Reimbursement for Orthopaedic Surgeries in Commercial and Public Payors: A Race to the Bottom.
The purpose of this study was to compare surgeon professional fee reimbursement and trends from Medicare versus commercial payors for inpatient orthopaedic surgeries: total knee arthroplasty (TKA), total hip arthroplasty (THA), total shoulder arthroplasty (TSA), anterior cervical diskectomy and fusion (ACDF), and posterior lumbar fusion (PLF). Patients undergoing TKA, THA, TSA, single-level ACDF, and single-level PLF from 2010 to 2018 were queried in a commercially insured claims database. Medicare reimbursements and the work relative value unit (wRVU) of each procedure were obtained from the Medicare Physician Fee Schedule. All costs were adjusted for inflation and reported in 2018 real dollars. Compound annual growth rates were calculated to assess the mean growth rate for each procedure. Linear regression was done to assess trends. On average, payments from Medicare were 57% less than payments from commercial payors. From 2010 to 2018, both Medicare and commercial payments decreased significantly for each surgery (P < 0.05 for all). Compared with inflation-adjusted commercial payments, Medicare payments decreased 2.1 times faster for TKA (-2.1% versus -1.0%), 2.8 times faster for THA (-1.4% versus -0.5%), 1.3 times faster for TSA (-1.0% versus -0.8%), and 1.9 times faster for ACDF (-1.1% versus -0.6%). PLF was the only procedure for which Medicare payments declined slower than commercial payments (-0.6% versus -1.21%). Medicare payments per wRVU markedly declined for TKA (-0.83%), THA (-0.80%), TSA (-0.75%), and ACDF (-1.10%), whereas commercial payments per wRVU for those surgeries showed no notable change. For PLF, there was a notable decrease in both Medicare (-0.63%) and commercial (-1.21%) payments per wRVU. Over the past decade, both commercial and Medicare surgeon payments for commonly performed inpatient orthopaedic surgeries decreased markedly, with Medicare payments decreasing an average of 1.5 times faster than commercial payments. The impact of declining reimbursements on access and quality of care merits additional investigation.


Three chemosensory proteins from the sweet potato weevil, Cylas formicarius, are involved in the perception of host plant volatiles.
Chemosensory proteins (CSPs) play important roles in chemical communication, but their precise physiological functions are still unclear. Cylas formicarius is the most serious pest attacking sweet potato around the world. At present, there is no effective way to control this pest. Our results showed that CforCSP1, 5 and 6 genes were highly expressed in the antennae of both sexes of C. formicarius. In addition, results from a fluorescence competitive binding assay showed that the CforCSP1, 5 and 6 proteins had high binding affinities for 17 plant volatiles including eight host plant volatiles. This indicated that the three proteins may be involved in the detection of host plant volatiles. Furthermore, results from four-arm olfactometer bioassays showed that there was a significant tendency for C. formicarius to be attracted to eucalyptol, β-carotene, benzaldehyde, vanillin and phenethyl alcohol, while it was repelled by β-ionone. Finally, the levels of expression of the three CforCSPs in C. formicarius were successfully inhibited by RNA interference (RNAi). Behavioral experiments showed that CforCSP1, 5 and 6-deficient C. formicarius were partly anosmic to β-cyclocitral, benzaldehyde, octyl aldehyde, and β-ionone and exhibited a reduced ability to locate the host plant volatiles β-carotene and vanillin. Our data suggest that CforCSP1, 5 and 6 likely are involved in the chemical communication between C. formicarius and host plant volatiles, which may play pivotal roles in oviposition and feeding site preferences. More importantly, these results could provide information for the development of monitoring and push-pull strategies for the control of C. formicarius. © 2021 Society of Chemical Industry.


Incidence and risk factors for medical adhesive-related skin injury in catheters of critically ill patients: A prospective cohort study.
The skin in contact with the adhesives used to secure catheters is vulnerable to medical adhesive-related skin injury (MARSI). The incidence of these injuries and the risks associated with their development have not been accurately estimated previously in critically ill patients. The aim of this study was to investigate the incidence and risk factors for MARSI in catheters of critically ill patients. A prospective cohort study was conducted in adult intensive care units of two Brazilian university hospitals. A total of 150 patients (439 catheters) were included. The skin exposed to the catheter fixation adhesives (central venous, nasogastric, nasoenteral, and indwelling urinary) was examined daily by four trained researchers. The patients' sociodemographic and clinical data were collected from their electronic medical records. The association between independent variables and MARSI was investigated by bivariate statistics, followed by a multiple logistic regression. The MARSI incidence was 42% (86.5 MARSIs per 1000 patient-days). Advanced age, prolonged hospital stay, dry skin, repetitive adhesive removal, low Braden Scale score, and hypoalbuminemia were associated with MARSI (p < .05). According to the multivariate logistic regression, dry skin increased the chance of MARSI by 5.2 times (odds ratio: 5.2; 95% confidence interval: 2.4-11.1), while the Braden Scale score was a protective factor, showing 30% less chance of MARSI for each added score (odds ratio: 0.7; 95% confidence interval: 0.6-0.9). A higher incidence of MARSI was observed in nasoenteral catheters and in those fixed with adhesive using natural rubber. The MARSI types were predominantly mechanical (70.3%): skin stripping (41.3%), skin tear (26.1%), and tension injury or blister (2.9%). MARSI is a common event in adult intensive care units, and most risk factors are modifiable. Preventive actions are potentially capable of reducing incidence, optimising financial resources, and improving clinical results.


Transplantation of CD95 ligand-expressing grafts: influence of transplantation site and difficulty in protecting allo- and xenografts.
CD95 and its ligand (CD95L) have been implicated in the regulation of immune responses. Recently, it was reported that CD95L expression prevented rejection of allogeneic grafts transplanted under the kidney capsule. In contrast, we reported that enforced CD95L expression in subcutaneously grafted cells induced acute rejection even in the syngeneic or immunodeficient hosts. In this study, we investigated whether the CD95L-expressing cells could be protected from rejection when transplanted under the kidney capsule. CD95-negative cells (baby hamster kidney and L5178Y lymphoma cells) were transfected with CD95L cDNA to express functional CD95L. The cells were transplanted into skin or renal subcapsular space of immunocompetent or T cell-deficient nu/nu mice. The parental cells grew well in nu/nu or syngeneic mice but were rejected in allogeneic or xenogeneic immunocompetent mice. The CD95L transfectants were rejected when transplanted subcutaneously in all types of mice studied. However, when transplanted under the kidney capsule, they survived in nu/nu or syngeneic mice but were rejected in allogeneic or xenogeneic immunocompetent mice. These results imply that CD95L expression may not be sufficient to protect the grafts from rejection, and the survival of CD95L-bearing grafts is substantially influenced by the site of transplantation.


META RNA profiling: Multiplexed quantitation of targeted RNAs across large numbers of samples.
META RNA profiling is a simple and inexpensive method to measure the expression of multiple targeted RNAs across many samples. By assigning sample-specific tags up-front during reverse-transcription, cDNAs from multiple samples can be pooled prior to amplification and deep sequencing. Such early parallelization of samples simplifies the workflow, minimizes cross-sample experimental variability, and reduces reagent and sequencing costs. Herein we describe the theoretical framework of the method and provide a detailed protocol to facilitate its implementation.


The chicken leukocyte receptor cluster.
Receptors of the immunoglobulin-like superfamily are critically involved in virtually every aspect of immune responses. One large chromosomal area encoding such immunoregulatory receptors is the leukocyte receptor cluster. Here we review various aspects of the chicken Ig-like receptor (CHIR) family, located on microchromosome 31, an orthologous position to the mammalian leukocyte receptor cluster. The CHIR family has been massively expanded with over hundred CHIR genes that are further distinguished into activating, inhibitory and bifunctional receptors. Comparisons of various features such as amino acid motifs, genomic structure, expression and associated adaptor molecules reveal the homology of CHIR to both the killer Ig-like and the leukocyte Ig-like receptor families, with most pronounced correlation of certain CHIR to the NK cell receptor KIR2DL4. To date the CHIR ligands remain largely obscure with the exception of CHIR-AB1 that binds to chicken IgY. Detailed analyses of CHIR-AB1, its crystal structure, the interaction to IgY and functional capabilities allow us to draw conclusions regarding Fc receptor phylogeny and function.


Carboplatin plus pemetrexed for platinum-pretreated, advanced non-small cell lung cancer: a retrospective study with pharmacogenetic evaluation.
In the present study, the combination of carboplatin (CBDCA) plus pemetrexed (PMX) for the treatment of patients with platinum-pretreated, pemetrexed-naïve, advanced non-small cell lung cancer (NSCLC) was investigated. Also, single nucleotide polymorphisms (SNPs) at the XRCC3, XPD, ERCC1, GARFT, DHFR, and TS genes were investigated. Eighty patients treated with CBDCA/PMX at two Italian institutions were evaluable. Of these, 73 patients had blood samples collected for pharmacogenetic evaluation. Overall, the median age was 59 years (26-78), 59 patients (73.7%) had a performance status of 0, and 34 patients (42.5%) had stage IIIB disease. Thirty-eight patients (47.5%) had responded to prior first-line platinum-based therapy. Study treatment resulted into one complete and 33 partial responses for an overall response rate of 42.5%. The disease control rate was 77.5%. The median progression-free survival (PFS) and overall survival (OS) were 5.8 and 17.4 months, respectively. Responders achieved a significant longer PFS and OS versus non-responders (P = 0.007 and P = 0.003, respectively). The only grade 3-4 adverse event occurring in more than 5.0% of patients was neutropenia (6 patients, 7.5%). No statistically significant association was noted between polymorphisms of the genes analyzed and clinical outcome. In patients with platinum-pretreated, advanced NSCLC and favorable clinical prognostic factors, treatment with CBDCA/PMX is associated with a good clinical outcome and toxicity profile. None of the SNPs analyzed was found to be a useful predictor of treatment efficacy.


The case of self-resolving type III achalasia after bilateral lung transplant.
Post-surgical achalasia has been previously described in large case series but there are limited data on the natural progression of the disease process. In general, achalasia is considered an "incurable" disease as per published guidelines. We present here, the first report of a patient with post-surgical achalasia which resolved spontaneously. This is a retrospective chart review. A 60-year-old male presented for dysphagia 3 months status post-bilateral lung transplant and was diagnosed with achalasia following positive manometry. Absent any treatment, his repeat manometry showed complete, spontaneous resolution of the achalasia 2 years following lung transplant. To our knowledge, this is the first such case of spontaneously resolving achalasia following bilateral lung transplant. This case warrants further study in to the natural progression of post-surgical achalasia.


