Novel radiation dose reduction fluoroscopic technology facilitates chronic total occlusion percutaneous coronary interventions.
Radiation exposure and prolonged procedure time continue to limit the complexity of CTO-PCI procedures attempted. This study aimed to assess the impact of radiation dose-limiting equipment on radiation dosage and fluoroscopic time in chronic total occlusion (CTO) percutaneous coronary interventions (PCI). Retrospective clinical and dosimetric data from diagnostic catheterisations (DXC) and CTO-PCI procedures performed on one of three variants of interventional fluoroscopic equipment were collected. Fluoroscopic time, air kerma, kerma area product and contrast utilisation were stratified by procedure type and compared among equipment types. To standardise comparisons among equipment configurations, an efficiency index (EI) was calculated. In total, 2,947 DXC and 276 CTO-PCI procedures were studied. For DXC, radiation dose (AK) decreased by 45% (despite modest increases in fluoroscopic time [FT]) between the reference (REF) and moderately dose-optimised (ECO) machines. A further 20% decrease in AK was observed on the highly dose-optimised machine (CLA). For CTO-PCI, AK declined by almost half (48%), despite a 76% increase in FT and higher procedural success rates (69.8% versus 83.0%) between REF and CLA. • Conclusions: Novel dose-optimised fluoroscopic equipment allows longer FT with a decrease in radiation dose to both patient and operator. This should allow operators to undertake increasingly longer and more complex procedures and reduce operators' lifetime irradiation.


Coverage with evidence development: ethical issues and policy implications.
Coverage with evidence development (CED) is an evolving method of providing provisional access to novel medical interventions while generating the evidence needed to determine whether unconditional coverage is warranted. In this article we review the policy rationale for CED and present a normative analysis that addresses ethical concerns and policy implications.


Lack of efficacy of carbamazepine in the treatment of panic disorder.
The authors conducted a controlled study of carbamazepine in the treatment of 14 patients with panic disorder. Although there was a statistically significant reduction in symptoms of anxiety on several measures, only one of the patients was judged to have a marked and sustained clinical improvement while taking carbamazepine. Forty percent of the patients had a decrease in frequency of panic attacks during carbamazepine treatment, 50% had an increase, and 10% showed no change. The presence of either EEG abnormalities or prominent psychosensory symptoms did not predict response to carbamazepine. These findings are discussed within the context of an epileptiform model for panic disorder.


Fludarabine induces differential expression of proteins in human leukemia and lymphoma cells.
The purine analog fludarabine (FdAMP) is widely used for chemotherapy of B-lymphoid malignancies, and multiple mechanisms of action leading to apoptosis have been proposed. We examined changes at the protein level induced in the Raji cell line (Burkitt's lymphoma) by fludarabine nucleoside (FdA). Raji cells are sensitive to FdA. Raji cells treated with FdA (3 micro M, 24 hours), accumulate multiple phosphorylated forms of p53 in the nucleus that in turn degrade to phosphorylated forms of p40. Using CD antibody microarrays to determine surface expression profiles for Raji cells treated with FdA, we found up-regulation of the following CD antigens: CD20, CD54, CD80, CD86, and CD95. FdA thus induces changes in the genetic program of the cells that might be exploited to obtain synergy with therapeutic antibodies.


Prospective evaluation of implants connected to teeth.
This prospective clinical trial examined the effect on teeth and implants when rigidly or non-rigidly connected in a cross-arch model. Thirty patients received 2 implants, 1 on each side of the mandible, and were restored with 3-unit fixed partial dentures connected either rigidly or non-rigidly to an abutment tooth. Patients were followed for at least 5 years post-restoration. Repeated-measures analysis revealed no significant difference in crestal bone loss at implants (rigid versus non-rigid methods). An overall significant difference (P < .001) was found comparing methods for teeth. Paired t tests revealed no significant differences in crestal bone levels for implants or teeth at the 5-year recall. Kaplan-Meier methods and the Cox proportional hazards model showed no differences between attachment methods with regard to success based on survival and bone loss criteria. During the 5-year recall period, 1 implant (rigid side) was removed. Four implants developed bone loss greater than 2 mm during the course of this trial. One tooth on the rigid side and 2 teeth on the non-rigid side had greater than 2 mm of crestal bone loss and were removed secondary to fractures. In all, 5 abutment teeth were removed, all of which had been treated with root canal therapy and fractured at the interface of the post within the tooth. There was no clear relationship of tooth fracture to attachment. Repeated-measures analysis of mobility values revealed no significant changes over the time course of this study, and paired t tests revealed no statistically significant differences between implants for mobility. Repeated-measures analysis and paired t tests for probing depth revealed no significant changes over the time course of this study. There were no significant differences in soft tissue indices for either attachment method. The percentage of patients who had measurable intrusion was 66% for the non-rigid group, and 44% for the rigid group; 25% of the non-rigid teeth had greater than 0.5 mm intrusion, compared with 12.5% for the rigid group. For the 2 time periods evaluated, there was no significant increase in intrusion over time. The non-rigid-side implant required more nonscheduled visits to treat problems than the rigid implant and the teeth. Most patients were treated successfully with rigid or non-rigid attachment of implants to teeth. The high incidence of intrusion and non-scheduled patient visits suggest that alternative treatments without connecting implants to teeth may be indicated.


