Long-term clinical behavior of jejunoileal involvement in Crohn's disease.
Diffuse and extensive jejunoileal Crohn's disease is an uncommon entity. In 39 patients, including 21 males and 18 females, followed for a mean duration of over 16 years between 1979 and 2004, the extent of disease was defined and disease behaviour characterized. Over 80% of patients had concomitant colonic and/or gastroduodenal involvement with Crohn's disease, suggesting that this entity may represent a specific clinical phenotype of extensive disease localization. Classification of Crohn's disease behaviour using the Vienna classification schema revealed that virtually all patients in this study suffered from intestinal stricture formation or penetrating disease complications. Moreover, pharmacological therapies with corticosteroids and immunosuppressant drugs were rarely successful, with virtually all patients requiring at least one, and usually multiple, intestinal resections. Finally, most patients required long-term nutritional support, often with home parenteral nutrition. New treatments are required, possibly defined on the basis of their effectiveness in reducing the severity and extent of intestinal disease, rather than more conventional statistically driven reductions in disease activity indexes.


Sexual Trauma, the Dopamine D4 Receptor, and Suicidal Ideation Among Hospitalized Adolescents: A Preliminary Investigation.
Though an association exists between sexual trauma and adolescent suicidal thoughts and behaviors (STBs), not all adolescents with a sexual assault history develop STBs. The present study examined whether carrier status of the DRD4 VNTR polymorphism (DRD4 L vs. DRD4S) moderated the relationship between sexual trauma and STBs in a sample of psychiatrically hospitalized adolescents. A total of 76 psychiatrically hospitalized adolescents provided saliva samples for genotyping procedures and completed assessment measures. Using hierarchical regression analyses, results indicated that DRD4 L carriers with a sexual trauma history reported significantly more severe suicidal ideation than DRD4S homozygotes. There was no interaction evident for the prediction of suicide attempts. To our knowledge, this is the first study to provide preliminary support for synergistic effects of sexual trauma, DRD4, and severity of SI in adolescents. Further studies of the relationship between sexual trauma, DRD4, and STBs utilizing larger samples are needed.


Accumulation and separation of membrane-bound proteins using hydrodynamic forces.
The separation of molecules residing in the cell membrane remains a largely unsolved problem in the fields of bioscience and biotechnology. We demonstrate how hydrodynamic forces can be used to both accumulate and separate membrane-bound proteins in their native state. A supported lipid bilayer (SLB) was formed inside a microfluidic channel with the two proteins streptavidin (SA) and cholera toxin (CT) coupled to receptors in the lipid bilayer. The anchored proteins were first driven toward the edge of the lipid bilayer by hydrodynamic forces from a flowing liquid above the SLB, resulting in the accumulation of protein molecules at the edge of the bilayer. After the concentration process, the bulk flow of liquid in the channel was reversed and the accumulated proteins were driven away from the edge of the bilayer. Each type of protein was found to move at a characteristic drift velocity, determined by the frictional coupling between the protein and the lipid bilayer, as well as the size and shape of the protein molecule. Despite having a similar molecular weight, SA and CT could be separated into monomolecular populations using this approach. The method also revealed heterogeneity among the CT molecules, resulting in three subpopulations with different drift velocities. This was tentatively attributed to multivalent interactions between the protein and the monosialoganglioside G(M1) receptors in the lipid bilayer.


Rapidly acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines through de-repression of FGFR2 and FGFR3 expression.
Despite initial and sometimes dramatic responses of specific NSCLC tumors to EGFR TKIs, nearly all will develop resistance and relapse. Gene expression analysis of NSCLC cell lines treated with the EGFR TKI, gefitinib, revealed increased levels of FGFR2 and FGFR3 mRNA. Analysis of gefitinib action on a larger panel of NSCLC cell lines verified that FGFR2 and FGFR3 expression is increased at the mRNA and protein level in NSCLC cell lines in which the EGFR is dominant for growth signaling, but not in cell lines where EGFR signaling is absent. A luciferase reporter containing 2.5 kilobases of fgfr2 5' flanking sequence was activated after gefitinib treatment, indicating transcriptional regulation as a contributing mechanism controlling increased FGFR2 expression. Induction of FGFR2 and FGFR3 protein as well as fgfr2-luc activity was also observed with Erbitux, an EGFR-specific monoclonal antibody. Moreover, inhibitors of c-Src and MEK stimulated fgfr2-luc activity to a similar degree as gefitinib, suggesting that these pathways may mediate EGFR-dependent repression of FGFR2 and FGFR3. Importantly, our studies demonstrate that EGFR TKI-induced FGFR2 and FGFR3 are capable of mediating FGF2 and FGF7 stimulated ERK activation as well as FGF-stimulated transformed growth in the setting of EGFR TKIs. In conclusion, this study highlights EGFR TKI-induced FGFR2 and FGFR3 signaling as a novel and rapid mechanism of acquired resistance to EGFR TKIs and suggests that treatment of NSCLC patients with combinations of EGFR and FGFR specific TKIs may be a strategy to enhance efficacy of single EGFR inhibitors.


Varicella vaccination in pediatric kidney transplant candidates.
Existing studies support the use of varicella vaccine in a two-dose regimen in patients with renal disease prior to transplantation. Levels of anti-varicella zoster virus antibody should be monitored on a regular basis after immunization, and where a loss of a previously protective antibody titer occurs, a third booster dose should be considered pretransplant. Further data need to be collected regarding the use of the vaccine in seronegative patients who have already undergone transplantation.


Formation of the 12q14-q15 amplicon precedes the development of a well-differentiated liposarcoma arising from a nonchondroid pulmonary hamartoma.
Pulmonary hamartoma is a benign neoplasm that rarely recurs or undergoes malignant transformation. Herein, we report a 48-year-old woman with a history of an incomplete excised nonchondroid pulmonary hamartoma presenting as an indolent tumor recurrence. Excision of the tumor revealed a well-differentiated liposarcoma arising from the hamartomatous component. Fluorescence in situ hybridation analysis for HMGA2 and MDM2 was performed on both hamartomatous and liposarcomatous component. MDM2 and HMGA2 amplification were found in a subset of stromal cells in the hamartomatous component and in most cells of the well-differentiated liposarcoma. No rearrangement HMGA2 was found in the pulmonary hamartoma component. These findings suggest that the formation of the 12q14-q15 chromosome amplicon, the characteristic cytogenetic finding of well-differentiated liposarcomas and the structural genomic component of the supernumerary ring and giant rod chromosomes, occurred before the morphologic changes characteristic of these malignant adipose tissue tumors and likely represents a very early molecular event in their development.


Poly(ADP-ribose) polymerase triggers the microvascular mechanisms of hepatic ischemia-reperfusion injury.
Activation of poly(ADP-ribose) polymerase (PARP) mediates oxidative stress-induced cell injury. We tested the hypothesis that PARP contributes to ischemia-reperfusion (I/R) damage of the liver by triggering the mechanisms of microcirculatory failure. Leukocyte- and platelet-endothelial cell interactions as well as sinusoidal perfusion were analyzed by intravital fluorescence microscopy after lobar hepatic I/R (90 min/30 min) in C57BL/6 x 129/Sv wild-type (PARP+/+) and PARP-deficient (PARP-/-) mice. Hepatic I/R induced leukocyte/platelet-endothelial cell interactions and tissue injury in PARP+/+ mice, as indicated by impaired sinusoidal perfusion and increased alanine aminotransferase (ALT)/aspartate aminotransferase (AST) serum activities. In PARP-/- mice, however, the postischemic increase in the numbers of rolling/adherent leukocytes and platelets was significantly lower. In addition, I/R-induced translocation of CD62P as well as mRNA expression of CD62E, CD54, and CD106 were attenuated. The degree of perfusion failure was reduced and the increase in the ALT/AST activities was lower in PARP-/- mice compared with PARP+/+ mice. We conclude that PARP contributes to hepatic microvascular injury by triggering the expression/translocation of adhesion molecules and modulating leukocyte/platelet-endothelial cell interactions.


Endogenous factors responsible for the textural characteristics of buckwheat products.
Endogenous factors responsible for the textural characteristics of buckwheat products were studied. An analysis with various buckwheat samples showed that there were variations in protein, starch, amylose and amylopectin contents among the various buckwheat flours examined. The protein contents of the buckwheat flours were significantly negatively-correlated to the starch, amylose and amylopectin contents of buckwheat. A texturometric analysis showed that the springiness of heated-dough made from buckwheat flour was positively correlated to its starch content and amylopectin content, and the springiness and chewiness was negatively correlated to the protein content. Experiments adding isolated buckwheat protein or starch to buckwheat dough confirmed the above-mentioned correlation between texture and components. This study suggests that both the protein and starch present in buckwheat flour may be important factors responsible for the textural characteristics of buckwheat products.


Newspaper coverage of controversies about large-scale swine facilities in rural communities in Illinois.
The building and expansion of large-scale swine facilities has created considerable controversy in many neighboring communities, but to date, no systematic analysis has been done of the types of claims made during these conflicts. This study examined how local newspapers in one state covered the transition from the dominance of smaller, diversified swine operations to large, single-purpose pig production facilities. To look at publicly made statements concerning large-scale swine facilities (LSSF), the study collected all articles related to LSSF from 22 daily Illinois newspapers over a 3-yr period (a total of 1,737 articles). The most frequent sets of claims used by proponents of LSSF were that the environment was not harmed, that state regulations were sufficiently strict, and that the state economically needed this type of agriculture. The most frequent claims made by opponents were that LSSF harmed the environment and neighboring communities and that stricter regulations were needed. Proponents' claims were primarily defensive and, to some degree, underplayed the advantages of LSSF. Pro-and anti-LSSF groups were talking at cross-purposes, to some degree. Even across similar themes, those in favor of LSSF and those opposed were addressing different sets of concerns. The newspaper claims did not indicate any effective alliances forming between local anti-LSSF groups and national environmental or animal rights groups.


Ternary Eutectic Ezetimibe-Simvastatin-Fenofibrate System and the Physical Stability of Its Amorphous Form.
In this study, the phase diagram of the ternary system of ezetimibe-simvastatin-fenofibrate was established. It has been proven that the ternary composition recommended for the treatment of mixed hyperlipidemia forms a eutectic system. Since eutectic mixtures are characterized by greater solubility and dissolution rate, the obtained result can explain the marvelous medical effectiveness of combined therapy. Considering that another well-known method for improving the aqueous solubility is amorphization, the ternary system with eutectic concentration was converted into an amorphous form. Thermal properties, molecular dynamics, and physical stability of the obtained amorphous system were thoroughly investigated through various experimental techniques compared to both: neat amorphous active pharmaceutical ingredients (considered separately) and other representative concentrations of ternary mixture. The obtained results open up a new way of selecting the therapeutic concentrations for combined therapies, a path that considers one additional variable: eutecticity.


