decrease of serum creatinine. Median progression-free survival (PFS) in the NRF group and IRF group was 266 days and 181 days respectively. Overall survival (OS) in the NRF group and IRF group was 877 days and 238 days respectively. There was no significant difference in the objective response rate (ORR) between the IRF group and the NRF group. It is suggested that CAR-T cells therapy could improve the renal function during the treatment of RRMM. The renal function could be more significantly improved in RRMM patients with light chain type than with other types.


Two pediatric patients with Von Hippel-Lindau disease type 2b: from patient to screening, from screening to patient.
Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited tumor susceptibility disease characterized by the development of hemangioblastomas of the brain, spinal cord and retina; pheochromocytomas and renal cell carcinoma. The disease is caused by mutations in the VHL tumor suppressor gene located on chromosome 3p26-p25. In this paper, we present two patients with VHL disease type 2B confirmed by genetic analysis. Diagnosis in the first patient was based on demonstration of retinal hemangioblastoma in association with bilateral pheochromocytoma. Family screening revealed renal cell carcinoma in her father and uncle. The second patient was discovered during family screening of another index case in adult age. VHL disease should be clinically suspected in any individual with a pheochromocytoma especially when there is bilateral and/or multifocal disease or family history. Screening of patients and at-risk family members for VHL-associated tumors should be essential in management of VHL.


Pneumomediastinum in COVID-19 disease: Clinical review with emphasis on emergency management.
Pneumomediastinum can be primary (spontaneous) or secondary to iatrogenic, traumatic, and non-traumatic causes. The incidence of spontaneous and secondary pneumomediastinum is higher in patients with coronavirus disease 2019 (COVID-19) compared to the general population. So, pneumomediastinum should be considered in the differential diagnosis of any patient with COVID-19 presenting with chest pain and breathlessness. A high level of suspicion is required to diagnose this condition promptly. Unlike in other disease conditions, pneumomediastinum in COVID-19 has a complicated course with higher mortality in intubated patients. No guidelines exist for managing pneumomediastinum patients with COVID-19. Therefore, emergency physicians should be aware of the various treatment modalities besides conservative management for pneumomediastinum and life-saving interventions for tension pneumomediastinum.


Endoscopic-assisted aortic replacement of the descending aorta through the 8th intercostal space to preserve collateral vessels: a case report.
We present the case of a 75-year-old man with repeated lower limb hematoma caused by consumptive coagulopathy from a type B chronic aortic dissection. His abdominal aorta was replaced with a Y-shaped graft 30 years prior to admission. As his previous aortic stent graft treatment failed, he underwent open surgical prosthetic graft replacement of the descending aorta under deep hypothermia. To reduce intra- and postoperative bleeding, we avoided cutting the ribs and intercostal arteries. The aneurysm was approached only through the 8th intercostal space; however, as the proximal descending aorta was inaccessible from this site, total endoscopic or endoscopic-assisted procedure was performed to approach the proximal descending aorta. All intercostal arterial orifices were securely closed by suture. The postoperative course was uneventful, and he was discharged home on postoperative day 11. The endoscopic surgery reduced impairment of collateral vessels during surgery and might have reduced the risk of paraplegia.