Revisiting the hydration structure of aqueous Na.
A combination of theory, X-ray diffraction (XRD) and extended x-ray absorption fine structure (EXAFS) are used to probe the hydration structure of aqueous Na+. The high spatial resolution of the XRD measurements corresponds to Qmax = 24 Å-1 while the first-reported Na K-edge EXAFS measurements have a spatial resolution corresponding to 2k = Qmax = 16 Å-1. Both provide an accurate measure of the shape and position of the first peak in the Na-O pair distribution function, gNaO(r). The measured Na-O distances of 2.384 ± 0.003 Å (XRD) and 2.37 ± 0.024 Å (EXAFS) are in excellent agreement. These measurements show a much shorter Na-O distance than generally reported in the experimental literature (Na-Oavg ∼ 2.44 Å) although the current measurements are in agreement with recent neutron diffraction measurements. The measured Na-O coordination number from XRD is 5.5 ± 0.3. The measured structure is compared with both classical and first-principles density functional theory (DFT) simulations. Both of the DFT-based methods, revPBE and BLYP, predict a Na-O distance that is too long by about 0.05 Å with respect to the experimental data (EXAFS and XRD). The inclusion of dispersion interactions (-D3 and -D2) significantly worsens the agreement with experiment by further increasing the Na-O distance by 0.07 Å. In contrast, the use of a classical Na-O Lennard-Jones potential with SPC/E water accurately predicts the Na-O distance as 2.39 Å although the Na-O peak is over-structured with respect to experiment.


The group-specific murine coronavirus genes are not essential, but their deletion, by reverse genetics, is attenuating in the natural host.
In addition to a characteristic set of essential genes coronaviruses contain several so-called group-specific genes. These genes differ distinctly among the three coronavirus groups and are specific for each group. While the essential genes encode replication and structural functions, hardly anything is known about the products and functions of the group-specific genes. As a first step to elucidate their significance, we deleted the group-specific genes from the group 2 mouse hepatitis virus (MHV) genome via a novel targeted recombination system based on host switching (L. Kuo, G. J.Godeke, M. J. Raamsman, P. S. Masters, and P. J. M. Rottier, 2000, J. Virol. 74, 1393-1406). Thus, we obtained recombinant viruses from which the two clusters of group-specific genes were deleted either separately or in combination in a controlled genetic background. As all recombinant deletion mutant viruses appeared to be viable, we conclude that the MHV group-specific genes are nonessential, accessory genes. Importantly, all deletion mutant viruses were attenuated when inoculated into their natural host, the mouse. Therefore, deletion of the coronavirus group-specific genes seems to provide an attractive approach to generate attenuated live coronavirus vaccines.


Role of Scl39a13/ZIP13 in cardiovascular homeostasis.
Zinc plays a critical role in many physiological processes, and disruption of zinc homeostasis induces various disorders, such as growth retardation, osteopenia, immune deficiency, and inflammation. However, how the imbalance in zinc homeostasis leads to heart disease is not yet fully understood. Cardiovascular diseases are a major cause of death worldwide, and the development of novel therapeutic targets to treat it is urgently needed. We report that a zinc transporter, ZIP13, regulates cardiovascular homeostasis. We found that the expression level of Zip13 mRNA was diminished in both primary neonatal cardiomyocytes and mouse heart tissues treated with the cardiotoxic agent doxycycline. Primary neonatal cardiomyocytes from Zip13 gene-knockout (KO) mice exhibited abnormal irregular arrhythmic beating. RNA-seq analysis identified 606 differentially expressed genes in Zip13-KO mouse-derived primary neonatal cardiomyocytes and Gene ontology (GO) analysis revealed that both inflammation- and cell adhesion-related genes were significantly enriched. In addition, telemetry echocardiography analysis suggested that arrhythmias were likely to occur in Zip13-KO mice, in which elevated levels of the cardiac fibrosis marker Col1a1, vascular inflammation-related gene eNOS, and Golgi-related molecule GM130 were observed. These results indicate the physiological importance of ZIP13-it maintains cardiovascular homeostasis by resolving inflammation and stress response. Our findings suggest that optimizing ZIP13 expression and/or function may improve cardiovascular disease management.


[Molecular aspects of pituitary tumorigenesis].
Pituitary tumors, almost invariably adenomas, are of frequent occurrence, accounting for 10% to 15% of all the intracranial neoplasm. They are classified as microadenomas (< 10 mm) or macroadenomas (> 10 mm) and as secreting or clinically non-secreting (or not functioning) adenomas. These tumors are autonomously capable to release pituitary hormones such as the growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The occurrence of metastases, characterizing a pituitary carcinoma, is exceedingly rare. However tumors with aggressive behavior, leading to local invasion, are relatively common. Although the pathogenesis of pituitary tumors is fully characterized, many molecular mechanisms of pituitary tumorigenesis had already been revealed. This review intends to describe advances in the understanding of the involved advances that have been made in the last decade concerning pituitary tumors progression, including the participation of oncogenes, tumor suppressor genes and growth factors.