T-cell receptor expression in the T-cell malignancies.
Twenty-eight cases with T-cell neoplasms (10 with T-cell acute lymphoblastic leukemia [T-ALL], 10 with T-lymphoblastic lymphoma, and 8 with peripheral T-cell lymphomas) and 2 cases with reactive lymph nodes were immunohistochemically stained with monoclonal antibodies beta F1, delta TCS1, and WT31; beta F1 antibody recognizes the beta-subunit of T-cell receptor (TCR), whereas delta TCS1 and WT31 recognize the delta- and alpha beta-subunits of TCR, respectively. Five cases with T-ALL, four with T-lymphoblastic lymphoma (T-LL), and seven with peripheral T-cell lymphomas were positive for beta F1. None showed positive reactivity for delta TCS1. One case with T-LL and four cases with peripheral T-cell lymphomas were positive for WT31. Of the nine cases positive for beta F1 among T-ALLs and T-LLs, six were also positive for CD1 (OKT6), whereas six of seven positive cases for CD1 were positive for beta F1. The authors therefore suggest that TCR beta is expressed in the immature T-cells just earlier than or around the same stage of differentiation as those expressing CD1. The authors' immuno-electron microscopy study revealed that positive reactivity for beta F1 was localized predominantly in the cytoplasm of the neoplastic cells in the cases with T-ALL, T-LL and peripheral T-cell lymphomas, and in the cytoplasm of the reactive T-cells. However, it was not localized on the surface membrane. In contrast, positive reactivity for WT31 was localized on the surface membrane of the neoplastic and reactive T-cells. Only half of the cases of peripheral T-cell lymphomas showed positive reactivity for WT31. The authors consider that it may not be a very useful antibody for the detection of TCR alpha beta on the T-cell neoplasms using frozen tissue sections.


Determinants of potential drug-drug interaction associated dispensing in community pharmacies in the Netherlands.
There are many drug-drug interactions (D-DI) of which some may cause severe adverse patient outcomes. Dispensing interacting drug combinations should be avoided when the risks are higher than the benefits. The objective of this study was to identify determinants of dispensing undesirable interacting drug combinations by community pharmacies in the Netherlands. A total of 256 Dutch community pharmacies were selected, based on the dispensing of 11 undesirable interacting drug combinations between January 1st, 2001 and October 31st, 2002. These pharmacies were sent a questionnaire by the Inspectorate for Health Care (IHC) concerning their process and structure characteristics. The number of times the 11 undesirable interacting drug combinations were dispensed. Two hundred and forty-six questionnaires (response rate 96.1%) were completed. Dispensing determinants were only found for the D-DI between macrolide antibiotics and digoxin but not for the other 10 D-DIs. Pharmacies using different medication surveillance systems differed in the dispensing of this interacting drug combination, and pharmacies, which were part of a health care centre dispensed this interacting drug combination more often. Medication surveillance in Dutch community pharmacies seems to be effective. Although for most D-DIs no determinants were found, process and structure characteristics may have consequences for the dispensing of undesirable interacting drug combinations.


α-naphthaleneacetic acid positively regulates soybean seed germination and seedling establishment by increasing antioxidant capacity, triacylglycerol mobilization and sucrose transport under drought stress.
Drought stress is an important constraint for the germination of soybean (Glycine max [L.] Merr.) seeds and seedling establishment. A pot experiment was conducted to determine the effects of priming soybean seeds with 5 μM α-naphthaleneacetic acid (NAA) and the mechanism responsible for the induced tolerance of drought stress (soil relative water content of 55%). NAA priming inhibited drought-induced oxidative damage in seeds, and further analysis indicated that it induced an early spike in hydrogen peroxide content by the upregulation of abscisic acid-dependent GmRbohC2, resulting in an enhancement of antioxidant capacity. Moreover, NAA priming also improved the hydrolysis of triacylglycerol (TAG) to sucrose in stressed cotyledons by causing a 2- to 5-fold increase in the transcript levels of GmSDP1, GmACX2, GmMFP2, GmICL, GmMLS, GmGLI1, GmPCK1, GmFBPase1, GmSPS1 and GmSPS2. Consistently, it upregulated the expression levels of GmSUT1, GmCWINV1 and GmMST2 under drought stress, thus enhancing the transport of sucrose from cotyledons to embryonic axes, providing carbon skeletons and energy for axis growth. The seed germination percentage increased by 208.1% at 21 h after sowing, and seedling establishment percentage increased by 47.8% at 14 days after sowing. Collectively, the positive effects of NAA priming on seed germination and seedling establishment can be attributed to enhanced antioxidant ability in seeds, TAG mobilization in cotyledons and sucrose transport from cotyledons to embryonic axes under drought stress.


Risk estimates for dichotomous genetic disease traits based on a cohort study of relatedness in purebred dog populations.
As a result of strong selection in closed gene pools, dog breeds represent populations of highly related animals. Prominent founder-effects are responsible for inherited diseases occurring in particular breeds, and each breed may have several breed-related diseases, often with a high incidence. Such inherited diseases are a major problem in purebred dog populations, and probably threaten their survival. On the basis of pedigree information held by the National Kennel Clubs and reliable medical data of a representative longitudinal cohort, estimates have been made of the relative risks of dichotomous disease traits in all combined breeding stock. This approach is independent of assumptions about modes of inheritance or thresholds. In a cohort study, all the common ancestors of the cases are selected and their degree of relatedness to both cases and controls is estimated. The ancestors which are positively associated with the dichotomous disease trait are selected on the basis of scores of relatedness. To reduce the number of parameters, while maintaining maximal informativeness, a principal component analysis is applied. Finally a logistic model, based on the principal components and the case control definitions, describes the most likely pattern of the passage of genetic risk factors down the generations. Estimates of relatedness to seven highly related ancestors were sufficient to describe the distribution of disease in a population of Dutch labrador retrievers. This approach may be used for genetic counselling for any clinical phenotypically dichotomous trait in such a highly related population of companion animals, and may also help to identify suitable dogs for molecular studies of the underlying defect.


Hypermetabolic Syndrome and Dyskinesia After Neurologic Surgery for Labrune Syndrome: A Case Report.
A 20-year-old man with a rare neurodegenerative disease developed hypermetabolic symptoms with dyskinesia after a third ventriculostomy for hydrocephalus. The initial presentation was concerning for an acute dystonic reaction after metoclopramide was administered for nausea. He concurrently developed hypermetabolic symptoms, including hyperthermia, tachycardia, and a lactic acidosis. The diagnosis was broadened to include neuroleptic malignant syndrome, serotonin syndrome, and malignant hyperthermia. Although perhaps less intellectually satisfying but more true to clinical reality, we did not isolate a single diagnosis but treated effectively all 3 with dantrolene sodium and benzodiazepine.


Family assets and child outcomes: evidence and directions.
For poor families, the possession of assets--savings accounts, homes, and the like--has the potential not only to relieve some of the stress of living in poverty but also to make a better future seem like a real possibility. If children in families that own certain assets fare better than children in families without them, then helping poor families build those assets would be an effective strategy for two-generation programs. Indeed, write Michal Grinstein-Weiss, Trina Williams Shanks, and Sondra Beverly, plenty of evidence shows that assets are connected to positive outcomes for poor children. For example, young people who have any college savings at all, even a very small amount, are more likely to go to college; children in households with assets score higher on standardized achievement tests; and children of homeowners experience fewer behavioral problems. But this evidence comes from longitudinal data sets and is therefore correlational. Looking for causal relationships, the authors examine the results of experimental programs that opened various types of savings accounts for poor people and matched their contributions. Several of these trials included a control group that did not receive a savings account, making it possible to attribute any positive outcomes directly to the savings accounts rather than to their owners' personal characteristics. These programs dispelled the myth that poor people can't save; participants were generally able to accumulate savings. It's too early to tell, however, whether assets and asset-building programs have long-term effects on children's wellbeing, though one experiment found positive impacts on disadvantaged children's social-emotional development at age four. The most promising programs share several features: they are opened early in life; they are opened automatically, with no action required from the recipients; and they come with an initial deposit.


Role of hybrid tRNA-binding states in ribosomal translocation.
During translation, tRNAs must move rapidly to their adjacent sites in the ribosome while maintaining precise pairing with mRNA. This movement (translocation) occurs in a stepwise manner with hybrid-state intermediates, but it is unclear how these hybrid states relate to kinetically defined events of translocation. Here we analyze mutations at position 2394 of 23S rRNA in a pre-steady-state kinetic analysis of translocation. These mutations target the 50S E site and are predicted to inhibit P/E state formation. Each mutation decreases growth rate, the maximal rate of translocation (k(trans)), and the apparent affinity of EF-G for the pretranslocation complex (i.e., increases K(1/2)). The magnitude of these defects follows the trend A > G > U. Because the C2394A mutation did not decrease the rate of single-turnover GTP hydrolysis, the >20-fold increase in K(1/2) conferred by C2394A can be attributed to neither the initial binding of EF-G nor the subsequent GTP hydrolysis step. We propose that C2394A inhibits a later step, P/E state formation, to confer its effects on translocation. Replacement of the peptidyl group with an aminoacyl group, which is predicted to inhibit A/P state formation, decreases k(trans) without increasing K(1/2). These data suggest that movements of tRNA into the P/E and A/P sites are separable events. This mutational study allows tRNA movements with respect to both subunits to be integrated into a kinetic model for translocation.


Infection-induced lymphatic zippering restricts fluid transport and viral dissemination from skin.
Lymphatic vessels are often considered passive conduits that flush antigenic material, pathogens, and cells to draining lymph nodes. Recent evidence, however, suggests that lymphatic vessels actively regulate diverse processes from antigen transport to leukocyte trafficking and dietary lipid absorption. Here we tested the hypothesis that infection-induced changes in lymphatic transport actively contribute to innate host defense. We demonstrate that cutaneous vaccinia virus infection by scarification activates dermal lymphatic capillary junction tightening (zippering) and lymph node lymphangiogenesis, which are associated with reduced fluid transport and cutaneous viral sequestration. Lymphatic-specific deletion of VEGFR2 prevented infection-induced lymphatic capillary zippering, increased fluid flux out of tissue, and allowed lymphatic dissemination of virus. Further, a reduction in dendritic cell migration to lymph nodes in the absence of lymphatic VEGFR2 associated with reduced antiviral CD8+ T cell expansion. These data indicate that VEGFR2-driven lymphatic remodeling is a context-dependent, active mechanism of innate host defense that limits viral dissemination and facilitates protective, antiviral CD8+ T cell responses.