Lupeol acetate as a potent antifungal compound against opportunistic human and phytopathogenic mold Macrophomina phaseolina.
Antifungal activity of Monotheca buxifolia methanolic extract and its various fractions were assessed against Macrophomina phaseolina, a soil-borne fungal pathogen of more than 500 vegetal species as well as rare and emerging opportunistic human pathogen. Different concentrations of methanolic extract (3.125 to 200 mg mL-1) inhibited fungal biomass by 39-45%. Isolated n-hexane, chloroform and ethyl acetate fractions suppressed fungal biomass by 32-52%, 29-50% and 29-35%, respectively. Triterpenes lupeol and lupeol acetate (1, 2) were isolated from n-hexane while betulin, β-sitosterol, β-amyrin, oleanolic acid (3-6) were isolated from chloroform fraction. Vanillic acid, protocatechuic acid, kaempferol and quercetin (7-10) were isolated from the ethyl acetate fraction and identified using various spectroscopic techniques namely mass spectroscopy and NMR. Antifungal activity of different concentrations (0.0312 to 2 mg mL-1) of the isolated compounds was evaluated and compared with the activity of a broad spectrum fungicide mancozeb. Different concentrations of mencozeb reduced fungal biomass by 83-85%. Among the isolated compounds lupeol acetate (2) was found the highest antifungal against M. phaseolina followed by betulin (3), vanillic acid (7), protocatechuic acid (8), β-amyrin (5) and oleanolic acid (6) resulting in 79-81%, 77-79%, 74-79%, 67-72%, 68-71% and 68-71%, respectively. Rest of the compounds also showed considerable antifungal activity and reduced M. phaseolina biomass by 41-64%.


Characterization of the interaction between farrerol and bovine serum albumin by fluorescence and circular dichroism.
The binding of farrerol to bovine serum albumin (BSA) in aqueous solution was investigated by fluorescence quenching spectra, synchronous fluorescence spectra, circular dichroism (CD) and the three-dimensional (3D) fluorescence spectra at pH 7.40. The results of fluorescence titration indicated that farrerol could quench the intrinsic fluorescence of BSA in a static quenching way. The cause of showing upward curvy patterns in Stern-Volmer plots was analyzed. The binding sites number n and binding constant K using fluorescence quenching equation at 310 K were calculated. The binding distance and the energy transfer efficiency between farrerol and BSA were also obtained according to the theory of Förster's non-radiation energy transfer. The effect of some metal ions on the binding constant of farrerol with BSA was also studied. The effect of farrerol on the conformation of BSA was analyzed using CD, synchronous fluorescence spectra and three-dimensional (3D) fluorescence spectra under experimental conditions. Furthermore, the fluorescence displacement experiments indicated that farrerol could bind to the site I of BSA.


Steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT) or Hashimoto's encephalopathy: a case and review.
Steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT) is a condition of presumed autoimmune etiology that can present with a variety of neuropsychiatric signs and symptoms. To illustrate the clinical findings and treatment options of this underdiagnosed condition. We present a case of a patient diagnosed with SREAT and review the available literature including management of psychiatric symptoms. Little has been reported about the psychiatric management of patients with SREAT. Psychiatrists practicing in the general hospital setting should be aware of this often unrecognized entity to ensure accurate diagnosis and timely treatment.


[Connective tissue diseases and psoriasis].
Psoriasis is an autoimmune chronic inflammatory skin disease that is common in Spain. Connective tissue diseases are a heterogeneous group of conditions characterized by the abnormal function or structure of one or more of the elements that make up connective tissue. These diseases are also autoimmune in origin. In spite of the high prevalence of psoriasis in the general population, its association with a connective tissue disease such as systemic lupus erythematosus, dermatomyositis, scleroderma, or rheumatoid arthritis has only occasionally been reported. It is nevertheless important to have an understanding of such associations, given their significant clinical and therapeutic implications. The association between psoriasis and systemic lupus erythematosus is the one most often described, although the few reports available in the literature have mostly involved single cases. This review will also look at the characteristics of patients with psoriasis and dermatomyositis, mainly focusing on clinical features. The associations between psoriasis and either rheumatoid arthritis or systemic sclerosis will be examined more briefly. The review therefore aims to reflect the literature on psoriasis in association with rheumatic diseases, including coverage of etiologic, pathogenic, clinical, and therapeutic aspects. We emphasize that such cases should be managed by a multidisciplinary team in which care will usually be shared by a rheumatologist and a dermatologist.


and a poem.
"Survival is life after disaster, life in honor of our ancestors, despite the genocidal forces worked against them specifically so we would not exist. - from "The Shape of My Impact," by Dr. Alexis Pauline Gumbs. This poem explores the practice of mindful living within the context of remembering, bearing witness, and survival (personal and generational). The poem referenced within the title, "and a poem" is, "Remember the wind," written after Joy Harjo's poem, "Remember." "Remember the wind" uses the life cycle of a dandelion to explore the concepts of mindfulness, impermanence and interconnectedness. This poem is an homage to three brilliant Black women, Drs. Dara D. Méndez, Alexis Pauline Gumbs, and Tameka Cage Conley, whose scholarship, creative practice, and troublemaking have taught me how to turn my voice up. To view the original version of this poem, see the supplemental material section of this article online.