Edifications on Indirect IgM ELISA and Immunofluorescence assay (IFA) of scrub typhus in humans and erudition of Orientia tsutsugamushi in the vector of cohabiting rodents.
Scrub typhus is a vector-borne disease caused by Orientia tsutsugamushi, propagated into humans by the bite of infected mite belonging to genus Leptotrombodium. The present study was conducted in the Nagpur region of central India aiming towards a survey of cohabiting rodents and their potential vectors for the presence of Orientia tsutsugamushi by PCR method. The study also emphasizes serological diagnosis of the disease by employing indirect IgM ELISA and IFA amongst the human cases of pyrexia of unknown origin. Indirect IgM ELISA recorded 39.69% (31/92) seropositive patients, further processing of ELISA positive samples for IFA revealed 67.74 % (21/31) positivity for Boryong, Gilliam, Karp, and Kato serotypes. A total of 50 rodents were trapped from the cohabit areas of the patients. Three different types of rodents were identified; among which, Rattus bandicoot was highest. From these rodents, 164 vectors viz mites, lice, and fleas were collected. The highest chiggar index was recorded for Ornithonyssus biscotti mites (3.4). This study prompts a detailed analysis of different species of rodents and vectors in the said endemic region.


Management of children and adults with all stages of nodular lymphocyte predominant Hodgkin lymphoma - All StAGEs: A consensus-based position paper from the Hodgkin lymphoma subgroup of the UK National Cancer Research Institute.
A consensus statement for the management for patients of all ages with all stages of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) - All StAGEs - is proposed by representatives of the UK National Cancer Research Institute (NCRI) Hodgkin lymphoma study group and the Children's Cancer & Leukaemia Group. Based on current practices and published evidence, a consensus has been reached regarding diagnosis, staging and risk-ik7 stratified management which includes active surveillance, low- and standard-dose immunochemotherapy and radiotherapy.


Electronic and magnetic properties of low-dimensional system Co2TeO3Cl2.
The electronic and magnetic properties of transition metal oxyhalide compound Co2TeO3Cl2 are investigated using first principle calculations within the framework of density functional theory. To find the underlying spin-lattice of this compound, various hopping integrals and exchange interactions are calculated. The calculations reveal that the dominant inter-chain and intra-chain interactions are in the ab plane. The exchange path is visualized by Wannier function plotting. The nearest neighbor and next nearest neighbor exchange interactions are antiferromagnetic, making the system frustrated in low dimension. Calculations are also done with spin-orbit coupling (SOC) to find out the effect of SOC on this compound. Calculation of magnetocrystalline anisotropy suggests that the easy axis is along the crystallographic b direction.


Childhood maltreatment and self-harm in Chinese adolescents: moderation and mediation via resilience.
Published studies examining the association between childhood maltreatment (CM) and self-harm (SH) among adolescents have been accumulated. It is possible that resilience serves as a moderator or mediator in CM-SH association, nevertheless, this topic has never been thoroughly investigated. In this population-based cross-sectional study, we surveyed 3146 students aged 10-17 in southwest China. The Childhood Trauma Questionnaire (CTQ), the Modified version of Adolescents Self-Harm Scale (MASHS), and the Resilience Scale for Chinese Adolescents (RSCA) were used to measure CM, SH, and resilience. Correlational analyses, hierarchical multivariate linear regression, and structural equation modeling (SEM) were performed to test the moderation and mediation of resilience in CM-SH association. Findings revealed that, resilience with its five dimensions, CM, and SH were significantly correlated with each other. Resilience partially moderated and mediated the association between CM and SH. Besides, among all dimensions of resilience, emotion regulation, interpersonal assistance, and family support presented the strongest mediation in CM-SH association. Our results highlight the importance of resilience in CM related SH among Chinese teenagers. Resilience-oriented intervention could be considered in SH intervention measures for adolescents who had experienced CM.


The role of research in advanced dental education.
Research is an integral part of quality advanced programs. Clinical research should be done in all departments where advanced dental education occurs, because this is the best way to improve the scientific base and rationality of clinical treatment. At present, many departments with postdoctoral programs lack faculty and others resources for research productivity. Programs to produce clinical faculty with research training are needed. The development of clinical research centers would offer the potential of combined clinical training and research. Combining existing resources for maximum effectiveness will be important in producing stronger programs.


Can electrodynamic interaction between a molecule and metal dominate a continuum background in surface-enhanced Raman scattering?
A continuum background is always coincident with the Raman spectrum enhanced by metallic nanostructures and still remains elusive. Not only does it constitute a stymied mystery in the origin per se, but also it reduces the useful quantifiable range of detection based on surface-enhanced Raman scattering (SERS). We examined theoretically near-field molecule-metal interaction to reveal its contribution to the SERS background. The results show that the spectral broadening of fluorescence and Raman scattering due to a nearby metal object is insignificant compared with experimental findings. This study abnegates the role of near-field interaction in the SERS continuum background and elucidates the microscopic molecule-metal electromagnetic interaction, despite being unable to pinpoint the primary source of the SERS background.