Use of Internal Endoconduit for Unfavorable Iliac Artery Anatomy in Patients Undergoing Transcatheter Aortic Valve Replacement - A Single Center Experience.
Transfemoral (TF) access is associated with lower rates of surgical conversion and mortality compared with non-TF access for transcatheter aortic valve replacement (TAVR). Therefore, efforts should be made to make this procedure even less invasive, allowing more TAVR procedures to be performed through femoral access. We herein describe our single-center experience of using one-stage percutaneous internal endoconduits for TAVR in patients with unfavorable iliac artery anatomy. Between March 2013 andMarch 2016, 113 consecutive patients with severe aortic stenosis at high risk for conventional cardiac surgery underwent TAVR at the Cheng Hsin General Hospital. The patients can be divided into Cohort A (March 2013-December 2014) and Cohort B (January 2015-March 2016). In the Cohort A, 6 out of the 53 (11.4%) with unfavorable iliac artery anatomy were treated by trans-subclavian approach (n = 3, 5.7%) or direct aortic approach (n = 3, 5.7%); while in the Cohort B, none (0%) of the 5 patients with unfavorable iliac artery anatomy among 60 consecutive TAVR cases needed non-TF approach (Cohort A vs. Cohort B = 11.4% vs. 0%, p = 0.024) and they were all successfully treated with the use of an internal endoconduit. The use of internal endoconduits can further increase the number of patients who can be treated through femoral artery access for TAVR and substantially reduce the need of non-TF approaches.


Inborn errors of metabolism: Lessons from iPSC models.
The possibility of reprogramming human somatic cells to pluripotency has opened unprecedented opportunities for creating genuinely human experimental models of disease. Inborn errors of metabolism (IEMs) constitute a greatly heterogeneous class of diseases that appear, in principle, especially suited to be modeled by iPSC-based technology. Indeed, dozens of IEMs have already been modeled to some extent using patient-specific iPSCs. Here, we review the advantages and disadvantages of iPSC-based disease modeling in the context of IEMs, as well as particular challenges associated to this approach, together with solutions researchers have proposed to tackle them. We have structured this review around six lessons that we have learnt from those previous modeling efforts, and that we believe should be carefully considered by researchers wishing to embark in future iPSC-based models of IEMs.


The effect of core translucency on the aesthetics of all-ceramic restorations.
Recent advances in ceramic technology have revolutionized aesthetic dentistry. When treating a single anterior tooth in need of a full-coverage restoration, a multitude of options in restorative materials and techniques is available to the clinician. The learning objective of this article is to present and evaluate a selection of all-ceramic dental materials currently available for aesthetic full-coverage crown restorations. When selecting an all-ceramic system, there are several major factors to consider, including the inherent translucency of the ceramic material and of the adjacent dentition, the color of the prepared tooth, and the forces anticipated in that region. Preparation and restoration of discolored and nondiscolored tooth structure are reviewed. The techniques presented can be utilized to obtain predictable results in the anterior region for aesthetic all-ceramic full-coverage restorations.


Evidence for genes in addition to Tlr7 in the Yaa translocation linked with acceleration of systemic lupus erythematosus.
The accelerated development of systemic lupus erythematosus (SLE) in male BXSB mice is associated with the genetic abnormality in its Y chromosome, designated Yaa (Y-linked autoimmune acceleration). Recently, the Yaa mutation was identified to be a translocation from the telomeric end of the X chromosome (containing the gene encoding TLR7) onto the Y chromosome. In the present study, we determined whether the Tlr7 gene duplication is indeed responsible for the Yaa-mediated acceleration of SLE. Analysis of C57BL/6 mice congenic for the Nba2 (NZB autoimmunity 2) locus (B6.Nba2) bearing the Yaa mutation revealed that introduction of the Tlr7 null mutation on the X chromosome significantly reduced serum levels of IgG autoantibodies against DNA and ribonucleoproteins, as well as the incidence of lupus nephritis. However, the protection was not complete, because these mice still developed high titers of anti-chromatin autoantibodies and retroviral gp70-anti-gp70 immune complexes, and severe lupus nephritis, which was not the case in male B6.Nba2 mice lacking the Yaa mutation. Moreover, we found that the Tlr7 gene duplication contributed to the development of monocytosis, but not to the reduction of marginal zone B cells, which both are cellular abnormalities causally linked to the Yaa mutation. Our results indicate that the Yaa-mediated acceleration of SLE as well as various Yaa-linked cellular traits cannot be explained by the Tlr7 gene duplication alone, and suggest additional contributions from other duplicated genes in the translocated X chromosome.


Integrating bevacizumab into the treatment of patients with early-stage breast cancer: focus on cardiac safety.
Significant advances have been made in the treatment of patients with breast cancer in recent years. As increasing numbers of patients become long-term survivors, there must be a greater focus on treatment-induced chronic toxicities, such as left ventricular dysfunction, congestive heart failure (CHF), and/or secondary treatment malignancies. More recently, the HER2-targeted monoclonal antibody (MoAb) trastuzumab has been found to increase the risk for CHF, particularly when used in combination with an anthracycline or in anthracycline-pretreated patients. In early-stage breast cancer, CHF has been reported in up to 4% of trastuzumab-treated, anthracycline-pretreated patients. Given this background, the clinical development of bevacizumab, a MoAb to vascular endothelial growth factor, is proceeding--with careful consideration given to cardiac safety--in this setting. Cardiac toxicity has been reported in association with bevacizumab-based therapy in patients with advanced or metastatic breast cancer, many of whom were previously exposed to anthracyclines. Although there is currently little evidence to suggest that bevacizumab increases the risk or worsens the severity of cardiac events in these patients, it is anticipated that ongoing, well-designed prospective trials will fully evaluate the cardiac safety of bevacizumab in patients with early-stage breast cancer. This review analyzes the cardiac safety profile of bevacizumab in breast cancer, with a focus on early-stage disease, and the ongoing clinical development of this important new drug.


The Extent and Scope of Prosthodontic Practice in Iowa.
The purpose of this questionnaire was to ask general dentists in private practice in the state of Iowa about the extent and scope of their prosthodontic practice. A 22-item questionnaire was developed and tested on 5 general dentists. The Iowa Dental Association agreed to electronically distribute the survey to all general practice dentists in their database. After three rounds, a total of 289 responses were received from the 996 general dentists in the database. The average age of the respondents was 50.3 ± 13.2 years (range 28 to 78 years), and 56.3% were in solo practice. The respondents stated that 68.1% had made at least one set of complete dentures and 88.9% had made a removable partial denture (RPD) in the last 3 months, while 76.4% had restored a least one implant in the last 3 months and 11.6% had surgically placed one. Nearly 20% of the respondents had a digital impression scanner in their office. There was a statistically significant difference between the dentists who had made complete dentures in the past 3 months and those who had not with regard to age, gender, and years in practice (p < 0.05 for all instances). No significant difference was found between the general dentists who had made an RPD in the past 3 months and those who had not. Compared to their counterparts, general dentists who had an AEGD or GPR training (p = 0.0312), whose primary practices were in cities of 50,000+ (p = 0.0065), or had a digital scanner (p = 0.0062) and a CAD/CAM milling machine (p = 0.0504) in their office were more likely to have restored an implant in the last 3 months. Furthermore, the general dentists who had surgically placed an implant in the last 3 months were more likely to be male (p = 0.0301) or have a digital impression scanner (p < 0.0001) and/or a CAD/CAM milling machine (p = 0.0007) in their office. The majority of general dentists in this survey are still making complete and partial removable dentures, and a majority is using implants, while only a minority is surgically placing them. PRACTICAL IMPLICATIONS: Although Iowa general dentists are carrying out sophisticated procedures such as implant placement and restoring implants, as well as using digital technology, there is still a need for removable prosthodontic services in their practices. Therefore, these skills will still need to be taught in dental school.


Novel integrated microdialysis-amperometric system for in vitro detection of dopamine secreted from PC12 cells: design, construction, and validation.
A novel dual channel in vitro apparatus, derived from a previously described design, has been coupled with dopamine (DA) microsensors for the flow-through detection of DA secreted from PC12 cells. The device, including two independent microdialysis capillaries, was loaded with a solution containing PC12 cells while a constant phosphate-buffered saline (PBS) medium perfusion was carried out using a dual channel miniaturized peristaltic pump. One capillary was perfused with normal PBS, whereas extracellular calcium was removed from extracellular fluid of the second capillary. After a first period of stabilization and DA baseline recording, KCl (75 mM) was added to the perfusion fluid of both capillaries. In this manner, a simultaneous "treatment-control" experimental design was performed to detect K+-evoked calcium-dependent DA secretion. For this purpose, self-referencing DA microsensors were developed, and procedures for making, testing, and calibrating them are described in detail. The electronic circuitry was derived from previously published schematics and optimized for dual sensor constant potential amperometry applications. The microdialysis system was tested and validated in vitro under different experimental conditions, and DA secretion was confirmed by high-performance liquid chromatography with electrochemical detection (HPLC-EC). PC12 cell viability was quantified before and after each experiment. The proposed apparatus serves as a reliable model for studying the effects of different drugs on DA secretion through the direct comparison of extracellular DA increase in treatment-control experiments performed on the same initial PC12 cell population.


Magnetic anisotropy of a high-spin octanuclear nickel(II) complex with a meso-helicate core.
The octanickel(II) cluster 2b has been synthesized from the novel ferromagnetically coupled dinickel(II) metallacryptand 1b assembled from the m-phenylene-bis(oxamate) ligand. Complex 2b exhibits a dimer-of-tetramers structure, with two oxamate-bridged propeller-shaped tetranuclear units connected through three meta-substituted phenylenediamidate bridges, giving a metallacryptand core of the meso-helicate type. Complex 2b behaves as a ferromagnetically coupled dimer of two S=2 Ni(II)4 units with appreciable magnetic anisotropy.