4D flow cardiovascular magnetic resonance for monitoring of aortic valve repair in bicuspid aortic valve disease.
Aortic valve repair has become a treatment option for adults with symptomatic bicuspid (BAV) or unicuspid (UAV) aortic valve insufficiency. Our aim was to demonstrate the feasibility of 4D flow cardiovascular magnetic resonance (CMR) to assess the impact of aortic valve repair on changes in blood flow dynamics in patients with symptomatic BAV or UAV. Twenty patients with adult congenital heart disease (median 35 years, range 18-64; 16 male) and symptomatic aortic valve regurgitation (15 BAV, 5 UAV) were prospectively studied. All patients underwent 4D flow CMR before and after aortic valve repair. Aortic valve regurgitant fraction and systolic peak velocity were estimated. The degree of helical and vortical flow was evaluated according to a 3-point scale. Relative flow displacement and wall shear stress (WSS) were quantified at predefined levels in the thoracic aorta. All patients underwent successful aortic valve repair with a significant reduction of aortic valve regurgitation (16.7 ± 9.8% to 6.4 ± 4.4%, p < 0.001) and systolic peak velocity (2.3 ± 0.9 to 1.9 ± 0.4 m/s, p = 0.014). Both helical flow (1.6 ± 0.6 vs. 0.9 ± 0.5, p < 0.001) and vortical flow (1.2 ± 0.8 vs. 0.5 ± 0.6, p = 0.002) as well as both flow displacement (0.3 ± 0.1 vs. 0.25 ± 0.1, p = 0.031) and WSS (0.8 ± 0.2 N/m2 vs. 0.5 ± 0.2 N/m2, p < 0.001) in the ascending aorta were significantly reduced after aortic valve repair. 4D flow CMR allows assessment of the impact of aortic valve repair on changes in blood flow dynamics in patients with bicuspid aortic valve disease.


Extracorporeal life support in pediatric cardiac dysfunction.
Low cardiac output (LCO) after corrective surgery remains a serious complication in pediatric congenital heart diseases (CHD). In the case of refractory LCO, extra corporeal life support (ECLS) extra corporeal membrane oxygenation (ECMO) or ventricle assist devices (VAD) is the final therapeutic option. In the present study we have reviewed the outcomes of pediatric patients after corrective surgery necessitating ECLS and compared outcomes with pediatric patients necessitating ECLS because of dilatated cardiomyopathy (DCM). A retrospective single-centre cohort study was evaluated in pediatric patients, between 1991 and 2008, that required ECLS. A total of 48 patients received ECLS, of which 23 were male and 25 female. The indications for ECLS included CHD in 32 patients and DCM in 16 patients. The mean age was 1.2 ± 3.9 years for CHD patients and 10.4 ± 5.8 years for DCM patients. Twenty-six patients received ECMO and 22 patients received VAD. A total of 15 patients out of 48 survived, 8 were discharged after myocardial recovery and 7 were discharged after successful heart transplantation. The overall mortality in patients with extracorporeal life support was 68%. Although the use of ECLS shows a significantly high mortality rate it remains the ultimate chance for children. For better results, ECLS should be initiated in the operating room or shortly thereafter. Bridge to heart transplantation should be considered if there is no improvement in cardiac function to avoid irreversible multiorgan failure (MFO).