Evolutionary history of phosphatidylinositol- 3-kinases: ancestral origin in eukaryotes and complex duplication patterns.
Phosphatidylinositol-3-kinases (PI3Ks) are a family of eukaryotic enzymes modifying phosphoinositides in phosphatidylinositols-3-phosphate. Located upstream of the AKT/mTOR signalling pathway, PI3Ks activate secondary messengers of extracellular signals. They are involved in many critical cellular processes such as cell survival, angiogenesis and autophagy. PI3K family is divided into three classes, including 14 human homologs. While class II enzymes are composed of a single catalytic subunit, class I and III also contain regulatory subunits. Here we present an in-depth phylogenetic analysis of all PI3K proteins. We confirmed that PI3K catalytic subunits form a monophyletic group, whereas regulatory subunits form three distinct groups. The phylogeny of the catalytic subunits indicates that they underwent two major duplications during their evolutionary history: the most ancient arose in the Last Eukaryotic Common Ancestor (LECA) and led to the emergence of class III and class I/II, while the second - that led to the separation between class I and II - occurred later, in the ancestor of Unikonta (i.e., the clade grouping Amoebozoa, Fungi, and Metazoa). These two major events were followed by many lineage specific duplications in particular in vertebrates, but also in various protist lineages. Major loss events were also detected in Vidiriplantae and Fungi. For the regulatory subunits, we identified homologs of class III in all eukaryotic groups indicating that, for this class, both the catalytic and the regulatory subunits were presents in LECA. In contrast, homologs of the regulatory class I have a more recent origin. The phylogenetic analysis of the PI3K shed a new light on the evolutionary history of these enzymes. We found that LECA already contained a PI3K class III composed of a catalytic and a regulatory subunit. Absence of class II regulatory subunits and the recent origin of class I regulatory subunits is puzzling given that the class I/II catalytic subunit was present in LECA and has been conserved in most present-day eukaryotic lineages. We also found surprising major loss and duplication events in various eukaryotic lineages. Given the functional specificity of PI3K proteins, this suggests dynamic adaptation during the diversification of eukaryotes.


Association Between Costs Related to Productivity Loss and Modified Risk Factors Among Users of the Brazilian National Health System.
The aim of this study was to investigate the associations between costs related to productivity losses and its risk factors among users of the Brazilian National Health System. The public cost associated with productivity losses of 342 adults has been estimated, taking into account a period of 18 months. Costs related to productivity loss were estimate using data provided by the Brazilian National Health System (disability retirements) and absenteeism. Modifiable risk factors and unhealthy behaviors were assessed through interviews (physical inactivity, alcohol consumption, and smoking) and clinical assessments (obesity). Smoking and physical inactivity affected significantly the amount of money lost with productivity losses related to absenteeism. The presence of obesity generated higher expenditures with disability retirement, while low back pain and sleep disorder were the most relevant confounders in multivariate models for disability retirement and absenteeism. Among users of the Brazilian National Health System, obesity, smoking, and physical inactivity seem to have a significant effect on productivity losses associated with health problems. Moreover, low back pain and sleep quality seem variables few explored but with potential to affect health care costs.


Raman spectroscopy enabled investigation of carbon nanotubes quality upon dispersion in aqueous environments.
Dispersion of high quality carbon nanotubes (CNTs) in aqueous solutions is of central importance for their potential biological and biomedical applications. Although it is now possible to obtain highly dispersed CNT solutions by means of surfactant assisted processing, organic functionalization, and mechanical mixing, a concern remains about preservation of CNTs' quality during these dispersion procedures. In this report, the authors demonstrate that by employing Raman spectroscopy, one can study changes in CNTs' quality post-dispersion. Specifically, the authors focused on mechanical mixing via sonication and quantitatively determined the effects of various parameters such as surfactants, CNTs' geometry, sonication time, and sonication method on CNTs' quality post-sonication. While not addressed here, our method could be extended to monitor CNTs' quality as a function of other parameters that could potentially compromise their quality, such as chemical functionalization or doping.


Designation of oripavine as a basic class of controlled substance. Final rule.
This is a final rule issued by the Drug Enforcement Administration (DEA) designating oripavine (3-O-demethylthebaine or 6,7,8,14-tetradehydro-4,5-alpha-epoxy-6-methoxy-17-methylmorphinan-3-ol) as a basic class in schedule II of the Controlled Substances Act (CSA). Although oripavine was not previously listed in schedule II of the CSA, it has been controlled in the United States as a derivative of thebaine and, as such, is controlled as a schedule II controlled substance which includes "Opium and opiate, and any salt, compound, derivative, or preparation of opium or opiate." Oripavine is a derivative of thebaine, a natural constituent of opium, hence oripavine has been and continues to be, by virtue of the definition of "narcotic drug", a schedule II controlled substance. International control of oripavine in schedule I of the 1961 Single Convention on Narcotic Drugs (1961 Convention) during the 50th session of the Commission on Narcotic Drugs (CND) in 2007 prompted the DEA to specifically designate oripavine as a basic class of controlled substance in schedule II of the CSA.


Leaving no-one behind: how CENP-E facilitates chromosome alignment.
Chromosome alignment and biorientation is essential for mitotic progression and genomic stability. Most chromosomes align at the spindle equator in a motor-independent manner. However, a subset of polar kinetochores fail to bi-orient and require a microtubule motor-based transport mechanism to move to the cell equator. Centromere Protein E (CENP-E/KIF10) is a kinesin motor from the Kinesin-7 family, which localizes to unattached kinetochores during mitosis and utilizes plus-end directed microtubule motility to slide mono-oriented chromosomes to the spindle equator. Recent work has revealed how CENP-E cooperates with chromokinesins and dynein to mediate chromosome congression and highlighted its role at aligned chromosomes. Additionally, we have gained new mechanistic insights into the targeting and regulation of CENP-E motor activity at the kinetochore. Here, we will review the function of CENP-E in chromosome congression, the pathways that contribute to CENP-E loading at the kinetochore, and how CENP-E activity is regulated during mitosis.