Contraction-relaxation coupling is unaltered by exercise training and infarction in isolated canine myocardium.
The two main phases of the mammalian cardiac cycle are contraction and relaxation; however, whether there is a connection between them in humans is not well understood. Routine exercise has been shown to improve cardiac function, morphology, and molecular signatures. Likewise, the acute and chronic changes that occur in the heart in response to injury, disease, and stress are well characterized, albeit not fully understood. In this study, we investigated how exercise and myocardial injury affect contraction-relaxation coupling. We retrospectively analyzed the correlation between the maximal speed of contraction and the maximal speed of relaxation of canine myocardium after receiving surgically induced myocardial infarction, followed by either sedentary recovery or exercise training for 10-12 wk. We used isolated right ventricular trabeculae, which were electrically paced at different lengths, frequencies, and with increasing β-adrenoceptor stimulation. In all conditions, contraction and relaxation were linearly correlated, irrespective of injury or training history. Based on these results and the available literature, we posit that contraction-relaxation coupling is a fundamental myocardial property that resides in the structural arrangement of proteins at the level of the sarcomere and that this may be regulated by the actions of cardiac myosin binding protein C (cMyBP-C) on actin and myosin.


Elevated human placental heat shock protein 5 is associated with spontaneous preterm birth.
Specific heat shock proteins are associated with pregnancy complications, including spontaneous preterm birth (SPTB). Placental proteomics and whole exome sequencing recently suggested an association between heat shock protein HSPA5 and uncomplicated SPTB. In the present study, we investigated the localization of and possible roles for HSPA5 in SPTB. Western blot was performed to validate the result from the previously published proteomic analysis. We used qPCR to assess mRNA expression of genes and immunohistochemistry and immunoelectron microscopy to examine localization of HSPA5 in placental tissue. We silenced the HSPA5 gene in the HTR8/SVneo human trophoblast cell line to investigate possible functions of HSPA5. HSPA5 was upregulated in placentas from SPTBs compared to spontaneous term births. We did not observe upregulation of HSPA5 mRNA in placental samples. The protein was localized in placental trophoblast in both spontaneous preterm and term placentas. Gene silencing of HSPA5 in human trophoblast cell culture affected the inflammatory response and decreased the expression of several proinflammatory genes. We suggest that upregulation of HSPA5 in the placenta is associated with spontaneous preterm labor. HSPA5 may promote the inflammatory response and alter the anti-inflammatory state of the placenta which could eventually lead to premature labor. We validated upregulation of HSPA5 in placentas from spontaneous preterm birth. HSPA5 was not upregulated at transcriptional level which suggests that it may be regulated post-translationally. Silencing HSPA5 in a human trophoblast-derived cell line suggested that HSPA5 promotes expression of proinflammatory cytokines. The emerging inflammation could lead to spontaneous preterm labor. Identifying inflammatory pathways and factors associated with spontaneous preterm birth increases knowledge of the molecular mechanisms of premature labor. This could provide cues to predict imminent premature labor and lead to information about how to safely maintain pregnancies.


Pseudo-aneurysm formation complicating the Rastelli procedure.
We report a patient presenting with a pseudo-aneurysm arising from the extra-cardiac conduit and dehisced intra-cardiac patch following the Rastelli procedure. Since the aneurysm was adherent to the sternum, re-operation was facilitated by establishing extra-thoracic cardio-pulmonary bypass and hypothermia before opening the chest.


Association of IGHM polymorphisms with susceptibility to type 1 diabetes.
Differentiation of B lymphocytes is accompanied by a regulated switch in the expression pattern and stability of surface and secretory immunoglobulins (Igs). Several lines of evidence show that autoimmune responses evolving in much autoimmune pathologies were associated with a high level of humoral Ig, but their pathogenic role remains elusive. The aim of this study was to test the hypothesis that variants at the immunoglobulin heavy-chain IGH locus are genetic determinants to T1D susceptibility. Here, we tested the genetic association of the variants of the immunoglobulin heavy-chain IGH locus as a genetic determinant to T1D susceptibility. A total of 255 subjects from 59 Tunisian families were genotyped for 15 SNPs mapping in 4 regions in IGH locus. We found that rs1950942, rs2180790, rs1808152, and rs1956596 of IGHM and rs2516751 variant located in the IGHA1/IGHG2 region were significantly associated with a risk for T1D p = 7E-3; p = 0.03; p = 0.02; p = 0.043; and p = 3.65E-5, respectively. The TATGG haplotype derived from LD across three SNPs from IGHM gene and two SNPs from IGHD gene was significantly over-transmitted from parents to affect offspring. Our results suggest that genetic variants at the IGH locus are associated with T1D susceptibility. These variations may predispose to IgG AutoAbs production against pancreatic antigens and AutoAbs multi-reactivity, leading to T1D development.


A Proactive Policy to Eliminate Viral Hepatitis Infection: Five-Year Results for the Subdistrict Model in Thailand.
The objective of this study was to ascertain hepatitis B (HBV) and hepatitis C (HCV) infection rates in individuals toward the early initiation of treatment and prevention of developing hepatocellular carcinoma (HCC). This cross-sectional study was performed on 2084 participants from two subdistricts in Chiang Mai and Lampang provinces, northern Thailand. Screening for viral hepatitis in the general population was conducted at subdistrict health-promoting hospitals in Nong Pa Krang, in the suburb of Chiang Mai city, and Thoenburi, a subdistrict in the rural area of Lampang province, northern Thailand. Ninety-one (4.4%) participants tested positive for either HBV or HCV, with 3.3% of all participants infected with HBV and 1.1% infected with HCV. Treatment follow-up was 29.0% of HBV and 54.5% of HCV. A proactive approach to eliminate viral hepatitis can be carried out at the subdistrict level in Thailand. Success could increase participation in other subdistricts in a cascade-like manner by 2030. The identified factors of success are leadership by the local government supported by the Local Health Fund and Village Health Volunteers.


A model for membrane potential and intracellular ion distribution.
Most cells carry a negative electric charge. It produces a potential difference across the membrane, which regulates voltage-sensitive ion transport and ATP synthesis in mitochondria. The negative charge comes partly from an excess of negative ions in the cell interior (Donnan potential) and partly from ionized groups on the membrane (surface potential). In this work we propose some important modifications to the existing theory of membrane potential. First, we calculate the concentration profile of intracellular positive ions and derive a simple equation to assess the submembrane depletion of positive ions that gives rise to the Donnan potential. The extent of depletion varies with potential, which may provide a regulatory mechanism for ion pumps and channels. Next we consider the surface component of the potential and note that the standard Gouy-Chapman theory has been developed for planar membranes, whereas real cell membranes have a closed geometry. In this case, charges on the membrane surface are not expected to generate fields extending into the cell interior. This fact calls for reinterpretation of some theoretical points as well as experimental data. In particular, the experimentally demonstrated electrostatic attraction between cationic proteins and the negative membrane must now be explained without invoking intracellular fields, and we suggest a new mechanism that can account for this interaction.


Impact of post-void residual urine volume on intravesical recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma.
To examine the impact of post-void residual urine volume on the risk of postoperative recurrence of intravesical carcinoma in patients with upper urinary tract urothelial carcinoma undergoing nephroureterectomy. We retrospectively reviewed the data of 81 patients who were admitted to Chiba University Graduate School of Medicine Hospital and underwent nephroureterectomy for upper urinary tract urothelial carcinoma without bladder carcinoma. We assessed the predictive factors for intravesical recurrence after nephroureterectomy in all patients. Next, we compared patients with and without a residual urine volume using propensity score-matching analysis. The presence of a residual urine volume was defined as ≥30 mL. The median follow-up period among all patients was 48 months. The presence of pyuria and a residual urine volume were associated with bladder recurrence in the multivariate analysis. A total of 19 patients each were selected after matching, and we confirmed a significant difference between the presence and absence of a residual urine volume (P = 0.0291). The 2-year postoperative recurrence-free rate of patients with and without a residual urine volume was 32% and 82%, respectively. This is the first study to evaluate the post-void residual urine volume and intravesical recurrence rate after nephroureterectomy for upper urinary tract urothelial carcinoma. The presence of residual urine might be a risk factor for postoperative recurrence of intravesical carcinoma.


Taking a Motivational Interviewing Approach to Prevention Science: Progress and Extensions.
This commentary reviews advances gleaned from the current set of papers to Motivational Interviewing (MI) in prevention science. We begin by acknowledging the pioneering work of Miller and Rollnick to develop the construct of MI, then Dishion's use of MI principles to adapt applications of MI for the field of prevention science. We then highlight some of the contributions provided by the current set of papers and other recent extensions of MI. These novel applications are directed to parents, teachers, and older youth in the service of facilitating behavior change to promote youth development.


Changes in muscle activity during fast, alternating flexion-extension movements of the knee.
The effects of high frequency alternating knee flexion-extension on muscle activity of the quadriceps and hamstring muscle groups has been investigated. Standard loads were used for each subject. The muscle activity in vastus medialis, vastus lateralis, rectus femoris and the lateral hamstrings were recorded by electromyography during increasing velocities. Rectus femoris and hamstrings were found to increase their activities significantly with increasing speed while vastus medialis and vastus lateralis showed no such change. The individual thigh muscles thus differ in function in relation to the velocity of movement.


A multi-channel sensor based on 8-hydroxyquinoline ferrocenoate for probing Hg(II) ion.
A new sensing molecule 8-hydroxyquinoline ferrocenoate (Fc-Q) which combines ferrocene and 8-hydroxyquinoline moieties was synthesized and applied as a multi-channel sensor for the detection of Hg(2+) ion. Fc-Q can coordinate with Hg(2+) to give colorimetric, fluorescent and electrochemical responses. Upon complexation with Hg(2+) ion, the characteristic absorption peak is red-shifted (Δλ=45 nm), the fluorescent intensity is quenched at 303 nm, and the oxidation peak is cathodic shifted (ΔE(1/2)=-149 mV). Quantitatively analyzed Hg(2+) ions at the range of ppb level could be achieved by electrochemical response. For the practical application of sensing Hg(2+) in real world water, Fc-Q modified screen-printed carbon electrodes were obtained for facile, sensitive, and on-site analysis of Hg(2+).