Osteocyte density in woven bone.
Woven bone forms rapidly during tissue growth, following injury and in response to certain anabolic stimuli. Functional differences between woven and lamellar bone may be due, in part, to differences in osteocyte density (cells per unit tissue). Woven bone has been estimated to contain four to eight times more osteocytes than lamellar bone, although primary data to support this assertion are limited. Given recent findings implicating osteocytes as regulators of bone remodeling, bone formation and bone volume, such large differences in osteocyte density between woven and lamellar bone may have important consequences. In this study, we compared the density of osteocyte lacunae (lacunae/mm(2) tissue) in rat lamellar bone with that in woven bone formed under several different circumstances. We found that the lacunar density of lamellar cortical bone in the rat (834+/-83 cells/mm2, mean+/-SD) did not differ significantly from that of periosteal woven bone formed via intramembranous osteogenesis, either in response to mechanical loading (921+/-204 cells/mm2) or in the periosteal buttressing region of the fracture callus (1138+/-168 cells/mm2). In contrast, lacunar density of endochondrally derived woven bone in the center (gap) region of fracture callus was nearly 100% greater (1875+/-270 cells/mm2) than in lamellar cortical bone while lacunar density of primary spongiosa of the growth plate was 40% greater (1674+/-228 cells/mm2) than that in lamellar cancellous bone (1189+/-164). These findings demonstrate that lacunar density in woven bone varies depending on skeletal site and developmental history and appears to be elevated in endochondrally derived woven bone adjacent to marrow space. Given the considerable evidence supporting osteocytes as local initiators of bone remodeling, we suggest that woven bone with increased lacunar density may undergo remodeling at an accelerated rate.


Management of therapeutic unfractionated heparin in COVID-19 patients: A retrospective cohort study.
Patients hospitalized with severe acute respiratory syndrome coronavirus 2 infection are at risk for thrombotic complications necessitating use of therapeutic unfractionated heparin (UFH). Full-dose anticoagulation limits requirements for organ support interventions in moderately ill patients with coronavirus disease 2019 (COVID-19). Given this benefit, it is important to evaluate response to therapeutic anticoagulation in this population. The aim of this study was to assess therapeutic UFH infusions and associated bleeding risk in patients with COVID-19. This retrospective cohort study includes patients at Brigham and Women's Hospital, Boston, Massachusetts, receiving weight-based nursing-nomogram titrated UFH infusion during a 10-week surge in COVID-19 hospitalizations. Of 358 patients on therapeutic UFH during this interval, 97 (27.1%) had confirmed COVID-19. Patient characteristics, laboratory values, and information regarding UFH infusion and bleeding events were obtained from the electronic medical record. Patients who were COVID-19 positive had fewer therapeutic activatrd partial thromboplastin times (aPTTs) compared to COVID-19-negative patients (median rate, 40.0% vs 53.1%; P < .0005). Both major and clinically relevant nonmajor bleeding were increased in COVID-19-positive patients, with major bleeding observed in 10.3% (95% confidence interval [CI], 5.7%-17.9%) of patients who were COVID-19 positive and 3.1% (95% CI, 1.6%-5.9%) of patients who were COVID-19 negative (P < .005). In logistic regression, bleeding events were associated with receiving UFH for longer than 7 days, but not platelet count, coagulation, or inflammatory measurements. Our data indicate a higher incidence of bleeding complications in patients with COVID-19 receiving weight-based nursing-nomogram titrated UFH infusions despite a higher prevalence of subtherapeutic aPTTs in this population. These data underscore the need for prospective studies aimed at improving the quality and safety of therapeutic anticoagulation in patients with COVID-19.