SLAM expression is not downregulated by measles virus infection.
It has been reported that the signaling lymphocyte-activation molecule (SLAM), the second receptor of Measles virus (MV) on the cell surface appears to be downregulated by MV infection or by expression of MV hemagglutinin (H) (Tanaka et al., 2002; Welsteadt et al., 2004). The aim of this study was to analyze this phenomenon in more detail using a Chinese vaccine strain (S191) of MV. Flow cytometry confirmed apparent downregulation of SLAM in the virus-infected cells and in the cells transfected with a plasmid expressing viral H. Moreover, a similar effect was obtained by incubation of the cells with UV-inactivated virus or soluble viral H. Real-time quantitative PCR showed that the SLAM mRNA level remained stable during the virus infection, and Western blot analysis demonstrated that the SLAM content of total membrane proteins did not change change after the virus infection. Thus we conclude that SLAM expression is stable during the MV infection and that its apparent downregulation reported earlier and confirmed also in this study was just the result of masking of the antibody recognition sites on SLAM with MV H during the flow cytometry assay.


Modified Cross-Linking, Ligation, and Sequencing of Hybrids (qCLASH) Identifies Kaposi's Sarcoma-Associated Herpesvirus MicroRNA Targets in Endothelial Cells.
Kaposi's sarcoma (KS) tumors are derived from endothelial cells and express Kaposi's sarcoma-associated herpesvirus (KSHV) microRNAs (miRNAs). Although miRNA targets have been identified in B cell lymphoma-derived cells and epithelial cells, little has been done to characterize the KSHV miRNA targetome in endothelial cells. A recent innovation in the identification of miRNA targetomes, cross-linking, ligation, and sequencing of hybrids (CLASH), unambiguously identifies miRNAs and their targets by ligating the two species while both species are still bound within the RNA-induced silencing complex (RISC). We developed a streamlined quick CLASH (qCLASH) protocol that requires a lower cell input than the original method and therefore has the potential to be used on patient biopsy samples. Additionally, we developed a fast-growing, KSHV-negative endothelial cell line derived from telomerase-immortalized vein endothelial long-term culture (TIVE-LTC) cells. qCLASH was performed on uninfected cells and cells infected with either wild-type KSHV or a mutant virus lacking miR-K12-11/11*. More than 1,400 cellular targets of KSHV miRNAs were identified. Many of the targets identified by qCLASH lacked a canonical seed sequence match. Additionally, most target regions in mRNAs originated from the coding DNA sequence (CDS) rather than the 3' untranslated region (UTR). This set of genes includes some that were previously identified in B cells and some new genes that warrant further study. Pathway analysis of endothelial cell targets showed enrichment in cell cycle control, apoptosis, and glycolysis pathways, among others. Characterization of these new targets and the functional consequences of their repression will be important in furthering our understanding of the role of KSHV miRNAs in oncogenesis.IMPORTANCE KS lesions consist of endothelial cells latently infected with KSHV. Cells that make up these lesions express KSHV miRNAs. Identification of the targets of KSHV miRNAs will help us understand their role in viral oncogenesis. The cross-linking and sequencing of hybrids (CLASH) protocol is a method for unambiguously identifying miRNA targetomes. We developed a streamlined version of CLASH, called quick CLASH (qCLASH). qCLASH requires a lower initial input of cells than for its parent protocol. Additionally, a new fast-growing KSHV-negative endothelial cell line, named TIVE-EX-LTC cells, was established. qCLASH was performed on TIVE-EX-LTC cells latently infected with wild-type (WT) KSHV or a mutant virus lacking miR-K12-11/11*. A number of novel targets of KSHV miRNAs were identified, including targets of miR-K12-11, the ortholog of the cellular oncogenic miRNA (oncomiR) miR-155. Many of the miRNA targets were involved in processes related to oncogenesis, such as glycolysis, apoptosis, and cell cycle control.


Obesity and hypertension.
Obesity and in particular the excessive visceral fat distribution is accompanied by several alterations at hormonal, inflammatory and endothelial level. These alterations induce a stimulation of several other mechanisms that contribute to the hypertensive state and on the other side to increase the cardiovascular morbidity. In these chapter we will examine the main mechanisms of obesity and obesity-related hypertension and in particular the role of sympathetic nervous system, the alterations of the renal function and at the microvascular level. We will also depict the role of insulin resistance as factor stimulating and potentiating the other mechanisms. The second part will be focalized on the major target organ damage linked with obesity and obesity-related hypertension. We will finally describe the management and treatment of obesity and the antihypertensive drug therapies more effective in hypertensive obeses.


The first example of MEEKC-ICP-MS coupling and its application for the analysis of anticancer platinum complexes.
MEEKC is a powerful electrodriven separation technique with many applications in different disciplines, including medicinal chemistry; however, up to now the coupling to highly sensitive and selective MS detectors was limited due to the ion suppressive effect of the commonly used surfactant SDS. Herein, the first example of the coupling of MEEKC to ICP-MS is presented and an MEEKC method for the separation of Pt(II) and Pt(IV) anticancer drugs and drug candidates was developed. Different compositions of microemulsions were evaluated and the data were compared with those collected with standard ultraviolet/visible (UV/vis) spectroscopy detection. The MEEKC-ICP-MS system was found to be more sensitive than MEEKC-UV/vis and the analysis of UV/vis silent compounds is now achievable. The migration behavior of the Pt(II) and Pt(IV) compounds under investigation is correlated to their different chemical structures.