Development and verification of a hydrostatic pressure chamber for determining the efffect of pressure on liver progenitor cells.
Hepatic progenitor cells (HPCs) have regenerative properties that could aid the development of treatments for severe liver disease. To study how pressure influences HPC fate, a hydrostatic pressure-controlled cell culture chamber was developed. The design incorporates custom LabView scripting for enhanced pressure regulation and data acquisition. Pressure can be controlled within ±0.2mmHg. Continuous airflow permits gas exchange, and CO2 is maintained at 5%±0.2%. Applied pressures range from 5 to 20 mmHg, reflecting interstitial pressure conditions in healthy and diseased livers, respectively. Bipotential Murine Oval Liver (BMOL) cells, an HPC-like cell line, were cultured in the chamber to test for maintenance of cell viability, adequate CO2 regulation, and maintenance of adequate media volume over 24 hours. Cultured cells were exposed to 5 or 19 mmHg. After 24 hours, media pH was measured, viable cells were counted (Trypan Blue, n=3), and plates were weighed to assess fluid loss. The number of live cells cultured under pressure vs. control conditions was not statistically different (p>.05). The pH remained constant at 7.0 for all conditions, suggesting adequate gas exchange. Evaporation of media was minimal at 3.97%. Results indicate that the pressure chamber provides appropriate environmental conditions for future studies on HPC pressure sensitivity.


Silent corticotroph adenoma: case report and literature review.
To review the initial clinical manifestations and diagnosis of silent corticotroph adenoma. We report a case and summarize the relevant literature. A 52-year-old patient with hypopituitarism underwent resection of a silent corticotroph adenoma. A circulating species was detected postoperatively, reactive in a highly sensitive adrenocorticotropic hormone (ACTH) 1-39 immunoradiometric assay (IRMA) and beta-endorphin or beta-lipotropin radioimmunoassay. The basal morning cortisol concentration consistently was <10 microg/dL. Dynamic testing was performed to screen for Addison's disease, congenital adrenal hyperplasia, and Cushing's syndrome. During dexamethasone suppression, the molar concentration of circulating ACTH precursors by a two-site IRMA was 55-fold greater than the concentration of ACTH 1-39 by IRMA. We concluded that the tumor displayed impaired processing of pro-opiomelanocortin (POMC) and secreted a bioinactive POMC-derived peptide that was reactive in the ACTH 1-39 IRMA. Patients with silent corticotroph adenoma do not have clinically evident Cushing's syndrome. In some cases, bioinactive ACTH precursors may be detected by a sensitive ACTH 1-39 IRMA.


Outcomes of mitral valve replacement with complete annular decalcification.
This study aimed to examine the clinical outcomes of mitral valve replacement (MVR) in patients with severe mitral annular calcification (MAC) who required extensive decalcification and mitral annular reconstruction. We reviewed 15 patients with severe MAC who underwent MVR between January 2016 and May 2022. In all cases, the calcified mitral annulus was resected completely using a Cavitron Ultrasound Surgical Aspirator, and a new annulus was created using bovine pericardium. In the acute postoperative phase, strict afterload reduction therapy using an intra-aortic balloon pump (IABP) was administered. The mean age of patients was 73 ± 8 years, and 13 (86.7%) were women. Concomitant aortic valve replacement was performed in 11 (73.3%) patients, tricuspid annuloplasty in 9 (60.0%), coronary artery bypass grafting in 1 (6.7%), and arrhythmia surgery in 7 (46.7%). The mean aortic cross-clamp and cardiopulmonary bypass times were 143 ± 32 min and 175 ± 34 min, respectively. In 13 patients, an IABP was used for 2 or 3 days postoperatively. There were no in-hospital deaths, left ventricular ruptures, or other MAC-related complications. Postoperative echocardiography revealed no paravalvular leakages. Our strategy for managing severe MAC is safe and reproducible even in relatively high-risk patients. Afterload reduction using an IABP in the acute postoperative phase may reduce the risk of fatal complications after extensive decalcification and mitral annular reconstruction.


Interaction of dengue virus nonstructural protein 5 with Daxx modulates RANTES production.
Dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS), caused by dengue virus (DENV) infection, are important public health problems in the tropical and subtropical regions. Abnormal hemostasis and plasma leakage are the main patho-physiological changes in DHF/DSS. A remarkably increased production of cytokines, the so called 'cytokine storm', is observed in the patients with DHF/DSS. A complex interaction between DENV proteins and the host immune response contributes to cytokine production. However, the molecular mechanism(s) by which DENV nonstructural protein 5 (NS5) mediates these responses has not been fully elucidated. In the present study, yeast two-hybrid assay was performed to identify host proteins interacting with DENV NS5 and a death-domain-associate protein (Daxx) was identified. The in vivo relevance of this interaction was suggested by co-immunoprecipitation and nuclear co-localization of these two proteins in HEK293 cells expressing DENV NS5. HEK293 cells expressing DENV NS5-K/A, which were mutated at the nuclear localization sequences (NLS), were created to assess its functional roles in nuclear translocation, Daxx interaction, and cytokine production. In the absence of NLS, DENV NS5 could neither translocate into the nucleus nor interact with Daxx to increase the DHF-associated cytokine, RANTES (CCL5) production. This work demonstrates the interaction between DENV NS5 and Daxx and the role of the interaction on the modulation of RANTES production.


Eu3+ Concentration Effects in Phosphate Glasses: An Experimental Study Linking Structural, Thermal, and Optical Properties.
Phosphate glasses incorporating large concentrations of Eu3+ ions are of interest for optical applications as their distinct red-emitting character resists deterioration with increasing Eu3+ content. Still, the low propensity for concentration quenching in these is not well understood, and thus evaluations linking structural, thermal, and optical properties with Eu3+ content are desired. In this work, 50P2O5-(50 - x)BaO-xEu2O3 (x = 0, 1, 2, 4, 6 mol %) glasses pertinent to photonics were prepared by melt-quenching and further scrutinized with regards to the composition-structure-property relationship. A comprehensive experimental investigation was carried out encompassing density and basic physical properties, X-ray diffraction (XRD), Raman scattering, dilatometry, differential scanning calorimetry (DSC), optical absorption, and photoluminescence (PL) spectroscopy with emission decay analysis. The data from six techniques are in strong agreement with the existence of a critical Eu2O3 concentration which divides the studied concentration range into two sections: (1) lower concentrations, up to about 2.5 (±0.1) mol %, with predominantly long-range (LR) effects of the modifier electrostatic field and (2) higher dopant concentrations, with predominantly short-range (SR) effects of the modifier field. The authors propose that LR interactions lead to shortening of the P-tetrahedral chains, while the SR interactions are expressed in increasing the covalent character of the bonds between the nonbridging oxygens and Eu3+ ions. Concentration correlations between diverse macroscopic data sets, such as densitometry, dilatometry, Raman scattering, calorimetry, and PL, concur synergistically, elucidating the microscopic physical LR-SR interplay between glass network former and the cationic electrostatic field of the modifiers.


Endometriosis and IVF: are agonists really better? Analysis of 1180 cycles with the propensity score matching.
To compare the outcomes of patients with confirmed endometriosis undergoing in vitro fertilization (IVF)-embryo transfer (ET) treated with either gonadotropin-releasing hormone agonist (GnRHa) or gonadotropin-releasing hormone antagonist (GnRHant) using the propensity score (PS) matching. Observational, retrospective analysis from January 2000 to December 2010. Private tertiary fertility clinic. Patients with endometriosis confirmed by ultrasound or surgery (American Fertility Society; AFS grades I-IV) that underwent an IVF-ET, stimulated with standard controlled ovarian hyperstimulation (COH) and GnRHa or GnRHant. A PS was assigned to all patients, which calculates the conditional probability of receiving a certain treatment; a higher PS (1) meant a higher probability of receiving treatment with GnRHa, and a lower PS (0) meant a higher probability of receiving GnRHant. The PS was calculated with a logistic regression model adjusted specifically for age, follicle stimulating hormone, antral follicle count and previous IVF cycles. All patients were divided into three groups according to their PS. pregnancy rate (PR) per cycle. 1180 patients were analyzed. Raw PR per cycle was 41.8% and 23.4%, and PR per ET was 44.3 and 27%, respectively. PR per cycle: 41.9 versus 30% in group A; in group B, 39.7% versus 36.4% and in group C, 15.4% versus 18.9%. The overall odds ratio for PR adjusted by PS was 1.10 [0.58-2.19]. After matching patients by PS, PR after COH with either GnRHa or GnRHant may be equally effective.


A new biologic membrane in cardiovascular surgery.
Reconstruction techniques for major vessels and intracardiac defect repair use synthetic grafts or autogenic pericardium. Here, autologous abdominal parietal peritoneum with the overlying posterior rectus sheath as a biologic membrane are evaluated. Twelve adult canines were used. Via a midline subumbilical incision, the parietal peritoneum and overlying posterior rectus sheath were harvested. In the first group of six, the membrane was used to repair the right ventricular infundibulum and perform pulmonary artery annuloplasty. In the second group of six, under cardiopulmonary bypass and moderate hypothermia, the right atrium was opened and a secundum type defect was created. Autopsies performed 90 days after surgery revealed mild intrapericardial adhesions and moderate pericardial reaction over the cardiotomy incisions. The right ventricular outflow tract patch was nonaneurysmal. The interatrial patch was intact without thrombi. Histologic examination revealed intact membrane morphology, fibroblasts, smooth muscle cells, and endothelialization. Proline C14 uptake and autoradiography detected cellular viability of implanted membranes. These findings suggest that the peritoneum with overlying sheath repaired vascular and intracardiac defects and substituted for pericardium. Future studies are needed before clinical use.


Canal complexity of a mandibular first molar.
The endodontic treatment of a mandibular molar with aberrant canal configuration can be diagnostically and technically challenging. This case report presents the treatment of a mandibular first molar with five root canals, of which three were located in the mesial root. A third canal was found between the mesiobuccal and mesiolingual root canals. The morphological pattern of separate apical terminations of three mesial root canals with separate orifices, as manifested in this case, is a rare one.