Dietary fatty acids modulate adipocyte TNFa production via regulation of its DNA promoter methylation levels.
The factors regulating TNF alpha (TNFa) levels could be considered therapeutic targets against metabolic syndrome development. DNA methylation is a potent regulator of gene expression and may be associated with protein levels. In this study we investigate whether the effect of dietary fatty acids on TNFa released from adipocytes might be associated with modifications of the TNFa promoter DNA methylation status. A group of rats was assigned to three diets with a different composition of saturated, monounsaturated and polyunsaturated fatty acids. Samples of visceral adipose tissues were taken for adipocyte isolation, in which released TNFa levels were measured, and for methylation and expression studies. In addition, 3 T3-L1 cells were treated with palmitic, oleic and linoleic acids, with and without 5-Azacitydine (5-AZA). After treatments, cells and supernatants were included in the same analyses as rat samples. TNFa promoter methylation levels, gene expression and secretion were different according to the diets and fatty acid treatments associated with them. Cells treated with 5-AZA displayed higher TNFa levels than in the absence of 5-AZA, without differences between fatty acids. According to our results, dietary fatty acid regulation of adipocyte TNFa levels may be mediated by epigenetic modifications of the TNFa promoter DNA methylation levels.


Correction: Effect of Hygrothermal Aging and Surface Treatment on the Dynamic Mechanical Behavior of Flax Fiber Reinforced Composites. Materials 2019, 12(15), 2376.
The Y-axis in both Figure 3 and Figure 4 of [...].


South Dakota statewide Nursing Minimum Data Set Project.
The elements of the Nursing Minimum Data Set (NMDS) were collected manually from 188 medical records in eight acute care facilities. These eight facilities represent 54 per cent of the beds in South Dakota. The purpose of the study was to describe discharge destination, nursing diagnoses, nursing interventions, and nursing resource utilization for patients with fractured femur with pinning. The sample was primarily female (69.1 per cent), with a mean age of 78.5 years. Most (84.0 per cent) patients were transferred to another facility, with 46.2 per cent going to extended care facilities. The most frequent nursing diagnoses were comfort (89.9 per cent) and physical mobility (59.6 per cent). Interventions were classified using the 16-category classification scheme developed by Werley and Lang. The most frequently recorded types of interventions were in the category of monitoring and/or surveillance (16.7 per cent of 7,555 interventions), whereas emotional support and/or counseling was much less frequent (3.0 per cent of 7,555). Discharge planning was the most frequent nursing intervention in the category of coordination and collaboration of care (54.8 per cent of 188 patients). Documentation systems have been structured to accommodate technical tasks on flow sheets, for example. Nursing resource utilization was the most difficult, and also presently the least meaningful, NMDS element to collect because each facility has different staffing, different patient classification systems, and no prescribed method for collecting these data. Manual data collection is time-consuming and expensive and therefore not recommended.


Valganciclovir dosing according to body surface area and renal function in pediatric solid organ transplant recipients.
Oral valganciclovir is effective prophylaxis for cytomegalovirus (CMV) disease in adults receiving solid organ transplantation (SOT). However, data in pediatrics are limited. This study evaluated the pharmacokinetics and safety of valganciclovir oral solution or tablets in 63 pediatric SOT recipients at risk of CMV disease, including 17 recipients < or =2 years old. Patients received up to 100 days' valganciclovir prophylaxis; dosage was calculated using the algorithm: dose (mg) = 7 x body surface area x creatinine clearance (Schwartz method; CrCLS). Ganciclovir pharmacokinetics were described using a population pharmacokinetic approach. Safety endpoints were measured up to week 26. Mean estimated ganciclovir exposures showed no clear relationship to either body size or renal function, indicating that the dosing algorithm adequately accounted for both these variables. Mean ganciclovir exposures, across age groups and organ recipient groups were: kidney 51.8 +/- 11.9 microg * h/mL; liver 61.7 +/- 29.5 microg * h/mL; heart 58.0 +/- 21.8 microg * h/mL. Treatment was well tolerated, with a safety profile similar to that in adults. Seven serious treatment-related adverse events (AEs) occurred in five patients. Two patients had CMV viremia during treatment but none experienced CMV disease. In conclusion, a valganciclovir-dosing algorithm that adjusted for body surface area and renal function provides ganciclovir exposures similar to those established as safe and effective in adults.