Cost of care for diabetes in Wisconsin hospitals and ambulatory surgery centers in 1996.
Diabetes mellitus imposes a significant financial burden on Wisconsin's health care system. One portion of this burden is attributable to the cost of hospitalizing diabetes patients. During 1996 hospital inpatients with a principal diagnosis of diabetes generated over $60 million in hospital charges (physician fees excluded). Ambulatory surgery patients generated an additional $3.4 million in facility charges. This article examines those costs, according to age and gender, expected pay source, and by county. It also reports the reasons for hospitalization and ambulatory surgery for patients whose principal diagnosis was diabetes. Employers, public health professionals, physicians and managed care firms are interested in containing the social and personal costs of diabetes mellitus. This paper explores the financial burden associated with hospitalization and ambulatory surgeries for diabetes in Wisconsin for 1996.


Adaptation of Nontypeable Haemophilus influenzae in Human Airways in COPD: Genome Rearrangements and Modulation of Expression of HMW1 and HMW2.
Chronic obstructive pulmonary disease (COPD) is a common debilitating disorder that is the third most common cause of death globally. Chronic lower airway infection by nontypeable Haemophilus influenzae (NTHi) in adults with COPD increases airway inflammation, causes increased symptoms, and accelerates progressive loss of lung function. Little is known about the mechanisms by which NTHi survives in COPD airways. To explore this question, the present study analyzes, in detail, 14 prospectively collected, serial isolates of a strain that persisted for 543 days in a patient with COPD, including analysis of four gap-free complete genomes. The NTHi genome underwent inversion of a ~400-kb segment three times during persistence. This inversion event resulted in switching of expression of the HMW1A and HMW2A adhesins as the inversion sites are in the promoter regions of HMW1 and HMW2. Regulation of the level of expression of HMW 1 and HMW2 in the human airways was controlled by the ~400-kb inversion and by 7-bp repeats in the HMW promoters. Analysis of knockout mutants of the persistent strain demonstrated that HMW1 and HMW2 proteins both function in the adherence of NTHi to human respiratory epithelial cells during persistence and that HMW1 also facilitates invasion of epithelial cells. An inverse relationship between biofilm formation and HMW1 expression was observed during persistence. This work advances understanding of the mechanisms of persistence of NTHi in COPD airways, which can inform the development of novel interventions to treat and prevent chronic NTHi infection in COPD. IMPORTANCE Nontypeable Haemophilus influenzae (NTHi) persists in the lower airways of adults with chronic obstructive pulmonary disease (COPD) for months to years, increasing airway inflammation that accelerates the progressive loss of lung function. Understanding the mechanisms of persistence in human airways by NTHi is critical in developing novel interventions. Here, in detail, we studied longitudinally collected sequential isolates of a strain of NTHi that persisted in an adult with COPD, including analysis of four gap-free genomes and knockout mutants to elucidate how the genome adapts in human airways. The NTHi genome underwent a genome rearrangement during persistence and this inversion impacted regulation of expression of key virulence phenotypes, including adherence to respiratory epithelial cells, invasion of epithelial cells and biofilm formation. These novel observations advance our understanding of the mechanisms of persistence of NTHi in the airways of adults with COPD.


Patterns of mRNA and protein expression for 12 GABAA receptor subunits in the mouse brain.
The GABAA receptor is the main inhibitory receptor in the brain and its subunits originate from different genes or gene families (α1-α6, β1-β3, γ1-γ3, δ, ε, θ, π, or ρ1-3). In the mouse brain the anatomical distribution of GABAA receptor subunit mRNAs so far investigated is restricted to subunits forming benzodiazepine-sensitive receptor complexes (α1-α3, α5, β2, β3 and γ2) in the forebrain and midbrain as assessed by in situ hybridization (ISH). In the present study the anatomical distribution of the GABAA receptor subunits α1-α6, β1-β3, γ1-γ2 and δ was analyzed in the mouse brain (excluding brain stem) by ISH and immunohistochemistry (IHC). In several brain areas such as hippocampus, cerebellum, bulbus olfactorius and habenula we observed that mRNA levels did not reflect protein levels, indicating that the protein is located far distantly from the cell body. We also compared the distribution of these 12 subunit mRNAs and proteins with that reported in the rat brain. Although in general there is a considerable correspondence in the distribution between mouse and rat brains, several species-specific differences were observed.