Duration of feeding on a sucrose-rich diet determines metabolic and morphological changes in rat adipocytes.
In this work, we studied the effect of a short-term (3 wk) and a long-term (15 wk) administration of a sucrose-rich diet (SRD) to Wistar rats on the morphological aspects and metabolic function of the epididymal adipose tissue that may contribute to the mechanism underlying the impaired glucose homeostasis and insulin resistance. The present work showed the following. 1) There was both a moderate increase of basal lipolysis and a decrease of the antilipolytic action of insulin in the adipocytes of rats fed a SRD for 3 wk. Neither size alterations nor increases in adipose tissue mass were recorded in this period. 2) There was a significant (P < 0.05) increase of epididymal weight after 15 wk on a SRD as well as a hypertrophy of adipocytes with a clear alteration in the cell size distribution. This was accompanied by a significant increase (P < 0.05) of basal and stimulated lipolysis and a marked decrease (P < 0.05) of the antilipolytic action of insulin. Moreover, these changes appear together with a worsening of both impaired glucose homeostasis and insulin resistance. Our results also indicate that the length of time on the SRD plays an important role in the evolution of the adiposity and metabolic changes observed in the fat pad. Furthermore, the latter precedes the detection of adiposity.


Transformative Possibilities: Politics and Cosmetic Surgery in the Bolivarian Revolution.
I examine the intersection of politics and aesthetics in a public hospital in Caracas, Venezuela in the first years of the twenty-first century. Given Venezuela's long-standing embrace of physical enhancement and the contradictions of the medical values of cosmetic surgery with those of Bolivarian socialism, the changing surgical practices at a well-established public site offer a significant case for considering how different actors negotiate the dialectics of care. In the face of increasing resource shortages, negotiations of aesthetic care contributed to tensions in the clinical encounter as patients creatively pushed Bolivarian policies to support their pursuits of aesthetic self-improvement.


Isolation of a replication-efficient mutant of West Nile virus from a persistently infected genetically resistant mouse cell culture.
Flavivirus-resistant mouse embryofibroblasts (C3H/RV) that were infected with West Nile virus, strain E101 (WNV), yielded fewer infectious virions than did cultures of congenic susceptible cells (C3H/HE). Analysis of intracellular viral RNA synthesis indicated that the incorporation of [3H]uridine into 40S genome RNA was markedly reduced in resistant cells, and about 100-fold less labeled 40S RNA was found in pelleted extracellular virions from resistant cultures than in those from susceptible ones. A non-temperature-sensitive mutant of WNV isolated from culture fluid of a persistently infected culture of genetically resistant mouse cells was found to produce higher yields of infectious virus than the parental WNV used to initiate the persistent infection. Analysis of intracellular actinomycin D-resistant RNA indicated that the mutant virus (WNV-RV) was more efficient at incorporating [3H]uridine into 40S RNA in resistant cells than was the parental virus. WNV-RV also synthesized 40S RNA more efficiently than parental virus in congenic susceptible cells and in BHK cells. Analysis of the incorporation of [35S]methionine into viral proteins was likewise enhanced in WNV-RV-infected cells. The WNV-RV mutant provides a tool for studying the regulation of transcription of flavivirus RNA.


New perspectives in the endoscopic treatment of brain purulent collections: targets, techniques, results in a case series, and overview of the literature.
Purulent intracranial infections are threatening conditions. Different surgical approaches have been described, respecting the rationale of evacuating the fluid component of the purulent collection. Emerging evidence supports the use of the endoscope for the treatment of cerebral abscesses and subdural empyemas; especially the peculiarities of flexible endoscopes could potentially offer a more effective and conclusive management as compared with the drainage through catheters. We describe our experience in the treatment of intracranial purulent collections with flexible endoscopy, comparing it with the most recent literature. Ten patients affected by intracranial suppuration were treated with endoscopy at our institution. The neurosurgical technique is thoroughly described. The related literature is reviewed, providing a comprehensive overview on the endoscopic treatment of intracranial suppuration so far. All the patients had a good clinical outcome, with no peri-operative complications. The postoperative scans showed significant radiological improvement, with important reduction of the pus volume. In all cases, the microbiological cultures showed positivity. In our experience, the use of the flexible scope proved feasible and effective in the treatment of intracranial purulent collections. Visual awareness of the internal capsule is not limited to a direct inspection of the fluid pus; it rather allows an active removal of the more solid (and perhaps more microbiologically significant) fibrinoid component, and also assists in final bleeding control and in assessing the extent of the evacuation. The steering capabilities of the fiberscope are particularly suitable for such purposes, allowing sampling the solid internal layer of the pyogenic membrane, and potentially shedding light on the actual clinical significance of this component of the abscess.


High photoluminescence from self-assembled Ag2Cl2(dppe)2 clusters through metallophilic interactions.
Ligand protected metal nanoclusters (NCs) are an emerging class of functional materials with intriguing photophysical and chemical properties. The size and molecular structure play an important role in endowing NCs with characteristic optical and electronic properties. Modulation of these properties through the chemical reactivity of NCs is largely unexplored. Here, we report on the synthesis of self-assembled Ag2Cl2(dppe)2 clusters through the ligand-exchange-induced transformation of [Pt2Ag23Cl7(PPh3)10] NCs [(dppe): 1,2-bis(diphenylphosphino)ethane; (PPh3): triphenylphosphine]. The single crystal x-ray structure reveals that two Ag atoms are bridged by one dppe and two Cl ligands, forming a Ag2Cl2(dppe) cluster, which is subsequently self-assembled through dppe ligands to form [Ag2Cl2(dppe)2]n. Importantly, the Ag2Cl2(dppe)2 cluster assembly exhibits high photoluminescence quantum yield: ∼18%, which is attributed to the metallophilic interactions and rigidification of the ligand shell. We hope that this work will motivate the exploitation of the chemical reactivity of NCs as a new path to attain cluster assemblies endowed with enhanced photophysical properties.


Persistent Campylobacter jejuni infection in an immunocompromised patient.
Recurrent bacteremia and enteritis due to a specific serotype of Campylobacter jejuni occurred over a 12-month period in a patient on hemodialysis with systemic lupus erythematosus who was also deficient in serum IgA and IgM. A bactericidal defect in the patient's sera for C. jejuni was shown. A role for immunoglobulins in the host response to C. jejuni is suggested, in that the IgA deficiency may have predisposed the patient to chronic gastrointestinal carriage and because the resolution of the bacteremia corresponded with the delayed appearance in the blood of IgG specific for the infecting strain.


Diuresis from stimulation of left atrial receptors: initial purification steps from plasma of the causative agent.
This paper reports the initial purification steps of a humoral agent which may mediate the diuresis resulting from stimulation of left atrial receptors in anaesthetized dogs. The agent was shown to be stabilized in plasma by acidification to pH 3.2. Acid acetone precipitation was found to be a convenient method as a first stage in the purification of the humoral agent in plasma. Heat stability studies showed that the agent was stable in acidified plasma for up to 20 min of heating in a boiling water bath. Precipitation of plasma proteins under these conditions made this another possible first stage in the purification of the agent in plasma. Some general conclusions about the possible nature of the humoral agent are discussed.


Lewis acid adducts of [PCl2N]3.
Reaction of aluminum trichloride or gallium trichloride with the extremely weak base hexachlorotriphosphazene gives adducts in which the group 13 element is bound to a phosphazene nitrogen atom. In solution, the adducts exhibit fluxional behavior. The phosphazene ring of the adducts is distorted into a slight chair conformation.


[How I explore... a cutaneous metastasis. What are you, from where are you coming from?].
Cutaneous metastases may accompany up to 3 to 10% of all malignancies. They are usually identified after diagnosing the primary neoplasm. However, their disclosure can be synchronous, or the metastasis may be the initial finding qualified as "precocious". The identification of the primary neoplasm sometimes proves to be difficult. Gender of the patient, the aspect and distribution of the metastases, as well as the histological and immunohistological examinations help establishing the diagnosis. The prognosis of the metastatic disease is often poor.


Unique genetic variation revealed by a microsatellite polymorphism survey in ten wild-derived inbred strains.
Here we report on a genome polymorphism survey using 254 microsatellite markers in ten recently wild-derived inbred strains. Allele size analysis showed that the rate of polymorphism of these wild-derived mouse strains when compared with any of the common laboratory strains is on average 79.8%. We found 632 wild-derived alleles that were not present in the common laboratory strains, representing a 61% increase over the genetic variation observed in the laboratory strains. We also found that on average 14.5% of the microsatellite alleles of any given wild-derived inbred strain were unique. Our results indicate that the recently wild-derived mouse strains represent repositories of unique naturally occurring genetic variability and may prove invaluable for the study of complex phenotypes and in the construction of new mouse models of human disease.


Sphingolipids in lung growth and repair.
Sphingolipids comprise a class of bioactive lipids that are involved in a variety of pathophysiologic processes, including cell death and survival. Ceramide and sphingosine-1-phosphate (S1P) form the center of sphingolipid metabolism and determine proapoptotic and antiapoptotic balance. Findings in animal models suggest a possible pathophysiologic role of ceramide and S1P in COPD, cystic fibrosis, and asthma. Sphingolipid research is now focusing on the role of ceramides during lung inflammation and its regulation by sphingomyelinases. Recently, sphingolipids have been shown to play a role in the pathogenesis of bronchopulmonary dysplasia (BPD). Ceramide upregulation was linked with vascular endothelial growth factor suppression and decreased surfactant protein B levels, pathways important for the development of BPD. In a murine model of BPD, intervention with an S1P analog had a favorable effect on histologic abnormalities and ceramide levels. Ceramides and S1P also regulate endothelial permeability through cortical actin cytoskeletal rearrangement, which is relevant for the pathogenesis of ARDS. On the basis of these observations, the feasibility of pharmacologic intervention in the sphingolipid pathway to influence disease development and progression is presently explored, with promising early results. The prospect of new strategies to prevent and repair lung disease by interfering with sphingolipid metabolism is exciting and could potentially reduce morbidity and mortality in patients with severe lung disorders.


Role of IGF-binding proteins in regulating IGF responses to changes in metabolism.
The IGF-binding protein family contains six members that share significant structural homology. Their principal function is to regulate the actions of IGF1 and IGF2. These proteins are present in plasma and extracellular fluids and regulate access of both IGF1 and II to the type I IGF receptor. Additionally, they have functions that are independent of their ability to bind IGFs. Each protein is regulated independently of IGF1 and IGF2, and this provides an important mechanism by which other hormones and physiologic variables can regulate IGF actions indirectly. Several members of the family are sensitive to changes in intermediary metabolism. Specifically the presence of obesity/insulin resistance can significantly alter the expression of these proteins. Similarly changes in nutrition or catabolism can alter their synthesis and degradation. Multiple hormones such as glucocorticoids, androgens, estrogen and insulin regulate IGFBP synthesis and bioavailability. In addition to their ability to regulate IGF access to receptors these proteins can bind to distinct cell surface proteins or proteins in extracellular matrix and several cellular functions are influenced by these interactions. IGFBPs can be transported intracellularly and interact with nuclear proteins to alter cellular physiology. In pathophysiologic states, there is significant dysregulation between the changes in IGFBP synthesis and bioavailability and changes in IGF1 and IGF2. These discordant changes can lead to marked alterations in IGF action. Although binding protein physiology and pathophysiology are complex, experimental results have provided an important avenue for understanding how IGF actions are regulated in a variety of physiologic and pathophysiologic conditions.