The Catch-Up Growth in Stunted Children: Analysis of First and Second India Human Development Survey Data.
Change in stunting as the children grow older is rarely found in published literature. The present paper compares the change in the prevalence of stunting among children as they grow from 0-4 years to 7-11 years. The present paper is a secondary analysis of India Human Development Survey-I (IHDS-I) (2005) and IHDS-II (2012) data for Kerala. In total, 411 children of age 0-4 years and 390 children of age 7-11 years with anthropometric measurements were included in the present study, respectively, from IHDS-I and IHDS-II. The statistical analyses were done using SPSS 21.0. The prevalence of stunting was estimated. Bivariate and multivariate analyses were performed using the Pearson Chi-square test. The prevalence of stunting among children has been drastically reduced (50.4% to 20.3%) while growing older from 0-4 years to 7-11 years. More than half of the stunted children below 5 years regained normal growth, as they grow older.


Adsorption of sulfur mustard on clean and water-saturated ZnO(101¯0): Structural diversity from first-principles calculations.
We investigate the adsorption of a chemical warfare agent, namely sulfur mustard (SM), on clean and water-saturated ZnO(101¯0) surfaces using density functional theory calculations to understand the first step of its efficient neutralization to less toxic chemical compounds. We determine the relative stability of various SM conformers adsorbed at different sites on both ZnO surfaces. The unique hydrogen bonding patterns obtained for the idealized clean and the more realistic water-saturated ZnO surface are analyzed and their influence on the stability of the SM@ZnO structures is demonstrated. We find that absolute values of the calculated binding and interaction energies are significantly higher for the clean than for the water-saturated ZnO surface due to the formation of Cl⋯Zn and S⋯Zn contacts. The high adsorptive reactivity of the clean ZnO surface is also evident from the strong structural changes of the initial local energy minimum gas-phase conformations of the SM molecules upon adsorption. This phenomenon is not observed for the water-saturated ZnO surface, which has almost no impact on the SM conformation after adsorption, leaving it as it exists in the gas phase. The insights from the results obtained provide a missing piece toward the understanding of the complex mechanism of SM neutralization on ZnO surfaces.


Effect of administration route on DDT on acute toxicity and on drug biotransformation in various rodents.
DDT was administered to the guinea pig, mouse and rat either ig or ip and to the hamster ig in order to investigate variations in the response of hepatic and duodenal drug-metabolizing enzymes to DDT. The intragastric dose (160 mg/kg) was found to produce gastric bleeding and severe tremor in rats and mice but not in other rodents. The hepatic aryl hydrocarbon hydroxylase activity and cytochrome P-450 concentration decreased after the ig administration of DDT to rats, mice and guinea pigs but in hamsters the activiy of aryl hydrocarbon hydroxylase and cytochrome P-450 concentration increased 12 hr after the dosage. The aryl hydrocarbon hydroxylase activity decreased also in the duodenal mucosa of the rat after the ig administration of DDT. The ip dose had no effects on the hepatic or duodenal monooxygenase system in 12 hr. The UDPglucuronosyltransferase activity was slightly lowered in hepatic microsomes of the rat and mouse after the ig dose of DDT, but the decrease was more profound when measured after in vitro trypsin digestion of microsomes. The trypsin digestion activated the hepatic UDPglucuronosyltransferase in all the species studied, i.e., guinea pig, hamster, mouse and rat (3-, 3-, 5-, and 8-fold, respectively). The duodenal UDPglucuronosyltransferase activity was not affected by DDT administration in any of the species studied. The results suggest that the acute toxic effects of DDT are species-dependent and the administration route is important in DDT toxicity. The hydroxylation step in drug metabolism is more sensitive to DDT than the glucuronidation step.


Downregulation of deoxycytidine kinase in cytarabine-resistant mantle cell lymphoma cells confers cross-resistance to nucleoside analogs gemcitabine, fludarabine and cladribine, but not to other classes of anti-lymphoma agents.
Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma associated with poor prognosis. Implementation of high-dose cytarabine (araC) into induction therapy became standard-of-care for all newly diagnosed younger MCL patients. However, many patients relapse even after araC-based regimen. Molecular mechanisms responsible for araC resistance in MCL are unknown and optimal treatment strategy for relapsed/refractory MCL patients remains elusive. Five araC-resistant (R) clones were derived by long-term culture of five MCL cell lines (CTRL) with increasing doses of araC up to 50 microM. Illumina BeadChip and 2-DE proteomic analysis were used to identify gene and protein expression changes associated with araC resistance in MCL. In vitro cytotoxicity assays and experimental therapy of MCL xenografts in immunodeficient mice were used to analyze their relative responsiveness to a set of clinically used anti-MCL drugs. Primary MCL samples were obtained from patients at diagnosis and after failure of araC-based therapies. Marked downregulation of deoxycytidine-kinase (DCK) mRNA and protein expression was identified as the single most important molecular event associated with araC-resistance in all tested MCL cell lines and in 50% primary MCL samples. All R clones were highly (20-1000x) cross-resistant to all tested nucleoside analogs including gemcitabine, fludarabine and cladribine. In vitro sensitivity of R clones to other classes of clinically used anti-MCL agents including genotoxic drugs (cisplatin, doxorubicin, bendamustine) and targeted agents (bortezomib, temsirolimus, rituximab) remained unaffected, or was even increased (ibrutinib). Experimental therapy of immunodeficient mice confirmed the anticipated loss of anti-tumor activity (as determined by overall survival) of the nucleoside analogs gemcitabine and fludarabine in mice transplanted with R clone compared to mice transplanted with CTRL cells, while the anti-tumor activity of cisplatin, temsirolimus, bortezomib, bendamustine, cyclophosphamide and rituximab remained comparable between the two cohorts. Acquired resistance of MCL cells to araC is associated with downregulation of DCK, enzyme of the nucleotide salvage pathway responsible for the first phosphorylation (=activation) of most nucleoside analogs used in anti-cancer therapy. The data suggest that nucleoside analogs should not be used in the therapy of MCL patients, who relapse after failure of araC-based therapies.


Corrigendum: Case report: MAP2K1 K57N mutation is associated with primary resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer.
[This corrects the article DOI: 10.3389/fonc.2022.1030232.].


Impact of COVID-19 on routine immunisation in South-East Asia and Western Pacific: Disruptions and solutions.
Data on COVID-19-induced disruption to routine vaccinations in the South-East Asia and Western Pacific regions (SEAR/WPR) have been sparse. This study aimed to quantify the impact of COVID-19 on routine vaccinations by country, antigen, and sector (public or private), up to 1 June 2020, and to identify the reasons for disruption and possible solutions. Sanofi Pasteur teams from 19 countries in SEAR/WPR completed a structured questionnaire reporting on COVID-19 disruptions for 13-19 routinely delivered antigens per country, based on sales data, government reports, and regular physician interactions. Data were analysed descriptively, disruption causes ranked, and solutions evaluated using a modified public health best practices framework. 95% (18/19) of countries reported vaccination disruption. When stratified by country, a median of 91% (interquartile range 77-94) of antigens were impacted. Infancy and school-entry age vaccinations were most impacted. Both public and private sector healthcare providers experienced disruptions. Vaccination rates had not recovered for 39% of impacted antigens by 1 June 2020. Fear of infection, movement/travel restrictions, and limited healthcare access were the highest-ranked reasons for disruption. Highest-scoring solutions were separating vaccination groups from unwell patients, non-traditional vaccination venues, virtual engagement, and social media campaigns. Many of these solutions were under-utilised. COVID-19-induced disruption of routine vaccination was more widespread than previously reported. Adaptable solutions were identified which could be implemented in SEAR/WPR and elsewhere. Governments and private providers need to act urgently to improve coverage rates and plan for future waves of the pandemic, to avoid a resurgence of vaccine-preventable diseases. Sanofi Pasteur.


Rapid synthesis of azepinoindole derivatives from tryptamine sulfonamides and bromoallyl sulfones via an acid-mediated cyclization and rearrangement.
The azepinoindole framework present in natural alkaloids such as subincanadine F, ibogaine and catharanthine was formed in a novel acid-promoted cyclization-rearrangement of tryptamine-derived N-sulfonyl enamines. The latter were conveniently prepared via a cesium carbonate mediated formal vinylic substitution reaction of 2-bromoallyl sulfones (allenyl sulfone surrogate) and tryptamine sulfonamides. The azepinoindole forming cyclization-rearrangement involves the initial generation of a six-membered tetrahydro-β-carboline derivative. The steric bulk of the N-sulfonyl group on tryptamine plays an important role in deciding the reaction outcome.


Detection of the acute effects of hydrocortisone in the hippocampus using pharmacological fMRI.
Impaired hippocampal function is believed to be important in the pathogenesis of depression. The hippocampus contains a high concentration of both mineralocorticoid (MR) and glucocorticoid receptors (GR), and the experimental administration of corticosteroids has been reported to mimic memory impairments seen in depression. Using pharmacological functional magnetic resonance imaging (phMRI) we investigated whether hippocampal function is altered after acute administration of hydrocortisone. Changes in BOLD signal following infusion of 100mg hydrocortisone given as a rapid intravenous bolus were measured in 14 healthy volunteers in a within-subject placebo-controlled crossover design. Subsequently, subjects completed an n-back task during an fMRI scan. Hydrocortisone infusion caused a significant, time-dependent increase in fMRI BOLD signal in hippocampus reaching a maximal effect at 11-19min. The n-back task increased BOLD signal in prefrontal and parietal cortical areas and decreased it in the hippocampus. After hydrocortisone the left hippocampal decrease in BOLD signal was attenuated with the magnitude of attenuation correlating with the increase seen after hydrocortisone infusion. No difference in behavioural task performance was observed. The results suggest acute hydrocortisone has rapid direct and modulatory influences on hippocampal function, probably acting through non-genomic GR or MR signalling. Hydrocortisone infusion phMRI may be a useful tool to investigate hippocampal corticosteroid receptor function in depression.


Protective effect of proton pump inhibitors and potassium competitive acid blockers against post-gastric endoscopic submucosal dissection bleeding: a single-center, propensity score-matched analysis.
Both potassium-competitive acid blockers (P-CABs) and proton pump inhibitors (PPIs) are known to be protective against bleeding after gastric endoscopic dissection (ESD) for early gastric cancers. The aim was to compare the effect of PPI and P-CAB treatment against bleeding after gastric ESD. This was a single-center, retrospective analysis. Among 541 patients who underwent gastric ESD during the period from 2014 to 2019, we recruited subjects who were treated with PPIs (intravenous lansoprazole followed by oral esomeprazole) or a P-CAB before and after ESD. The incidence of post-ESD bleeding was compared between treatment groups. The risks associated with post-ESD bleeding were examined by univariate and multivariate analyses after propensity score-matching. The overall incidence of post-ESD bleeding was not significantly different between patients treated with PPIs (n = 362) and those treated with a P-CAB (n = 156) (3.0% vs 2.6%, respectively; p = .77). Even after propensity score matching (n = 153 in each group), the incidence was not significantly different between groups (2.6% vs 2.6%, respectively; p = 1.00). A multivariate analysis revealed that antithrombotic therapy (OR 4.85, 95% CI 1.14-20.57) was an independent factor associated with post-ESD bleeding. The incidence of post gastric ESD bleeding is not different between patients treated with PPI and patients treated with P-CAB. Antithrombotic therapy is an independent risk factor associated with post-ESD bleeding.