Competition of opsonins and dysopsonins on the nanoparticle surface.
The biological behavior and fate of nanoparticles are dependent on their retention time in the blood circulation system. The protein corona components, especially opsonins, and dysopsonins, adsorbed on the nanoparticle surface determine their blood circulation time. The protein corona formation is a dynamic process that involves the competition between different proteins to be adsorbed on the nanoparticles. Therefore, studying how proteins compete and are oriented on the nanoparticle surface is essential. We hypothesized that the presence of opsonins (immunoglobulin (IgG)) might affect the adsorption of dysopsonins (human serum albumin (HSA)) and vice versa. Using the molecular dynamics simulations, we showed that the adsorption of HSA on the GO surface after the IgG adsorption is more probable than the opposite order of adsorption. It was also observed that the higher lateral diffusion of the HSA compared to the IgG helped the system reach a more stable configuration while the initial adsorption of the HSA limits the lateral diffusion of IgG. Therefore, replacing IgG adsorbed on the GO surface with HSA is plausible while the reverse process is less likely to occur. This study revealed that albumin might extend the blood circulation time of GO by replacing opsonins (IgG).


Depiction of a 17th-Century Tooth Extraction: A Drawing by Adriaen Pietersz van de Venne (Dutch, 1589-1662).
A prolific and inventive painter, draftsman, and poet, Adriaen Pietersz van de Venne was born in Delft in 1589. His wealthy parents had fled from Protestant persecution in the Southern (Spanish) Netherlands during the 1580s. Van de Venne was educated in Leiden, where he became part of the vibrant political and intellectual community around the University. He settled in Middleburg, in Zeeland, by 1614; his earliest dated paintings are also from this year. In 1625, van de Venne moved to The Hague, where he remained until his dealth. He executed several commissions for the Dutch stadholder Frederik Hendrik, was repeatedly elected dean of the guild of St. Luke, and in 1656 was one of the founding members of The Hague's painter's guild, "Pictura schilders confrerie." Van de Venne painted histories, portraits, and genre scenes; from 1618, he was also active as a printmaker and book illustrator, notably for the popular poet Jacob Cats. His literary accomplishments included satire and political propaganda, as well as several books of poetry.


Development of a directly patterned low-surface-energy polymer brush in supercritical carbon dioxide.
Carbon dioxide (CO2) is a sustainable solvent because it is nonflammable, exhibits a relatively low toxicity, and is naturally abundant. As a selective, nonpolar solvent, supercritical CO2 (scCO2) is an ideal fit for the development of low-surface-energy polymers. The development of directly patterned poly(2,2,2-trifluoroethyl methacrylate) (PTFEMA) brushes in scCO2 was investigated. PTFEMA, in particular, was selected over other fluorinated polymers because of its very high electron-beam (e-beam) sensitivity. PTFEMA brushes were grown on silicon substrates via controlled surface-initiated atom-transfer radical polymerization of TFEMA. Surface analysis techniques including ellipsometry, contact-angle goniometry, atomic force microscopy (AFM), and X-ray photoelectron spectroscopy were used to characterize the thickness, hydrophilicity, roughness, and chemical composition of the polymer brushes. PTFEMA brushes were directly patterned in a single step using e-beam lithography and were processed in an environmentally benign scCO2 solvent. Tapping-mode AFM imaging confirmed the successful e-beam patterning and development of these brushes. The sensitivity of PTFEMA brushes toward direct patterning with the e-beam, followed by scCO2 development, was studied and compared to development in tetrahydrofuran solvent. Using this direct-patterning method, followed by dry development in scCO2, highly resolved nanostructured polymer brush lines down to 78 nm could be prepared. This method can be generalized to prepare fluorinated low-surface-energy polymer brush surfaces in a single step for various applications.


Effect of triflusal and other salicylic acid derivatives on cyclic AMP levels in rat platelets.
The effect of triflusal, acetylsalicylic acid (ASA), and of their principal metabolites 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) and salicylic acid (SA), alone or combined with dypiridamole (DIP) and/or PGE1 on cyclic AMP levels in washed rat platelets (37 degrees C, 4 min), has been determined. DIP at 0.1 mM increased cyclic AMP levels by 25%. The effect of triflusal and HTB was significant at therapeutic concentrations of triflusal (1 mM: 36% increase) and HTB (0.5 mM: 37% increase). The effect of HTB was always greater than that of triflusal. ASA, at 1 mM and 5 mM, alone or combined with PGE1 was without effect. When 1 mM triflusal was combined with 0.1 mM DIP an increased effect was obtained (95%). ASA, at the highest concentration tested (5 mM), did not modify the DIP-induced increase of cyclic AMP levels.


Characterization of the Nicotiana tabacum L. genome by molecular cytogenetics.
Nicotiana tabacum (2n = 48) is a natural amphidiploid with component genomes S and T. We used non-radioactive in situ hybridization to provide physical chromosome markers for N. tabacum, and to determine the extant species most similar to the S and T genomes. Chromosomes of the S genome hybridized strongly to biotinylated total DNA from N. sylvestris, and showed the same physical localization of a tandemly repeated DNA sequence, HRS 60.1, confirming the close relationship between the S genome and N. sylvestris. Results of dot blot and in situ hybridizations of N. tabacum DNA to biotinylated total genomic DNA from N. tomentosiformis and N. otophora suggested that the T genome may derive from an introgressive hybrid between these two species. Moreover, a comparison of nucleolus-organizing chromosomes revealed that the nucleolus organizer region (NOR) most strongly expressed in N. tabacum had a very similar counterpart in N. otophora. Three different N. tabacum genotypes each had up to 9 homozygous translocations between chromosomes of the S and T genomes. Such translocations, which were either unilateral or reciprocal, demonstrate that intergenomic transfer of DNA has occurred in the amphidiploid, possibly accounting for some results of previous genetic and molecular analyses. Molecular cytogenetics of N. tabacum has identified new chromosome markers, providing a basis for physical gene mapping and showing that the amphidiploid genome has diverged structurally from its ancestral components.