The cancer/testis antigen HORMAD1 promotes gastric cancer progression by activating the NF-κB signaling pathway and inducing epithelial-mesenchymal transition.
HORMAD1 is a cancer/testis antigen (CTAs) that regulates DNA homologous recombination, mismatch repair, and other tumor characteristics. However, its role and regulatory mechanisms in gastric cancer remain unclear. We performed transcriptomic profiling on seven gastric cancers and paired tissues; HORMAD1 was significantly upregulated in gastric cancer samples and was related to poor prognosis survival. Furthermore, cancer pathway microarray, bioinformatic analysis, western blot, and immunochemistry assay demonstrated that HORMAD1 affected the NF-κB signaling pathway. In vitro and vivo studies confirmed that HORMAD1 knockdown inhibited cell growth and invasion, whereas overexpression reversed these effects. Mechanistically, HORMAD1 regulates the epithelial-mesenchymal transition process (EMT) via the NF-κB pathway by increasing the phosphorylation levels of NF-κB (p-65) and Iκκ-β. Downstream target genes of the NF-κB signaling pathway, such as c-Myc, CyclinD1, may be involved in HORMAD1-induced tumorigenesis in gastric cancer (GC). HORMAD1 plays an important role in gastric cancer progression and could be a promising prognostic biomarker and therapeutic target.


The transcription factor GLI1 cooperates with the chromatin remodeler SMARCA2 to regulate chromatin accessibility at distal DNA regulatory elements.
The transcription factor GLI1 (GLI family zinc finger 1) plays a key role in the development and progression of multiple malignancies. To date, regulation of transcriptional activity at target gene promoters is the only molecular event known to underlie the oncogenic function of GLI1. Here, we provide evidence that GLI1 controls chromatin accessibility at distal regulatory regions by modulating the recruitment of SMARCA2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 2) to these elements. We demonstrate that SMARCA2 endogenously interacts with GLI1 and enhances its transcriptional activity. Mapping experiments indicated that the C-terminal transcriptional activation domain of GLI1 and SMARCA2's central domains, including its ATPase motif, are required for this interaction. Interestingly, similar to SMARCA2, GLI1 overexpression increased chromatin accessibility, as indicated by results of the micrococcal nuclease assay. Further, results of assays for transposase-accessible chromatin with sequencing (ATAC-seq) after GLI1 knockdown supported these findings, revealing that GLI1 regulates chromatin accessibility at several regions distal to gene promoters. Integrated RNA-seq and ATAC-seq data analyses identified a subset of differentially expressed genes located in cis to these regulated chromatin sites. Finally, using the GLI1-regulated gene HHIP (Hedgehog-interacting protein) as a model, we demonstrate that GLI1 and SMARCA2 co-occupy a distal chromatin peak and that SMARCA2 recruitment to this HHIP putative enhancer requires intact GLI1. These findings provide insights into how GLI1 controls gene expression in cancer cells and may inform approaches targeting this oncogenic transcription factor to manage malignancies.


Prosthetic dentistry and the unilateral cleft lip and palate patient. The last 30 years. A review of the prosthodontic literature in respect of treatment options.
All cleft lip and palate patients are unique and present with their own diagnostic and prosthodontic problems. Many patients have benefited, recently, from alveolar bone grafting and orthodontic realignment and require little or no prosthodontic treatment. Some treatment, however, has been planned with a prosthesis as the final restoration, as a sizeable number of such patients have not undergone the alveolar graft procedure, (or this has been unsuccessful), or they were deemed to be unsuitable because of the extent of their defect. The patients who have not received grafting and orthodontic realignment are therefore the patients who present the greatest prosthodontic challenge. This paper presents an overview of the work that has been carried out over the last thirty years in relation to the prosthodontic rehabilitation of the cleft lip and palate patient. It is clear that multidisciplinary treatment planning by surgeons, orthodontists and restorative dentists is required for the long-term benefit of this small but challenging group of patients.


Role of autophagy in the pathogenesis of Pompe disease.
In Pompe disease, a deficiency of lysosomal acid alpha-glucosidase, glycogen accumulates in multiple tissues, but clinical manifestations are mainly due to skeletal and cardiac muscle involvement. A major advance has been the development of enzyme replacement therapy (ERT), which recently became available for Pompe patients. Based on clinical and pre-clinical studies, the effective clearance of skeletal muscle glycogen appears to be more difficult than anticipated. Skeletal muscle destruction and resistance to therapy remain unsolved problems. We have found that the cellular pathology in Pompe disease spreads to affect both the endocytic and autophagic pathways, leading to excessive autophagic buildup in therapy resistant muscle fibers of knockout mice. Furthermore, the autophagic buildup had a profound effect on the trafficking and processing of the therapeutic enzyme along the endocytic pathway. These findings may explain why ERT often falls short of reversing the disease process, and point to new avenues for the development of pharmacological intervention.


Time-Course Transcriptional and Chromatin Accessibility Profiling Reveals Genes Associated With Asymmetrical Gonadal Development in Chicken Embryos.
In birds, male gonads form on both sides whereas most females develop asymmetric gonads. Multiple early lines of evidence suggested that the right gonad fails to develop into a functional ovary, mainly due to differential expression of PITX2 in the gonadal epithelium. Despite some advances in recent years, the molecular mechanisms underlying asymmetric gonadal development remain unclear. Here, using bulk analysis of whole gonads, we established a relatively detailed profile of four representative stages of chicken gonadal development at the transcriptional and chromatin levels. We revealed that many candidate genes were significantly enriched in morphogenesis, meiosis and subcellular structure formation, which may be responsible for asymmetric gonadal development. Further chromatin accessibility analysis suggested that the transcriptional activities of the candidate genes might be regulated by nearby open chromatin regions, which may act as transcription factor (TF) binding sites and potential cis-regulatory elements. We found that LHX9 was a promising TF that bound to the left-biased peaks of many cell cycle-related genes. In summary, this study provides distinctive insights into the potential molecular basis underlying the asymmetric development of chicken gonads.


Minipuberty of human infancy - A window of opportunity to evaluate hypogonadism and differences of sex development?
Activation of the hypothalamic-pituitary-gonadal (HPG) axis happens in 3 phases during life. The first phase is during fetal life and is only separated from the second phase, called minipuberty, by the high concentration of placental hormones at birth. The third period of activation of the HPG axis is puberty and is well-described. Minipuberty consists of the neonatal activation of the HPG axis, mainly in the first 1-6 months, where the resulting high levels of gonadotropins and sex steroids induce the maturation of sexual organs in both sexes. With gonadal activation, testosterone levels rise in boys with peak levels after 1-3 months, which results in penile and testicular growth. In girls, gonadal activation leads to follicular maturation and a fluctuating increase in estrogen levels, with more controversy regarding the actual influence on the target tissue. The regulation of the HPG axis is complex, involving many biological and environmental factors. Only a few of these have known effects. Many details of this complex interaction of factors remain to be elucidated in order to understand the mechanisms underlying the first postnatal activation of the HPG axis as well as mechanisms shutting down the HPG axis, resulting in the hormonal quiescence observed between minipuberty and puberty. Minipuberty allows for the maturation of sexual organs and forms a platform for future fertility, but the long-term significance is still not absolutely clear. However, it provides a window of opportunity in the early detection of differences of sexual development, offering the possibility of initiating early medical treatment in some cases.


Prediction of maximal oxygen consumption. Comparison of the Bruce and Balke treadmill protocols.
This study investigated the hypothesis that an individual's maximal oxygen consumption can be realistically predicted by the maximal time achieved in the Balke or Bruce treadmill protocols. The range of maximal oxygen consumption that can be expected for healthy individuals of any given age and activity was also evaluated. The maximal oxygen consumptions achieved by 79 men exercised using the Balke protocol and 77 men using the Bruce protocol were linearly regressed by a least-squares fit technique on maximal treadmill time and on age with activity status classified. Statistical analysis demonstrated an inadequate relationship for predicting maximal oxygen consumption from maximal treadmill time using either protocol. Also, maximal oxygen consumption correlated poorly with age even though activity status was considered. These findings make the nomogram for predicting an individual's functional aerobic impairment a clinical technique of questionable value. Since maximal oxygen consumption can only be grossly estimated from the maximal time performed in the Bruce or Balke protocols, there is no necessity to use them in preference to other clinically acceptable protocols.


MicroRNA-335-5p Plays Dual Roles in Periapical Lesions by Complex Regulation Pathways.
MicroRNA-335-5p has been reported to regulate osteogenic and chondrogenic differentiations of mesenchymal stem cells. The aim of this study was to explore the function and regulation mechanism of miR-335-5p in apical periodontitis (AP). Total RNAs were extracted from human periodontal ligament fibroblasts (HPDLFs), 10 AP tissues, and 6 healthy periodontal ligament tissues using lysis buffer. Gene expression was detected using real-time polymerase chain reaction. The Dual Luciferase Assay (Promega, Madison, WI) was used to test miR-335-5p directly targeted urokinase-type plasminogen activator receptor (uPAR) and the receptor activator of nuclear factor kappa-B ligand (RANKL). Western Blot was used to detect protein expressions of RANKL, uPAR, and the fragile X-related 1 gene (FXR1). The enzyme-linked immunosorbent assay was used to detect the secretions of interleukin 6, tumor necrosis factor alpha, and RANKL. Data were analyzed using the Student t test. miR-335-5p acted as a positive mediator in HPDLF inflammation (P < .05). Two targets of miR-335-5p, uPAR and RANKL, were identified. Interestingly, uPAR was repressed by miR-335-5p at the basal level, but it can be relieved from miR-335-5p-mediated repression, which is called derepression, when HPDLFs were subjected to lipopolysaccharide stimulation. miR-335-5p promoted RANKL in HPDLFs regardless of whether or not it was under inflammatory conditions (P < .05). We proved FXR1 was responsible for the derepression of uPAR from miR-335-5p (P < .01). Both FXR1 and uPAR were positive mediators in HPDLF inflammation (P < .05). miR-335-5p, uPAR, RANKL, and FXR1 had the same expression profiles in HPDLF inflammation and AP tissues (P < .05). Our data showed that miR-335-5p may play dual roles in AP, and it might be considered as a target for therapeutic potency in clinical applications.