Successful treatment of acrodermatitis continua of Hallopeau with sequential combination of calcipotriol and tacrolimus ointments.
Acrodermatitis continua of Hallopeau (ACH) is a rare type of pustular psoriasis affecting the digits. We report on a 43-year-old female patient who had been suffering from ACH for more than 20 years. Despite the fact that the disease was localized on one finger during the whole period, several topical and systemic treatments resulted in only temporary or partial improvement of the lesion. Although the monotherapies with calcipotriol and tacrolimus ointments gave no satisfying results in the long-term management of the disease, the combination of both agents led to a continuous improvement of the patient's skin condition.


Pharmacokinetics and pharmacodynamics of nifedipine in patients at steady state.
The pharmacokinetics and associated pharmacodynamics of nifedipine were studied at steady state in 12 patients with angina pectoris who were receiving nifedipine 10-40 mg tid. After dosing, serum nifedipine concentrations rose rapidly and decayed in a log-linear fashion. The mean (+/- SEM) maximum serum concentration (Cmax) after dose normalization, and the time to Cmax (tmax) were 115 +/- 7 ng/mL and 0.72 +/- 0.13 hr, respectively. The mean area under the plasma concentration-time curve per 10-mg dose was 304 +/- 34 hr-ng/mL. The average elimination rate constant was 0.205 +/- 0.016 hr, and the harmonic mean elimination half-life was 3.4 hr (range, 2.5-4.9 hr). Heart rate increased (5-6 beats/min, P less than .05) from baseline for up to one hour after dose, while mean diastolic blood pressure decreased (6-15 mm Hg, P less than .05) for up to four hours. Cardiac output was increased (1.1-2.8 L/min, P less than .05), and calculated total systemic resistance (3.8-6.3 mm Hg/L/min, P less than .05) was decreased for the entire dosing interval after nifedipine dosing. Hysteresis plots for heart rate and mean diastolic blood pressure showed a time lag between changes in serum nifedipine concentrations and heart rate, but not between serum nifedipine concentrations and blood pressure. Changes in cardiac output did not correlate with serum nifedipine concentrations. The steady-state kinetic and dynamic parameter values in patients with angina pectoris in this study were similar to those found in healthy volunteers or hypertensive patients after acute nifedipine administration.(ABSTRACT TRUNCATED AT 250 WORDS)


Electrical Isolation of the Marshall Bundle by Radiofrequency Catheter Ablation: In Patients With Atrial Fibrillation.
This study sought to isolate arrhythmogenic Marshall bundles (MBs) by radiofrequency (RF) catheter ablation. The vein of Marshall (VOM) is surrounded by a muscular bundle called the MB. The MB is 1 of the arrhythmogenic sources of atrial fibrillation (AF) and electrically connects to either the left atrial (LA) myocardium or coronary sinus (CS) musculature. By eliminating such electric connections using RF catheter ablation, the MB might be electrically isolated. This retrospective study included 20 patients (64 ± 10 years old, 5 women) who underwent an MB isolation for nonparoxysmal AF. After pulmonary vein isolation, we performed venography of the VOM and inserted a 2-F electrode catheter into the VOM. RF applications were delivered to eliminate the MB electrograms from both the LA and CS when the MB was considered arrhythmogenic. MB isolation was achieved in 14 patients (70%). Of them, complete or partial MB isolation was accomplished in 7 patients (35%) each. The average number of RF applications in the LA (35 W, 30 s) and CS (25 W, 30 s) was 15 ± 14 and 4 ± 3, respectively. No severe adverse events were observed. During a follow-up of 23 ± 11 months, 18 patients (90%) maintained sinus rhythm. RF applications targeting recordings from an electrode catheter in the VOM were feasible, and the MB could be electrically isolated. Elimination of the MB potentials would be a clear endpoint for patients with an arrhythmogenic MB.


The Tabby phenotype is caused by mutation in a mouse homologue of the EDA gene that reveals novel mouse and human exons and encodes a protein (ectodysplasin-A) with collagenous domains.
Mouse Tabby (Ta) and X chromosome-linked human EDA share the features of hypoplastic hair, teeth, and eccrine sweat glands. We have cloned the Ta gene and find it to be homologous to the EDA gene. The gene is altered in two Ta alleles with a point mutation or a deletion. The gene is expressed in developing teeth and epidermis; no expression is seen in corresponding tissues from Ta mice. Ta and EDA genes both encode alternatively spliced forms; novel exons now extend the 3' end of the EDA gene. All transcripts recovered have the same 5' exon. The longest Ta cDNA encodes a 391-residue transmembrane protein, ectodysplasin-A, containing 19 Gly-Xaa-Yaa repeats. The isoforms of ectodysplasin-A may correlate with differential roles during embryonic development.


[Pediatric colonoscopy findings and changing patterns from Beijing in one institutional experience over 12 years].
To investigate the demographics and diagnostic yield in a cohort of Chinese pediatric patients undergoing colonoscopy in one institution over 12 years. The study participants were consecutive patients aged <18 years that underwent their first colonoscopy in the endoscopy center at Peking University Third Hospital between Jan. 1, 2005 and Dec. 31, 2017. Demographic, endoscopic, and pathological findings were collected. According to the age of the patients, they were divided into 0-3 year-old group, 4-6 year-old group, 7-14 year-old group and 15-17 year-old group. The patients were also divided into 2005-2011 group and 2012-2017 group, according to the time of colonoscopy. The cohort consisted of 326 patients, including 205 boys (62.9%) and 121 girls (37.1%). In the study, 31 patients (9.5%) were in 0-3 year-old group, 28 (8.6%) were in 4-6 year-old group, 96 (29.4%) were in 7-14 year-old group and 171 (52.5%) in 15-17 year-old group. The terminal ileum intubation success rate was 90.5% (295/326). No serious complications such as hemorrhage or perforation occurred during the procedures. The cleaning effect was good in 92.3% (301/326) of the patients. A total of 204 patients (62.6%) received a positive diagnosis under colonoscopy. 27.0% (88/326) of the patients was diagnosed as nonspecific colitis or terminal ileitis. 46 (14.1%) with inflammatory bowel disease (IBD) and 39 (12.0%) with polyp. The diseases were significantly different among the different age groups. The highest IBD diagnostic rate was found in 0-3 year-old group (7/31, 22.5%), while the highest polyp finding rate was in 4-6 year-old group (8/28, 28.6%). The number of the patients in 0-3 year-old group was significantly increasing in 2012-2017 group compared with 2005-2011 group (27/191 vs. 4/135, P=0.001), while the terminal ileum intubation success rate was higher (179/191 vs. 116/135, P=0.037). However, comparisons between years 2005-2011 and 2012-2017 showed that neither IBD nor polyp detection rate changed significantly (P=0.850). Colonoscopy in pediatric patients was a safe and effective procedure. Colitis or terminal ileitis was the primary finding during colonoscopy while IBD was the second one, and polyp was the third. However, the diagnostic yield did not change significantly. IBD was not as quickly increased in our hospital as it was in South China.


Comparison of cream of rice agar and horse serum for differentiating germ tubes of Candida albicans from filaments of Candida tropicalis.
Simple cream of rice agar was superior to horse serum for the demonstration of germ tubes by Candida albicans and in the differentiation of pseudohyphae of Candida tropicalis from germ tubes at 37 degrees C. Mycelium and chlamydospores were also produced on this medium.


The effect of Brucella abortus on hydrogen peroxide and nitric oxide production by bovine polymorphonuclear cells.
The effect of Brucella on the generation of microbicidal reactive oxygen and nitrogen metabolites by bovine peripheral polymorphonuclear cells (PMNs) was investigated. The PMNs were recovered from the peripheral blood of control calves and experimental calves previously vaccinated against brucellosis. Significantly larger quantities of NO and H2O2 were generated by PMNs from control and experimental calves following activation by heat-killed whole cells or outer membrane protein of Brucella abortus than by non-activated cells (p<0.05-0.01). In contrast, generation of H2O2 and NO decreased when PMNs were exposed to the lipopolysaccharide of Brucella. However, the generation of H2O2 and NO by activated PMNs from the control and experimental calves did not differ significantly.


Hepatoid Adenocarcinoma of the Lung Responsive to Frontline Combination Chemotherapy With Immunotherapy: Case Report.
Hepatoid adenocarcinoma of the lung (HAL) is a rare extrahepatic tumor characterized by histologic features of hepatocellular carcinoma. The standard treatment for nonresectable HAL has not been established, though traditionally, these tumors have been treated with platinum-based chemotherapy. Here, we report the use of combination chemotherapy and immunotherapy in a patient presenting with metastatic HAL and an elevated alpha-fetoprotein. The patient had an excellent clinical, radiographic, and biomarker response. This case supports the use of chemoimmunotherapy, which is now the standard of care first-line treatment in NSCLC, for HAL.


Teaching Surgical Hysteroscopy with a Computer
Using a hysteroscope can be simulated on a computer. It will improve physician training by measuring basic knowledge and abilities, allow different interventions and anatomic variations, minimize the trauma of surgical intervention, and reduce operative casualties. An integrated questionnaire covers instrumentation, fluid infusion, power source, indications and preparation for endometrial ablation, surgical techniques, and complications to evaluate the user's knowledge. The operation simulation then proceeds. In the endometrial cavity, by virtual simulation, the operating field should appear in real time to allow physicians to adapt the trajectory of the instruments. The computer is an IBM PC compatible. We use a modified joystick with optical encoders to know the instrument position. The simulation can be repeated as desired. An evaluation system is integrated in the software to keep the user informed on the amount of burn area(s) that have been completed. This prototype model is available.


Meaningful interpretation of risk reduction from clinical drug trials.
To illustrate the concepts of relative and absolute risk reduction, and by example, present and discuss the results of prevention trials that have evaluated the impact of drug therapy on cardiovascular disease. Additional approaches to evaluating the results of prevention trials are also presented. Data were gathered from eight frequently quoted major cardiovascular intervention trials. Reference to large reductions in relative risk in review papers, newspapers, and at professional meetings can lead to false expectations among clinicians and patients regarding the potential impact of the treatment in individual patients. When making decisions about preventive drug therapy, clinicians are encouraged to examine measures other than relative risk reduction and to include the patient in the decision process. Educators should emphasize these other measures of outcome and not rely solely on relative risk reduction in discussing particular areas of therapeutics.


Minimally invasive cytologic evaluation leading to the diagnosis of TFE3-rearranged renal cell carcinoma: A case report.
TFE3-rearranged renal cell carcinoma (RCC) has been categorized as a molecularly defined renal carcinoma in the 2022 WHO classification of tumors as it does not demonstrate a specific genotype-phenotype correlation. However, in order to arrive at the diagnosis, recognition of the broad spectrum of cytologic and histologic features that can be seen in TFE3-rearranged RCC is important for differential diagnostic consideration. Reported here is the diagnostic workup of a TFE3-rearranged RCC using very limited tissue sample. The initial evaluation was dependent on the cytomorphologic findings observed on a touch preparation made from the renal mass biopsy, directing appropriate selection of ancillary tests, and leading to a definitive diagnosis.


Targeted smoking cessation for dual users of combustible and electronic cigarettes: a randomised controlled trial.
Although many smokers use electronic cigarettes (e-cigarettes) to quit smoking, most continue to smoke while vaping. This dual use might delay cessation and increase toxicant exposure. We aimed to test the efficacy of a self-help intervention designed to help dual users to quit smoking. In this three-arm randomised controlled trial we recruited individuals in the USA using Facebook and multimedia advertisements. Included participants were 18 years or older, smoked at least weekly in the preceding year, and vaped at least weekly in the preceding month. We used computer generated randomisation with balanced-permuted blocks (block size 10, with 2-4-4 ratio) to allocate participants to assessment only (ASSESS group), generic smoking cessation self-help booklets (GENERIC group), or booklets targeting dual users (eTARGET group). Individuals in the generic or targeted intervention groups received monthly cessation materials for 18 months, with assessments every 3 months for 24 months. The main outcome was self-reported 7-day point-prevalence smoking abstinence at each assessment point. All randomly allocated participants were included in primary analyses using generalised estimating equations for each of 20 datasets created by multiple imputation. Analysis of the χ2s produced an F test. The trial is registered with ClinicalTrials.gov, NCT02416011, and is now closed. Between July 12, 2016, and June 30, 2017, we randomly assigned 2896 dual users (575 to assessment, 1154 to generic intervention, and 1167 to targeted self-help). 7-day point-prevalence smoking abstinence increased from 14% at 3 months to 42% at 24 months (F7,541·7=67·1, p<0·0001) in the overall sample. Targeted self-help resulted in higher smoking abstinence than did assessment alone throughout the treatment period (F1,973·8=10·20, p=0·0014 [α=0·017]). The generic intervention group had abstinence rates between those of the assessment and targeted groups, but did not significantly differ from either when adjusted for multiple comparisons (GENERIC vs eTARGET F1,1102·5=1·79, p=0·18 [α=0·05]; GENERIC vs ASSESS F1,676·7=4·29, p=0·039 [α=0·025]). Differences between study groups attenuated after the interventions ended. A targeted self-help intervention with high potential for dissemination could be efficacious in promoting smoking cessation among dual users of combustible cigarettes and e-cigarettes. National Institute on Drug Abuse, National Cancer Institute.


[Psychological aspects of obesity. Consquences for content, indication, and success of therapy].
To simply reduce obesity to the medical set of problems falls short due to the complexity of the disorder. The focus of the affected children and adolescents is less on acute and future somatic health impairments but on the psychosocial aspects of obesity. The high degree of stigmatization especially accounts for the psychosocial burdens of the persons concerned. Constraints in the quality of life and a higher prevalence of mental disorders are reported by overweight and obese children and adolescents. In the sense of a vicious psychosocial circle, these variables in turn influence our eating and exercise behavior and hence central influences of weight control actions. Therefore, complex multimodal programs, which take into account these relationships, have long since been established in therapy. Numerous studies have underscored the efficacy of such lifestyle interventions resulting in moderate weight loss effects. Parent involvement and including behavioral strategies is associated with better results. Future studies should focus more on various psychosocial outcomes and addressing the question of psychosocial predictors of short- and long-term treatment success.


Long-term Survival With Afatinib in a Patient With Lung Adenocarcinoma Harboring Double Uncommon EGFR L861Q and G719X Mutations.
In the majority of non-small cell lung cancer (NSCLC) patients with uncommon EGFR mutations, first generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are ineffective. The second-generation TKI, afatinib, is considered effective in patients with uncommon mutations, however, long-term survivors have been rare. We report herein a patient with lung adenocarcinoma harboring double uncommon EGFR L861Q and G719X mutations, who is free of disease 32 months after initiation of afatinib therapy. To our best knowledge, this patient has the longest response among other patients with double uncommon mutations. Patients with this type of NSCLC may obtain long-term survival with afatinib.


Aortic diastolic pressure decay in congenital arteriovenous malformations.
We describe three infants with large congenital arteriovenous malformations, two intracranial and one intrathoracic, who have high output congestive heart failure but normal pulse pressures. The theoretical basis of these pulse pressure findings in contrast to those in infants with shunting secondary to the patent ductus arteriosus is presented.


Issues in the natural history and treatment of coronary heart disease in black populations: surgical treatment.
Patient characteristics, treatment choices, and long-term survival were examined to seek possible explanations for marked differences in the racial distribution among 6594 consecutive patients who underwent arteriography or coronary artery bypass grafting (CABG) from 1970 to 1978. Overall, the percentage of whites undergoing coronary arteriography was 96% compared with 4% of the blacks; only black females showed a secular increase in the relative percentage. Clinical manifestations and predisposing factors for coronary atherosclerosis differed little between the blacks and the whites in this population. Angina, as measured by the Rose Questionnaire, had the same clinical significance in blacks as in whites. Findings indicated that similar covariates of comparable strength appeared to be operative as indices for severity of coronary heart disease in both blacks and whites. On the basis of regression analyses, whites had approximately a three times greater chance of having two or more diseased vessels than did blacks after adjustment for multiple clinical characteristics and risk factors. After adjusting for pertinent variables, whites with three-vessel disease were two and a half times more likely to have CABG than blacks (42.5% vs 16.2%). However, differences in choice of initial therapy for whites and blacks with multiple-vessel disease were significant only in those older than 50 years. Except for older blacks who demonstrated a decreased survival rate when managed surgically, survival rates were similar for blacks and whites. Trends in the evaluation and clinical management of black populations with suspect coronary heart disease should further clarify these preliminary findings.


Backward conditioning of tumor necrosis factor-α in a single trial: changing intervals between exposures to lipopolysaccharide and saccharin taste.
The current study examined the effect of backward conditioning with three different time intervals between exposures to lipopolysaccharide (LPS) as the unconditioned stimulus (US) and saccharin taste in water as the potential conditioned stimulus (CS). Forty-eight naïve female BALB/c mice at three months of age served as subjects, divided into six groups. Four groups were assigned to Experiment 1 for the tumor necrosis factor alpha (TNF-α) measure, and the remaining two groups were used in Experiment 2 to measure taste aversion behavior. Both experiments employed a single trial. The timing of introduction to the saccharin taste varied between 3 min, 7 h, and 24 h following an LPS injection in Experiment 1. Experiment 2 employed the three-minute interval only. These intervals correspond to distinct immunological, physiological, and behavioral events induced by LPS. On the day after re-exposure to the saccharin taste, the TNF-α groups were challenged with LPS to test the LPS tolerance response. While backward conditioning of taste aversion behavior was not observed, some evidence of conditioned TNF-α response and subsequent development of LPS tolerance was observed with backward conditioning in a single trial. This exploratory study demonstrated that the effect of backward conditioning on conditioned TNF-α response and LPS tolerance response in a single trial depended on the timing of when a CS is presented after LPS exposure.


Erratum: Phase Diagrams of n-Type Low Bandgap Naphthalenediimide-Bithiophene Copolymer Solutions and Blends. Polymers 2019, 11, 1474.
The authors wish to make a change to the published paper [...].


Endothelial glycocalyx is damaged in diabetic cardiomyopathy: angiopoietin 1 restores glycocalyx and improves diastolic function in mice.
Diabetic cardiomyopathy (DCM) is a serious and under-recognised complication of diabetes. The first sign is diastolic dysfunction, which progresses to heart failure. The pathophysiology of DCM is incompletely understood but microcirculatory changes are important. Endothelial glycocalyx (eGlx) plays multiple vital roles in the microcirculation, including in the regulation of vascular permeability, and is compromised in diabetes but has not previously been studied in the coronary microcirculation in diabetes. We hypothesised that eGlx damage in the coronary microcirculation contributes to increased microvascular permeability and hence to cardiac dysfunction. We investigated eGlx damage and cardiomyopathy in mouse models of type 1 (streptozotocin-induced) and type 2 (db/db) diabetes. Cardiac dysfunction was determined by echocardiography. We obtained eGlx depth and coverage by transmission electron microscopy (TEM) on mouse hearts perfusion-fixed with glutaraldehyde and Alcian Blue. Perivascular oedema was assessed from TEM images by measuring the perivascular space area. Lectin-based fluorescence was developed to study eGlx in paraformaldehyde-fixed mouse and human tissues. The eGlx of human conditionally immortalised coronary microvascular endothelial cells (CMVECs) in culture was removed with eGlx-degrading enzymes before measurement of protein passage across the cell monolayer. The mechanism of eGlx damage in the diabetic heart was investigated by quantitative reverse transcription-PCR array and matrix metalloproteinase (MMP) activity assay. To directly demonstrate that eGlx damage disturbs cardiac function, isolated rat hearts were treated with enzymes in a Langendorff preparation. Angiopoietin 1 (Ang1) is known to restore eGlx and so was used to investigate whether eGlx restoration reverses diastolic dysfunction in mice with type 1 diabetes. In a mouse model of type 1 diabetes, diastolic dysfunction (confirmed by echocardiography) was associated with loss of eGlx from CMVECs and the development of perivascular oedema, suggesting increased microvascular permeability. We confirmed in vitro that eGlx removal increases CMVEC monolayer permeability. We identified increased MMP activity as a potential mechanism of eGlx damage and we observed loss of syndecan 4 consistent with MMP activity. In a mouse model of type 2 diabetes we found a similar loss of eGlx preceding the development of diastolic dysfunction. We used isolated rat hearts to demonstrate that eGlx damage (induced by enzymes) is sufficient to disturb cardiac function. Ang1 restored eGlx and this was associated with reduced perivascular oedema and amelioration of the diastolic dysfunction seen in mice with type 1 diabetes. The association of CMVEC glycocalyx damage with diastolic dysfunction in two diabetes models suggests that it may play a pathophysiological role and the enzyme studies confirm that eGlx damage is sufficient to impair cardiac function. Ang1 rapidly restores the CMVEC glycocalyx and improves diastolic function. Our work identifies CMVEC glycocalyx damage as a potential contributor to the development of DCM and therefore as a therapeutic target.