Hypersensitivity pneumonitis in children.
Hypersensitivity pneumonitis in children is an underrecognized form of immune-mediated interstitial lung disease that results from repeated exposure to the inhalation of organic antigens. Because overt disease develops in only a small percentage of exposed individuals, complex interactions between the nature of the antigen, the intensity and duration of the exposure, and the host response in susceptible individuals are most likely involved. In most reported pediatric cases, hypersensitivity pneumonitis results from exposure to avian antigens, but it has also been seen with exposure to molds and methotrexate. The diagnosis is established by documented exposure, compatible clinical presentation, and consistent radiologic features; it is supported by positive precipitating antibodies, lymphocytosis in bronchoalveolar lavage fluid, and characteristic histologic changes on lung biopsy. Treatment consists of antigen avoidance in all cases, and corticosteroids in severe cases. The prognosis is excellent when prompt recognition and treatment are initiated.


Decision-analytic model and cost-effectiveness evaluation of postmastectomy radiation therapy in high-risk premenopausal breast cancer patients.
To present a decision model that describes the clinical and economic outcomes of node-positive breast cancer with and without postmastectomy radiation therapy (PMRT). A Markov process was constructed to project the natural history of breast cancer following mastectomy in premenopausal node-positive women. Biannual hazards of local and distant recurrence without PMRT were derived from a large meta-analysis of adjuvant systemic therapy trials for breast cancer. The addition of PMRT reduced the risk of disease relapse by an odds ratio of 0.69. Costs of PMRT ($11,600) and recurrent breast cancer ($4,250 to 16,200/year) were estimated from available literature. The model projected number of recurrences, relapse-free and overall survival, and costs to 15 years, using a discount rate of 3%. Cost-effectiveness ratios were calculated per incremental year of life and quality-adjusted year of life gained. One- and two-way sensitivity analyses were performed to determine the sensitivity of results to clinical and economic assumptions. The model projected 15-year relapse-free survival of 52% and 43% with and without PMRT, respectively. Overall survival was increased from 48% to 55% with PMRT, resulting in an incremental 0.29 years of life gained per subject. PMRT increased 15-year costs from $40,800 to $48,100. Cost per year of life gained was $24,900, or $22,600 when survival was adjusted for quality of life. Results of the model were relatively sensitive to radiation therapy cost and breast cancer relapse risk. This analysis suggests that PMRT offers substantial clinical benefits achieved in a cost-effective manner, with an average cost per year of life gained of $24,900. Results of the model were robust under a wide range of clinical and economic parameters.


CONcreTEXT norms: Concreteness ratings for Italian and English words in context.
Concreteness is a fundamental dimension of word semantic representation that has attracted more and more interest to become one of the most studied variables in the psycholinguistic and cognitive neuroscience literature in the last decade. Concreteness effects have been found at both the brain and the behavioral levels, but they may vary depending on the constraints of the context and task demands. In this study, we collected concreteness norms for English and Italian words presented in different context sentences to allow better control and manipulation of concreteness in future psycholinguistic research. First, we observed high split-half correlations and Cronbach's alpha coefficients, suggesting that our ratings were highly reliable and can be used in Italian- and English-speaking populations. Second, our data indicate that the concreteness ratings are related to the lexical density and accessibility of the sentence in both English and Italian. We also found that the concreteness of words in isolation was highly correlated with that of words in context. Finally, we analyzed differences between nouns and verbs in concreteness ratings without significant effects. Our new concreteness norms of words in context are a valuable source of information for future research in both the English and Italian language. The complete database is available on the Open Science Framework (doi: 10.17605/OSF.IO/U3PC4).


Structural characterization of three RNA hexanucleotide loops from the internal ribosome entry site of polioviruses.
Structural characteristics of three RNA hairpins from the internal ribosome entry site of poliovirus mRNAs have been determined in solution by NMR. Complete proton, phosphorus and carbon resonance assignments were made for the three 16 nt hairpins. The loop sequences, 5'-AAUCCA , AAACCA and GAACCA, have been shown to be essential for viral mRNA translation. NOESY spectra for the three oligomers were very similar indicating a common three dimensional structure. Stems were A-type duplexes with C3'-endo sugar pucker. In the loops, sequential base stacking interactions were detected for all bases except between U8/A8 and C9, indicating a turn in the phosphodiester backbone at this point. Only one nucleotide, U8/A8, had a sugar pucker which deviated appreciably from C3'-endo. The final base in the loop, A11, exhibited an unusual gauche (-) gamma angle. An ensemble of 10 structures calculated for one hairpin using restrained molecular dynamics shows that the first three bases of the loop are turned so as to be exposed to the exterior of the molecule, while the remaining three bases are in an orientation approximating a continuation of the stem helix. Structure calculations and NMR relaxation measurements indicate that the loop apex is subject to considerable local dynamics.


MRI in the evaluation of obstructive reproductive tract anomalies in paediatric patients.
To outline the anatomical variations of obstructive reproductive tract anomalies (ORTA) using magnetic resonance imaging (MRI) and its role in preoperative evaluation. MRI and treatment of 21 paediatric patients with ORTA were reviewed and analysed. MRI findings were correlated with ultrasound and surgical findings. Patients presented in two distinct ways: primary amenorrhoea with cyclic pelvic pain, or progressive dysmenorrhoea. MRI showed haematocolpos, haematocervix, haematometra, and/or haematosalpinx; it also provided detailed information regarding uterine morphology, ipsilateral kidney absence, and endometriosis. Diagnosis at MRI of the obstruction sites correlated completely (100%) with the surgical diagnosis. Obstruction occurred at different levels of the genital tract, and surgical treatment was given based on the obstruction sites. One patient underwent excision of the hymen tissue for imperforate hymen. Four cases of lower vaginal atresia were treated with vaginoplasty. Three patients with typical Herlyn-Werner-Wunderlich (HWW) syndrome underwent resection of the vaginal septum, and one patient with concurrent post-partum placenta increta was treated accordingly; one patient with atypical HWW syndrome had the left uterus resected. There were 11 cases of cervical agenesis or cervicovaginal dysgenesis, eight of which were complicated with uterine anomalies, and in all cases the uterus was removed. Among the 10 obstructive cervical anomalies, there were three cases of cervical agenesis and seven cases of cervical dysgenesis, including five obliterated cervical os (cervical obstruction), one cervical fibrous cord, and one cervical fragmentation. ORTA can occur from the hymen to the lower segment of the uterus and requires surgical intervention. The preoperative evaluation is vital to guide proper surgery. MRI, with its imaging advantages, is the imaging technique of choice to assess the obstructed sites and complicated anomalies of ORTA.


In vivo response to a low-modulus PMMA bone cement in an ovine model.
Poly(methyl methacrylate) (PMMA) is the most commonly used material for the treatment of osteoporosis-induced vertebral compression fractures. However, its high stiffness may introduce an increased risk of adjacent vertebral fractures post-surgery. One alternative in overcoming this concern is the use of additives. This presents its own challenge in maintaining an adequate biocompatibility when modifying the base cement. The aim of this study was to evaluate the in vivo biocompatibility of linoleic acid (LA)-modified acrylic bone cement using a large animal model for the first time, in order to further advance towards clinical use. A worst-case approach was used, choosing a slow-setting base cement. The in vitro monomer release from the cements was also assessed. Additional material characterization, including mechanical tests, are summarized in Appendix A. Unmodified and LA-modified cements were injected into a total of 56 bone defects created in the femur and humerus of sheep. Histopathologic and histomorphometric analysis indicated that LA-modified cement showed a harmless tissue response similar to that of the unmodified cement. Adjacent bone remodeling was observed microscopically 4 weeks after implantation, suggesting a normal healing process of the bone tissues surrounding the implant. LA-modified cement exhibited lower mechanical properties, with a reduction in the elastic modulus of up to 65%. The handling properties were slightly modified without negatively affecting the injectability of the base cement. LA-modified bone cement showed good biocompatibility as well as bone compliant mechanical properties and may therefore be a promising material for the treatment of osteoporotic vertebral fractures. The benefits of using linoleic acid to reduce the stiffness of poly(methyl methacrylate) bone cement has been demonstrated previously, with the in vitro and in vivo response of the modified cement in small animals reported as comparable to the base cement. However, biocompatibility evaluation of modified cement in large animal models for future clinical use has yet to be performed. In this study, modified and unmodified cements were injected into bone defects created in sheep. We showed that the inflammatory response of the modified cement was similar to the base cement, allowing remodelling of the bone surrounding the implant. This demonstrates the potential of low-modulus PMMA cement in the field of bone augmentation.


Genetics of vascular malformation and therapeutic implications.
Vascular malformations (VaMs) are a consequence of disrupted morphogenesis that may involve arterial, capillary, venous, or lymphatic endothelium alone or in a combination. VaMs can have serious health impacts, leading to life-threatening conditions sometimes. Genetic mutations affecting proliferation, migration, adhesion, differentiation, and survival of endothelial cells, as well as integrity of extracellular matrix are believed to be the pathogenesis of these disorders. Here, we present an updated review of genetic mutations and potential therapeutic targets for VaMs. Increased number of genetic mutations have been discovered in vascular anomalies via targeted deep sequencing. When a genetic defect is identified, it often presents in only a small percentage of cells within the malformation. In addition, mutations within the same gene may result in different clinical phenotypes. Management of VaMs can be challenging depending on the severity and functional impairment associated. There are no standard treatment algorithms available to date for VaMs, therefore the disorder has significant unmet clinical needs. Currently, the focus of therapeutic development is to target constitutively activated intracellular signaling pathways resulted from genetic mutations. Knowledge about the genetic mutations and altered signaling pathways related to VaMs have improved our understanding about the pathogenesis of vascular anomalies and provided insights to the development of new targeted therapies.


Are the mites of the genus Tarsonemus really parasites of man?
Mites of the genus Tarsonemus were found in several preparations of human skin samples. It was revealed that the mites got into the preparations from insufficiently cleaned coverslips. Similar previous reports are discussed on this occasion.