Gender-specific differences in the association of adiponectin gene polymorphisms with body mass index.
Adiponectin gene polymorphisms are associated with obesity, metabolic syndrome and type 2 diabetes (T2D). The study evaluated possible associations of +45T/G and -11391G/A adiponectin gene polymorphisms with body mass index (BMI), waist circumferences (WC), and blood pressure in diabetic and non-diabetic Iranians. This cross-sectional study involved two groups of subjects: 243 diabetic patients and 173 non-diabetic subjects recruited from Rafsanjan city in the south-east of Iran. No significant association was found between +45T/G and -11391G/A adiponectin gene polymorphisms and systolic or diastolic blood pressure. However, male carriers of the TT genotype of +45T/G had a significantly higher mean BMI than male GG homozygotes (p = 0.018). Also, male carriers of the GG genotype of -11391G/A had significantly higher mean BMI than male GA or AA homozygotes (p = 0.041). Female carriers of the GG genotype of -11391G/A had significantly higher mean WC than female GA or AA homozygotes (p = 0.038). We observed a significantly higher BMI in women, and GA or AA carriers of -11391G/A polymorphism. Also, there was a significantly lower WC in females and GG carriers of +45T/G. These results point to a gender-specific impact of the studied genotypes on BMI and WC.


Intimate partner violence and unplanned pregnancy in the Pacific Islands Families Study.
To examine the association between maternal intimate partner violence (IPV) victimization and unplanned pregnancy. Mothers of the Pacific Islands Families (PIF) Study cohort of Pacific infants born in Auckland, New Zealand during 2000 were interviewed when the children were 6 weeks old. A total of 1088 mothers cohabiting in married or de-facto partnerships were questioned about IPV and whether their pregnancy had been planned. Women identified as victims of physical violence were more likely to report an unplanned pregnancy than those who were not victims (68.7% vs 55.1%, odds ratio [OR] 1.78; 95% confidence interval [CI], 1.32-2.40). The adjusted odds remained statistically significant (OR 1.52; 95% CI, 1.01-2.26). The findings of this study suggest an association between IPV and unplanned pregnancy in the Pacific birth cohort.


Effect of orlistat in obese patients with binge eating disorder.
Binge eating disorder represents a significant public health problem, with up to 50% of weight loss program participants displaying this disorder. In previous studies with orlistat, patients with binge eating disorder were excluded. The goal of this study was to assess the efficacy of orlistat in obese patients with binge eating disorder. Eighty-nine patients with clinically diagnosed binge eating disorder and a BMI > or = 30 kg/m2 were randomized in double-blind fashion to 24 weeks of treatment with 120 mg of orlistat or placebo three times daily, in combination with a mildly reduced-calorie diet. After 24 weeks, the mean weight loss from baseline for orlistat-treated patients was significantly greater than for patients receiving placebo (-7.4% vs. -2.3%; p = 0.0001) (intent-to-treat analysis). The overall Eating Disorder Inventory 2 score at week 24 was significantly lower in patients treated with orlistat than in those in the placebo group (p = 0.011). Orlistat may be considered as part of the management for patients with obesity and binge eating disorder.


The post-mortem vacuoles of Schlemm's canal.
A two-part study was conducted in which post-mortem changes were investigated in the baboon outflow system. It was found that the meshwork cells closest to the chamber angle were particularly susceptible to post-mortem advance. Post-mortem vacuoles developed in the endothelium of Schlemm's canal and by light microscopy these structures could be mistaken for giant vacuoles. On the other hand it was shown by electron microscopy that the giant vacuoles which have been implicated in the transendothelial transfer of aqueous humour and post-mortem vacuoles were distinct and separate entities.


Enhancing effect of glucose microspheres in the viability of human mesenchymal stem cell suspensions for clinical administration.
A critical limiting factor of cell therapy is the short life of the stem cells. In this study, glucose containing alginate microspheres were developed and characterized to provide a sustained release system prolonging the viability of human mesenchymal stem cells (hMSCs) in a suspension for clinical application. The glucose microspheres were satisfactorily elaborated with alginate by emulsification/internal gelation method. Particle size was evaluated by light diffraction and optical microscopy. Shape and surface texture by scanning electron microscopy (SEM). Zeta potential, infrared spectra and release studies were also conducted. Also, rheological properties and stability of hMSCs suspensions with microspheres were tested. The viability of hMSCs was determined by trypan blue dye exclusion staining. Microspheres of 86.62 μm, spherical shaped and -32.54 mV zeta potential with excellent stability, good encapsulation efficiency and providing an exponential release of glucose were obtained. hMSCs had better survival rate when they were packed with glucose microspheres. Microspheres maintained the aseptic conditions of the cell suspension without rheological, morphological or immunophenotypic disturbances on hMSCs. Developed microspheres were able to enhance the functionality of hMSC suspension. This strategy could be broadly applied to various therapeutic approaches in which prolonged viability of cells is necessary.


Does routine nasogastric tube placement after an operation for perforated appendicitis make a difference?
Divergent opinions exist regarding the routine use of nasogastric (NG) tubes in the postoperative management of patients undergoing abdominal surgery. Empiric use of an NG tube after abdominal surgery is presumed to prevent abdominal distension, vomiting, and ileus, which may complicate the postoperative course. To investigate the validity of this assumption, we compared the postoperative course of patients who underwent appendectomy for perforated appendicitis who subsequently either had or did not have an NG tube placed postoperatively. A retrospective chart review of all children operated for perforated appendicitis between 1999 and 2004 was performed. Patients with prolonged hospitalizations were excluded to eliminate bias created by patients with multiple operations and opportunities for NG placement. The use of an NG tube, time to first and to full oral feeds, length of hospitalization, and complications were compared between groups. Patients with NG tubes left in place (N = 105) were compared with those who did not receive an NG tube (N = 54) following appendectomy for perforated appendicitis. Mean time to first oral intake was 3.8 d in those with NG tubes compared with 2.2 d in those without NG tubes (P < 0.001). Similarly, mean time to full feeds was 4.9 d when an NG tube was left compared with 3.4 d in those without tubes (P < 0.001). Mean length of stay was 6.0 d in those with NG tubes compared to 5.6 d in those without (P = 0.002). The use of NG decompression after an operation for perforated appendicitis does not appear to improve the postoperative course and we recommend that it is not routinely used in this patient population.


The effects of magnolol supplementation on growth performance, meat quality, oxidative capacity, and intestinal microbiota in broilers.
The aim of the present study was to evaluate the effect of magnolol (MAG) on growth performance, meat quality, oxidative capacity, and intestinal microbiota in the yellow-feather broilers. A total of 360 one-day-old male yellow-feather broiler chicks were allocated into 5 groups of 6 replicates and 12 chickens per replicate, were fed a basal diet supplemented with 0 (Control group, CON), 100, 200, 300, or 400 mg/kg MAG for 51 d. The results showed that dietary supplementation with 200 and 300 mg/kg MAG increased the average daily gain (ADG) but decreased feed to gain ratio (F/G) during the overall periods (P < 0.05). Dietary MAG increased significantly the redness value (a∗) of the breast muscle (P < 0.05), and decreased the water loss rate and shear force of the breast meat (P < 0.05). MAG supplement reduced the malondialdehyde (MDA) levels, and increased the glutathione (GSH), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC) levels in breast muscle and jejunum. PCR analysis showed that MAG increased the levels of NF-E2-related factor 2 (Nrf2), NAD(P)H/quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), glutathione-S transferase (GST), glutamate-cysteine ligase catalytic subunit (GCLC), glutamate-cysteine ligase modifier subunit (GCLM), and SOD expressions (P < 0.05). Analysis of differential enrichment of gut microbiota found that Faecalibacterium in the cecum of MAG supplemented broilers increased, and Coprobacillus has decreased (P < 0.05). In conclusion, MAG improved growth performance, meat quality of the broilers and antioxidant capacity, and modulated gut microbiota homeostasis.


Methylprednisolone stimulated gene expression (GILZ, MCL-1) and basal cortisol levels in multiple sclerosis patients in relapse are associated with clinical response.
Glucocorticoids (GCs) are the main treatment of relapse in multiple sclerosis (MS). Decreased sensitivity to GCs in MS patients has been associated with lack of the suppressive effect of GCs on inflammatory molecules as well as increased resistance to apoptosis. We investigated GC-sensitivity by measuring the effect of intravenous methylprednisolone (IVMP) treatment on transactivation of anti-inflammatory and apoptotic genes (GILZ, MCL-1 and NOXA respectively), in accordance to clinical outcome. Thirty nine MS patients were studied: 15 with clinically isolated syndrome (CIS), 12 with relapsing remitting (RRMS) and 12 with secondary progressive (SPMS) under relapse. Patients underwent treatment with IVMP for 5 days. Blood was drawn before IVMP treatment on day 1 and 1 h after IVMP treatment on days 1 and 5. GIlZ, MCL-1 and NOXA were determined by qPCR. The Expanded Disability Status was evaluated and patients were divided according to their clinical response to IVMP. GILZ and MCL-1 gene expression were significantly higher following first IVMP treatment in responders, compared to non-responders. Furthermore, serum basal cortisol and 1,25-OH Vitamin D levels were significantly higher in clinical-responders as compared to non-clinical responders. Our findings suggest that the differential GILZ and MCL-1 gene expression between clinical-responders and non-clinical responders may implicate the importance of GILZ and MCL-1 as possible markers for predicting glucocorticoid sensitivity and response to GC-therapy in MS patients following first IVMP injection.