Assessment and management of neutralizing antibodies in patients with multiple sclerosis.
The development of neutralizing antibodies (NAbs) to interferon beta (IFNbeta) products during treatment of MS poses a challenge for clinicians. Given the impact of NAbs on the clinical efficacy of IFNbetas, the immunogenicity of different IFNbeta products should be one of the factors that neurologists consider in the treatment of patients with MS. However, no clear guidelines are available for the practicing neurologist concerning which patients should be tested for NAbs and how to clinically manage patients who develop NAbs. This article summarizes the content of this supplement, discusses issues related to measuring NAbs in clinical practice, and gives practical alternatives for managing MS in patients who develop NAbs during IFNbeta therapy.


Prevalence and determinants of genital infection with papillomavirus, in female and male university students in Busan, South Korea.
Little is known about the prevalence of human papillomavirus (HPV) infection in young adults in Asia. We invited female and male students in Busan, South Korea, to participate in a survey that included, for females, self-collection of vaginal cells and, for males, physician-performed collection of exfoliated genital cells. The prevalences of 25 HPV types were evaluated, by a polymerase chain reaction-based assay, in 672 female students (median age, 19 years) and in 381 male students (median age, 22 years). HPV DNA was detected more frequently in female students (15.2%) than in male students (8.7%); in both sexes, high-risk HPV types were predominant. Among sexually active students, HPV prevalence was 38.8% in females and 10.6% in males. In female students, currently smoking cigarettes and having multiple lifetime sex partners were the strongest risk factors for HPV infection; in male students, associations between HPV prevalence and sexual habits were similar to those in female students but never attained statistical significance. Young women in South Korea start having penetrative sexual intercourse relatively late (median age, 18 years), but, once they begin, HPV prevalence quickly rises to levels comparable with those found in university students in the United States and in northern Europe. The high rate of participation in our study suggests that trials of new vaccines against HPV may be feasible among university students in South Korea.


Impact of chronic kidney disease on patients with unprotected left main coronary artery disease treated with coronary artery bypass grafting or drug-eluting stents.
This study aimed to evaluate clinical outcomes after percutaneous coronary intervention with drug-eluting stents (DESs) or coronary artery bypass grafting (CABG) in unprotected left main coronary artery (ULMCA) disease patients with and without chronic kidney disease. The optimal coronary revascularization strategy for ULMCA disease patients with chronic kidney disease remains uncertain. The sample included 818 ULMCA disease patients who received DESs (n=358) or underwent CABG (n=460). We retrospectively compared clinical parameters and outcomes between different endogenous creatinine clearance rates [estimated glomerular filtration rates (eGFRs), ml/min×1.73 m]. The incidences of major adverse cardiocerebral events, all-cause death, cardiac death, and stroke were not significantly different between the DES and the CABG groups. The DES group had significantly higher risks of myocardial infarction (MI) and target vessel revascularization than the CABG group. Compared with the CABG group, the hazard ratios for target vessel revascularization were 3.965 [95% confidence interval (CI): 1.743-9.023, P=0.001] in the eGFR of at least 60 group and 46.463 (95% CI: 4.558-473.639, P=0.001) in the eGFR 45-59 group. The rate of MI was higher in patients treated with DESs in the eGFR of less than 45 group (hazard ratio: 14.098, 95% CI: 1.123-176.988, P=0.040). For patients with ULMCA disease at risk of higher repeat revascularization with normal renal function or eGFR of at least 45 ml/min×1.73 m, DESs are a safe alternative to CABG. However, for patients with severely reduced kidney function (eGFR<45 ml/min×1.73 m), DESs should be selected after careful evaluation of MI risk.


[Mechanism of Yishen Tongluo Recipe reducing benzo(a)pyrene-induced sperm DNA damage: Exploration based on the BER pathway].
To explore the repairing effect of Yishen Tongluo Recipe (YTR) on sperm DNA damage and its action mechanism in male rats exposed to benzo(a)pyrene (BaP). Thirty-three adult male Wistar rats were equally divided into a normal control, a model control and a YTR intervention group. Sperm DNA damage was induced in the latter two groups of rats by exposing them to BaP at 20 mg/kg/d for 60 days, and the animals in the YTR group received a 30-day gavage administration of YTR suspension at 0.1 ml/10 g/d from the 31 day. Then the testis tissue of the rats was collected for examination of the sperm DNA fragmentation index (DFI) by fluorescence flow cytometry and determination of the expressions of APE1, FEN1, XRCC1 (and phosphorylated) proteins and mRNA in the BER pathway by Western blot and RT-PCR. After intervention, the sperm DFI was significantly decreased (P < 0.05) and the expressions of APE1, FEN1, XRCC1 (and phosphorylated) proteins and mRNA remarkably increased in the YTR group compared with the model controls (P < 0.05). Yishen Tongluo Recipe can reduce benzo(a)pyrene-induced sperm DFI in male rats by up-regulating the expression levels of APE1, FEN1, XRCC1 (and phosphorylated) proteins and improving the ability of sperm DNA base excision repair.


Mixed-metal sandwich complexes [M(II)2(H2O)2Fe(III)2(P2W15O56)2]14- (M(II) = Co, Mn): synthesis and stability. The molecular structure of [M(II)2(H2O)2Fe(III)2(P2W15O56)2]14-.
Two new mixed-metal sandwich complexes [M(II)2(H2O)2Fe(III)2(P2W15O56)2]14- (abbreviated [M2Fe2P4W30], M(II) = Co(II), Mn(II)) were obtained at pH 3 by addition of M2+ to [Na2(H2O)2Fe(III)2(P2W15O56)2]16- (abbreviated [Na2Fe2P4W30]) without substitution in the alpha-[P2W15O56]12- (abbreviated [P2W15]) units. Their X-ray structures are reported. At lower pH, back conversion to [Na2Fe2P4W30] was followed by 31P NMR, electrochemistry and UV-visible spectroscopy. The preparation and the characterization in solution of the lacunary intermediate [NaCo(II)(H2O)2Fe(III)2(P2W15O56)2]15- (abbreviated [NaCoFe2P4W30]) is also described.


Novel anti-inflammatory and analgesic agents: synthesis, molecular docking and in vivo studies.
Twelve new derivatives of benzothiazole bearing benzenesulphonamide and carboxamide were synthesised and investigated for their in vivo anti-inflammatory, analgesic and ulcerogenic activities. Molecular docking showed an excellent binding interaction of the synthesised compounds with the receptors, with 17c showing the highest binding energy (-12.50 kcal/mol). Compounds 17c and 17i inhibited carrageenan-induced rat paw oedema at 72, 76, and 80% and 64, 73, and 78% at 1 h, 2 h, and 3 h, respectively. In the analgesic activity experiment, compounds 17c, 17 g, and 17i had ED50 (µM/kg) of 96, 127, and 84 after 0.5 h; 102, 134, and 72 after 1 h and 89, 156, and 69 µM/kg after 2 h, respectively, which were comparable with 156, 72, and 70 µM/kg for celecoxib. The ulcerogenic index of the most active derivatives 17c and 17i were 0.82 and 0.89, respectively, comparable to 0.92 for celecoxib. The physicochemical studies of the new derivatives showed that they will not have oral bioavailability problems.


Selectively Biodegradable Polyesters: Nature-Inspired Construction Materials for Future Biomedical Applications.
In the last half-century, the development of biodegradable polyesters for biomedical applications has advanced significantly. Biodegradable polyester materials containing external stimuli-sensitive linkages are favored in the development of therapeutic devices for pharmacological applications such as delivery vehicles for controlled/sustained drug release. These selectively biodegradable polyesters degrade after particular external stimulus (e.g., pH or redox potential change or the presence of certain enzymes). This review outlines the current development of biodegradable synthetic polyesters materials able to undergo hydrolytic or enzymatic degradation for various biomedical applications, including tissue engineering, temporary implants, wound healing and drug delivery.


Feasibility of therapeutic plasma exchange-based combination therapy in the treatment of acquired hemophilia A: A retrospective 6 case series.
Poor availability and a lack of affordability of bypassing agents (recombinant activated factor VII and activated prothrombin complex concentrate) in west China prompted us to investigate an alternative cost-effective combination therapy. We aimed to explore the feasibility of therapeutic plasma exchange (TPE)-based combination therapy in the treatment of acquired hemophilia A (AHA).We retrospectively investigated the clinical features of AHA in 6 patients who were treated with a combination of TPE, corticosteroids, and rituximab in our department for 9 years between January, 2011 and December, 2019.We examined 1 male and 5 female patients. The median age at diagnosis of AHA was 51 years (18-66 years). In all patients, FVIII activity levels were low (median: 1.5%; 1-3%), FVIII inhibitor titers were high (median: 24.5 BU/mL; 13.2-48.6 BU/mL), and activated partial thromboplastin time was markedly prolonged (median: 99.4 s; 60.9-110.1 s). They underwent 2 to 8 cycles of plasma exchange and were given varying combinations of dexamethasone, methylprednisolone, prednisone, and rituximab. After TPE bleeding gradually stopped, and activated partial thromboplastin time decreased. After 3 months of treatment, FVIII inhibitors completely disappeared.TPE when combined with corticosteroids and rituximab, as adjunctive immunosuppressive agents, may be an effective and reliable treatment for AHA. When there is no alternative, intensive first-line treatment including TPE may be lifesaving.


Surveillance of maritime deaths on board Danish merchant ships, 1986-2009.
A previous study demonstrated a high death rate among seafarers signed on Danish ships during the years 1986-1993. This study aimed to examine and analyse the subsequent development until 2009. A total of 356 fatalities were identified from data supplied from the Danish Maritime Authority, an insurance company, and other sources. Maritime deaths among seafarers signed on Danish ships comprise deaths from 1) accidents, suicides and homicides; and 2) disease on board. Deaths due to 2) occurring ashore within 30 days after signing off were included. The overall and mode-specific death rates were calculated for three eight-year observation periods. The rates for work-related fatal accidents were compared with the rates for land-based trades. All categories of maritime deaths were significantly reduced from 1986 to 2009 - in particular during the last eight-year period (Accidents 1986-1993: 66.6 per 100,000 person years, 2002-2009: 27.0 per 100,000 person years, diseases 49.5-26.1, suicides 14.4-7.8). In spite of the remarkable improvement since 1986, seafarers remain in 2002-2009 more than six times more likely to die from occupational accidents (including shipwrecks) than do workers ashore. The favourable trend of maritime deaths in the Danish merchant fleet may be due to 1) preventive measures - e.g. interventions relating to vessel safety, work environment, and improved medical care on board - and to 2) technological and organizational changes - e.g. newer and larger vessels in the Danish merchant fleet, changed composition of the workforce, and reduced shore leaves. The persisting excess risk warrants further preventive actions.