Immunoglobulin abnormalities in multiple sclerosis. Relation to clinical parameters: disability, duration and age of onset.
Cerebrospinal fluid (CSF) and serum from 35 pairs of multiple sclerosis (MS) patients were analysed as regards mononuclear pleocytosis, concentrations of total protein, immunoglobulin G and A and beta-trace protein, and kappa:lambda ratios, as well as the serum/CSF ratios of IgG and albumin. The disability of the patients differed, whereas the age and the duration of the disease were similar in each pair. Similar analyses were also performed on CSF and serum from 72 patients, who were subdivided according to age at onset and severity of the disease. The highest mean values of the CSF-IgG and the lowest mean values of the serum/CSF IgG ratios were found in the more disabled patients. CSF immunoglobulin abnormalities were encountered more often and were more pronounced in the patients with the most malignant course of the disease, i.e., in those with severe disability after a short duration of the disease (less than 10 yr) and in severely disabled patients with an early age at onset of the disease(less than 25 yr). Contrarily, normal mean values of CSF-IgG concentrations and serum/CFS/IgG ratios were found in the groups of patients without disability after a duration of the disease of 10 years or more, and patients without disability and an early age at onset of the disease (less than 25 yr). The observations indicate that the immune response is most vigorous in disabled patients with a short duration or with an early age at onset of the disease. MS patients with a late age at onset (greater than 35 yr) showed a less pronouced immune response within the CNS, irrespective of the occurrence of disability. The most disabled patients also showed the most severe blood-brain barrier damage as manifested by high mean values of total protein in CSF and low serum/CSF albumin ratios. The patients with severe disability and a long duration of the disease (greater than 10 yr) had the highest content of beta-trace protein in the CSF, probably as a sign of destruction of brain matter.


Introduction to Kampo medicine for dental treatment - Oral pharmacotherapy that utilizes the advantages of Western and Kampo medicines.
Kampo medicine is a medical system that has been systematically organized based on the reactions of the human body. At present, in Western, herbal medicines means the whole herbal product. It is being called Kampo medicine as a medicinal drug in Japan. Since 2012, the "National Health Insurance Drug Price Standards Related to Dental Treatment" published by the Japan Dental Association have included seven Kampo formulations. In 2015, the Japan Dental Association sent a "Kampo Education Plan for Dentistry" to all dental universities in Japan. Furthermore, the Japanese Society of Oral Therapeutics and Pharmacology compiled a summary of "Evidence for Kampo Treatment in the Field of Oral Surgery." In addition, the phrase "including wakan-yaku" was included in the draft core model curriculum for dental education in 2016. Thus, Kampo medicine is expected to rapidly spread to the field of dental care and dental medical education. Therefore, the training of dentists with knowledge of both Western and Oriental medicine is required for the treatment of oral pain, periodontal disease, stomatitis, xerostomia, and other complaints concerning oral health. It is our hope that this paper provides a footing for dentists who wish to learn about Kampo medicine and incorporate it into clinical practice.


[Challenges for Representatives of Employees with Severe Disabilities Amid the Legal Reforms Resulting from the Federal Participation Act].
Representatives of employees with severe disabilities play a key role in achieving inclusive working conditions. This has been taken into account by the Federal Participation Act and the rights of the representatives of employees with severe disabilities have been expanded. The aims of the present exploratory analysis are to clarify the modified legal status from the perspective of the representatives of employees with severe disabilities, to identify challenges in the practical application of the legal reforms and to reveal unconsidered needs. Considering that research on the implementation and evaluation of social legislation are core elements of rehabilitation research, this study intends to close the gap between legal implementation and practical application and aims to advance the process of a learning legislation. Across Germany, a total of 1552 representatives of employees with severe disabilities were interviewed via online survey. The present analysis focuses on the answers regarding challenges for representatives of employees with severe disabilities. The answers were evaluated according to the content-structuring qualitative content analysis of Kuckartz and analysed with regard to the legal reforms resulting by the Federal Participation Act. The Federal Participation Act is critically evaluated from the perspective of the representatives of employees with severe disabilities. The survey data demonstrate that the representatives of employees with severe disabilities consider parts of the legal reforms not to be comprehensive enough. Certain provisions, such as the consultation of deputies and the lowering of the exemption limit, are seen as not extensive enough and only affect the subgroup of representatives in large companies. Other rights, such as the right to information and consultation, do not include the possibility for sanctions in case of non-application of the law by the employer. The introduction of the invalidity clause regarding terminations is considered insufficient. Although the rights of the representatives of employees with severe disabilities are being expanded by means of the Federal Participation Act, there are still challenges in the implementation, specification and binding nature of the individual reforms, which must be observed and further discussed in the sense of a learning legislation. The present results indicate that further involvement of the representatives of employees with severe disabilities is required in order to derive approaches for targeted optimisation of the application and the design of the legal reforms.


Morphological changes across the border zone of cat hearts subjected to regional ischaemia.
The left anterior descending coronary artery (LAD) was ligated for 3 h in six open chest cats. Six biopsies for electron microscopy were collected from the normal, the ischaemic and the border zones as defined by in vivo injection of fluorescein and as verified by blood flow measurements. Across the fluorescein demarcation line, we collected 3 mm long border zone biopsies, extending 1.5 mm in both the normal and the ischaemic direction. Starting from the normal end twenty subsequent areas (165 microns apart) were studied. By examining a total number of 5280 myocytes we observed an abrupt increase in the number of cells with sarcolemmal fragmentation. This point called border line is accompanied by an abrupt increase in the number of cells with chromatin clumping or margination, and of cells which are mainly necrotic with a massive cytoplasmic oedema. Morphometric analysis of 576 micrographs indicates a border zone on both sides of the border line. The border zone is characterized by a larger fractional volume of mitochondria (extending 1.5-2.0 mm in the normal direction) and by a larger lipid droplet accumulation (extending 1.2 mm or less in the normal direction) than seen in the ischaemic zone. These changes are in the normal part of the border zone accompanied with a moderate cytoplasmic oedema and a fragile sarcolemma with focal disruptions.


Neuromyelitis optica and astrocytic damage in its pathogenesis.
Neuromyelitis optica (NMO) is characterized by severe optic neuritis and longitudinally extended, transverse myelitis. There have been long controversial whether NMO is a variant of multiple sclerosis (MS) or a different disease. However, since the discovery of an NMO-specific autoantibody to aquaporin 4 (AQP4), a dominant water channel in the central nervous system densely expressed on foot processes of astrocytes, the clinical distinction between NMO and MS has become clear, and now AQP4 antibody status is critically important for neurologists in deciding on treatment strategy. Moreover, pathological studies demonstrated an extensive loss of immunoreactivities to AQP4 and glial fibrillary acidic protein (GFAP) with relative preservation of the staining of myelin basic protein in acute NMO lesions, which is not seen in MS. In fact, the GFAP levels in the cerebrospinal fluid during acute exacerbation of NMO are remarkably elevated, while the values in MS are not different from those in controls. In addition, recent experimental studies conducted in vitro and in vivo have shown that AQP4 antibody is pathogenic. These findings strongly suggest that AQP4 antibody has diagnostic, therapeutic and pathogenetic implications, and that severe astrocytic damage mediated by AQP4 antibody distinguishes NMO from MS.


Gamma dose rate distribution in the Unegt subbasin, a uranium deposit area in Dornogobi Province, southeastern Mongolia.
Unegt subbasin in Dornogobi Province, southeastern Mongolia, contains the Dulaan Uul uranium deposit, for which development for commercial mining has been conducted as of 2015. Zuunbayan is a commune located close to the Dulaan Uul uranium deposit, and residents of Zuunbayan and their livestock can easily approach the uranium deposit area, including an aboveground dump site, which was created as a result of the mining development. The present study measured and analyzed the gamma dose rate (absorbed dose rate in air) distribution in Unegt subbasin using data collected from a car-borne measurement survey. The gamma dose rate increased from the northern (45-65 nGy/h) to the central (50-69 nGy/h, including Zuunbayan) and the southern (54-195 nGy/h, including Dulaan Uul) parts of the study area. The gamma dose rates (up to 195 nGy/h) around the dump site in Dulaan Uul were significantly higher than the background level (< 80 nGy/h) at several points. Additional in-situ measurements showed that the gamma dose rates reached up to 450 nGy/h at these locations, which was primarily attributed to the gamma radiation emitted by 238U series elements. Spatial distribution of gamma dose rates around the dump site revealed that the gamma radiation did not originate from the dump, but from the ground, at the measurement points. Analysis of collected soil samples showed that 238U and 226Ra were concentrated in deeper soil. These results indicate that the gamma dose rates higher than the background level were not associated with the aboveground mine dump; rather, they were very probably caused by presence of uranium deposits close to the ground surface.


Id proteins: novel targets of activin action, which regulate epidermal homeostasis.
Activin is a member of the transforming growth factor beta (TGF-beta) family, which plays a crucial role in skin morphogenesis and wound healing. To gain insight into the underlying mechanisms of action, we searched for activin-regulated genes in cultured keratinocytes. One of the identified target genes encodes Id1, a negative regulator of helix-loop-helix transcription factors. We show that Id1, Id2, and Id3 are strongly downregulated by activin in keratinocytes in vitro and in vivo. To determine the role of Id1 in keratinocyte biology, we generated stable HaCaT keratinocyte cell lines overexpressing this protein. Our results revealed that enhanced levels of Id1 do not affect proliferation of keratinocytes in monoculture under exponential culture conditions or in response to activin or TGF-beta1. However, in three-dimensional organotypic cultures, Id1-overexpressing HaCaT cells formed a hyperthickened and disorganized epithelium that was characterized by enhanced keratinocyte proliferation, abnormal differentiation, and an increased rate of apoptosis. These results identify an important function of Id1 in the regulation of epidermal homeostasis.


Correlation of amino acid sequence and conformation in tobacco mosaic virus.
Correlation of the amino acid sequence with the conformation in tobacco mosaic virus protein is considered in this article. After division of the sequence into groups with helical or nonhelical potential, the segments likely to be helical were related to the X-ray diffraction patterns obtained by Franklin, Caspar, Holmes, and Klug. The approximate locations of these segments within the known boundaries of the subunit were predicted from the radial distribution and helical projection of electron density. As a result of these assignments, the number of possible conformations was also reduced for the nonhelical segments. The structure of the subunit was simulated by flexible models of rubber and electrical tubing, as well as by space-filling Corey-Pauling-Koltun models. These models were used to locate the protein segments impinging upon the ribonucleic acid of the virus. The two pairs of carboxyl groups believed to be responsible for the binding of lead were also tentatively identified on these models as aspartic acid residues 64 and 66 (first pair) and glutamic acid residues 131 and 145 (second pair).


The genus Bolbonema Cobb, 1920 (Nematoda: Desmodoridae): emended diagnosis, key to males, and description of three new species from the continental shelf off northeastern Brazil.
The marine nematode genus Bolbonema has three valid species, the most recent one described eight years ago. Characteristics of the genus include the well-defined globular cephalic capsule and the long and short somatic setae along the body. Three previously undescribed species of this genus were collected on the continental shelf of the Potiguar Basin in northeastern Brazil. Bolbonema braziliensis sp. n. has a relatively large cryptospiral fovea amphidialis, gubernaculum a bent rod dorsally oriented and two subventral precloacal setae inserted on two small papillae above the cloaca. Bolbonema papillae sp. n. has a large multispiral fovea amphidialis with three turns, arched spicules with the proximal region rounded, a laminar and well-developed gubernaculum enfolding the distal portion of the spicules, and two subventral precloacal papillae just above the cloaca. Bolbonema zildae sp. n. has a spiral fovea amphidialis, no supplements, arched spicules with a velum, and the gubernaculum with a dorsal apophysis. These three new species increase to six the number of taxa known in the genus. A dichotomous key based on males, an emended diagnosis of the genus, and the first record of Bolbonema brevicolle Cobb, 1920 from Brazil are provided.


Characterization and mapping of mitochondrial ribosomal RNA and mitochondrial DNA in Drosophila melanogaster.
We report the isolation and some properties of the mitochondrial ribosomal RNA (mt-rRNA) of Drosophila melanogaster, and a restriction map of the mtDNA of this organism which shows the position of the rRNA genes and of the A + T-rich region in the DNA. The mt-rRNAs are about 860 and 1500 nucleotides long and have the unusual composition of about 20% G+C. Some 25% of the mtDNA is very rich in A+T and is visualized as a contiguous early melting region in denaturation mapping. We mapped the three cleavage sites of the restriction endonuclease Hae III and the four sites of Hind III on mtDNA relative to each other and relative to the early melting region. The rRNA genes have been positioned on this map. The two rRNA genes are next to each other, separated by a gap of about 160 bases. We determined the polarity of the rRNA molecules: transcription proceeds in the direction small-to-large rRNA. Despite great divergence in nucleotide composition and sequence, the properties of mt-rRNA and the arrangement of mt-rRNA genes are very similar in Drosophila and vertebrate animals.


Replication of cucumber mosaic virus RNA 1 in cis requires functional helicase-like motifs of the 1a protein.
The cucumber mosaic virus (CMV) encoded 1a protein contains an NTPase/helicase-like domain. To investigate whether various helicase motifs were required for efficient replication and to establish whether CMV RNA 1 could be replicated efficiently in cis, we constructed deletion mutations in helicase motifs I, III and VI and analyzed their effects on CMV RNA replication in tobacco. CMV replication was not detectable for any of the three helicase mutants, indicating that the helicase domain is crucial for efficient CMV replication. Both the wild-type and mutant 1a proteins could be detected at similar levels after transient expression in infiltrated tissues, indicating that the helicase-motif mutations did not affect the stability of the proteins. Co-inoculation tests with various mutant combinations did not result in complementation. In protoplasts derived from CMV RNA 1-transgenic tobacco, which supported replication of CMV RNAs 2 and 3, the RNA 1 helicase mutants were not replicated detectably in trans, but also did not interfere with the replication of the genomic RNAs, indicating that the conserved helicase motifs of the 1a protein are required in cis for the effective accumulation of RNA 1.


Multicenter, prospective, phase II study of maintenance bevacizumab for children and adults with NF2-related schwannomatosis and progressive vestibular schwannoma.
Prospective data on maintenance therapy with bevacizumab for persons with NF2-related schwannomatosis (NF2-SWN) is lacking. In this prospective multicenter phase II study, we evaluated the efficacy, safety, and tolerability of bevacizumab for maintenance therapy in children and adults with NF2-SWN and hearing loss due to vestibular schwannomas (VS). Following induction therapy, participants received bevacizumab 5 mg/kg every 3 weeks for 18 months. Participants were monitored for changes in hearing, tumor size, and quality of life (QOL), and for adverse events. Hearing loss was defined as a statistically significant decline in word recognition score (WRS) or pure-tone average compared to the study baseline; tumor growth was defined as >20% increase in volume compared to baseline. Twenty participants with NF2-SWN (median age 23.5 years; range, 12.5-62.5 years) with hearing loss in the target ear (median WRS 70%, range 2%-94%) received maintenance bevacizumab. Freedom from hearing loss in the target ear was 95% after 48 weeks, 89% after 72 weeks, and 70% after 98 weeks. Freedom from tumor growth in the target VS was 94% after 48 weeks, 89% after 72 weeks, and 89% after 98 weeks. NF2-related QOL remained stable for 98 weeks whereas tinnitus-related distress decreased. Maintenance bevacizumab was well tolerated, with 3 participants (15%) discontinuing treatment due to adverse events. Maintenance bevacizumab (5 mg/kg every 3 weeks) is associated with high rates of hearing and tumor stability during 18 months of follow-up. No new unexpected adverse events related to bevacizumab were identified in this population.


Characteristics of lupus nephritis in Saudi lupus patients: A retrospective observational study.
Systemic lupus erythematosus (SLE) is a chronic autoimmune multi-systemic disorder of the connective tissue, characterized mainly by involvement of the skin, joints, kidneys, and serosal membranes. It affects females particularly at childbearing age more commonly than males. Lupus nephritis affects around half of patients with SLE. Data about SLE and lupus nephritis in Saudi Arabia are still scarce. In this study, we aimed to evaluate the prevalence, clinical and laboratory findings of SLE and different histological types of lupus nephritis among Saudi patients at King Fahad Medical City. This is a retrospective study for adult patients who have been evaluated at king Fahad medical city between 2014 and 2019 and fulfilled the Systemic Lupus International Collaborating Clinics classification criteria (SLICC). 112 patients, 103 (92%) females and 9 (8%) males, with confirmed diagnoses of SLE were reviewed. Skin rash (69.6%), photosensitivity (61.6%), mucosal ulcerations (45.9%), arthralgia and/or arthritis (44.6%) are the most common clinical features. Ninety seven (86.6%) out of 112 patients had a recorded first visit 24 hour urine protein level, out of those only 26 (23.2) patients presented with significant proteinuria of more than 0.5grams per day. Forty four (39.2%) have undergone kidney biopsy. Class IV and III lupus nephritis are the most common reported biopsy results (43.18% and 27.28% respectively). During the study period, three patients (2.7%) developed end-stage kidney disease requiring dialysis and five (4.5%) had renal transplant. Our study provided insight on the demographics, characteristics and presentation of SLE patients and the outcome of lupus nephritis in Saudi Arabia.


Fluocinonide vs halcinonide in atopic dermatitis. A paired comparison of two potent topical corticosteroids.
A study showing the superiority of fluocinonide (0.05 percent) cream over halcinonide (0.1 percent) cream in the treatment of atopic dermatitis is presented herein.


Current methods for reducing intussusception: survey results.
Intussusception is a common pediatric abdominal emergency, treated with image-guided reduction. Available techniques include fluoroscopic and ultrasonographic monitoring of liquid and air. The purpose of this study was to determine current practices and establish trends by comparing our findings with reports of previous surveys. This study is based on an e-mail survey sent to all 1,538 members of the Society for Pediatric Radiology. It included questions about demographics, presence of parents/surgeon during procedure, patient selection/preparation, use of sedation, preferred methods of reduction and technical details, approach to unsuccessful reduction, and self-reported incidence of success/perforation. The 456 respondents (30%) reported attempting 3,834 reductions in the preceding 12 months. Of these, 96% use fluoroscopy and 4% use US guidance for reduction; 78% use air, 20% prefer fluid; 75% require intravenous access; 63% expect a surgeon to be present in hospital; 93% do not sedate. Although inflating a rectal balloon is controversial, 39% do so, and 50% employ a pressure-release valve. Seventy-two percent attempt reductions three times in the same position. In case of unsuccessful reductions, 64% wait and re-attempt later, 19% apply manual pressure, and 15% try again in left decubitus position. About 20% reattempt reduction after waiting 2 h or more. By providing a better understanding of both trends in and diversity of current practice, we hope to increase the confidence with which the individual practitioner will approach each case.


Designing, synthesis and characterization of 2-aminothiazole-4-carboxylate Schiff bases; antimicrobial evaluation against multidrug resistant strains and molecular docking.
2-Aminothiazoles are significant class of organic medicinal compounds utilized as starting material for the synthesis of diverse range of heterocyclic analogues with promising therapeutic roles as antibacterial, antifungal, anti-HIV, antioxidant, antitumor, anthelmintic, anti-inflammatory & analgesic agents. Eight compounds 1a, 2a-2g were synthesized and characterized by FTIR and NMR (1H and 13C). Evaluation of antibacterial potential against multi-drug resistant clinical isolates was performed and minimum inhibitory concentration (MIC) values were determined. Antifungal activity was also performed. Protein-ligand interactions of compounds with target enzyme were evaluated through docking studies. Resistance profiling of bacterical clinical isolates (MDRs) depicted that some standard drugs used were not active against these MDRs while our synthesized compounds showed good MIC values. Among all the synthesized compounds, 2a and 2b showed significant antibacterial potential towards gram-positive Staphylococcus epidermidis and gram-negative Pseudomonas aeruginosa at MIC 250 µg/mL and 375 µg/mL respectively. Likewise, compound 2d and 2g exhibited inhibitory potential against gram-positive Staphylococcus aureus and gram-negative Escherichia coli at MIC values of 250 and 375 µg/mL respectively. Compound 2b showed maximum antifungal potential against Candida glabrata (ATCC 62934) with a zone of inhibition 21.0 mm as compared to the reference drug nystatin which showed lesser antifungal potential with a zone of inhibition of 19.1 mm. Candida albicans (ATCC 60387) showed maximum sensitivity to compound 2a with a zone of inhibition 20.0 mm. Its antifungal activity is more in comparison to reference drug nystatin with exhibited the zone of inhibition of 19.3 mm. Designed compounds were docked with the target enzyme UDP-N-acetylmuramate/l-alanine ligase. The compound 2b showed highest binding affinity (- 7.6 kcal/mol). The synthesized compounds showed moderate to significant antibacterial and antifungal potential. It is clear from the binding affinities that compounds having hydroxyl group substituted on benzene ring possess strong binding affinity as compared to other analogues. These designed compounds could be considered to act as antagonists against target UDP-N-acetylmuramate/l-alanine ligase.