The oral clearance of chlorhexidine solutions and gels.
The oral clearance of 4 chlorhexidine (CH) preparations was investigated. Two 0.2% CH-solutions, Plak-Out liquid, a 10% alcoholic CH-solution and an aqueous ICI-Hibitane solution were compared with two chlorhexidine gels, Corsodyl gel (0.1%) and a test CH-gel (1.0%) prepared in this laboratory. Thirty subjects, 17 to 57 years of age and exhibiting a variety of oral hygiene conditions, participated in supervised rinsing with CH-solutions and toothbrushing with gels carried out at weekly intervals to eliminate carry-over effects. Mixed saliva samples were taken 7.5, 15, 30, 60 and 120 minutes following each administration and were analysed spectrophotometrically. The relative oral CH-retention values were for Plak-Out liquid 91%, aqueous Hibitane solution 69%, Corsodyl gel 46% and with the laboratory chlorhexidine gel 37%.


Shear Behaviour and Calculation Methods of Bearing-Shear Connectors for Prefabricated Steel-Concrete Composite Beams.
The bearing-shear connector (B-SC) is a newly developed connector that exhibits excellent shear behaviour and is easy to process. However, research on the application of B-SCs as substitutes for grouped studs in prefabricated steel-concrete composite beams is rare, and systematically studying their shear behaviour is necessary. Thus, a refined numerical model was developed to study the shear behaviour of the B-SCs. The numerical model, validated by push-out tests, was conducted to analyse the stress of the B-SCs and concrete slab during loading and to explore the failure mechanism of B-SCs. Then, a parametric study was performed to identify the key factors influencing the shear behaviour of the B-SCs. The concrete strength, and the thickness and the tensile strength of the shear plate were found to significantly influence the shear behaviour of B-SCs. According to the experiments and numerical analysis, calculation formulae for the ultimate shear resistance and slip modulus were proposed.


Histone Deacetylase 11 Contributes to Renal Fibrosis by Repressing KLF15 Transcription.
Renal fibrosis represents a key pathophysiological process in patients with chronic kidney diseases (CKD) and is typically associated with a poor prognosis. Renal tubular epithelial cells (RTECs), in response to a host of pro-fibrogenic stimuli, can trans-differentiate into myofibroblast-like cells and produce extracellular matrix proteins to promote renal fibrosis. In the present study we investigated the role of histone deacetylase 11 (HDAC11) in this process and the underlying mechanism. We report that expression levels of HDAC11 were up-regulated in the kidneys in several different animal models of renal fibrosis. HDAC11 was also up-regulated by treatment of Angiotensin II (Ang II) in cultured RTECs. Consistently, pharmaceutical inhibition with a small-molecule inhibitor of HDAC11 (quisinostat) attenuated unilateral ureteral obstruction (UUO) induced renal fibrosis in mice. Similarly, HDAC11 inhibition by quisinostat or HDAC11 depletion by siRNA blocked Ang II induced pro-fibrogenic response in cultured RTECs. Mechanistically, HDAC11 interacted with activator protein 2 (AP-2α) to repress the transcription of Kruppel-like factor 15 (KLF15). In accordance, KLF15 knockdown antagonized the effect of HDAC11 inhibition or depletion and enabled Ang II to promote fibrogenesis in RTECs. Therefore, we data unveil a novel AP-2α-HDAC11-KLF15 axis that contributes to renal fibrosis.


miR-21 promotes fibrogenic epithelial-to-mesenchymal transition of epicardial mesothelial cells involving Programmed Cell Death 4 and Sprouty-1.
The lining of the adult heart contains epicardial mesothelial cells (EMCs) that have the potential to undergo fibrogenic Epithelial-to-Mesenchymal Transition (EMT) during cardiac injury. EMT of EMCs has therefore been suggested to contribute to the heterogeneous fibroblast pool that mediates cardiac fibrosis. However, the molecular basis of this process is poorly understood. Recently, microRNAs (miRNAs) have been shown to regulate a number of sub-cellular events in cardiac disease. Hence, we hypothesized that miRNAs regulate fibrogenic EMT in the adult heart. Indeed pro-fibrogenic stimuli, especially TGF-β, promoted EMT progression in EMC cultures, which resulted in differential expression of numerous miRNAs, especially the pleiotropic miR-21. Accordingly, ectopic expression of miR-21 substantially promoted the fibroblast-like phenotype arising from fibrogenic EMT, whereas an antagonist that targeted miR-21 blocked this effect, as assessed on the E-cadherin/α-smooth muscle actin balance, cell viability, matrix activity, and cell motility, thus making miR-21 a relevant target of EMC-derived fibrosis. Several mRNA targets of miR-21 was differentially regulated during fibrogenic EMT of EMCs and miR-21-dependent targeting of Programmed Cell Death 4 (PDCD4) and Sprouty Homolog 1 (SPRY1) significantly contributed to the development of a fibroblastoid phenotype. However, PDCD4- and SPRY1-targeting was not entirely ascribable to all phenotypic effects from miR-21, underscoring the pleiotropic biological role of miR-21 and the increasing number of recognized miR-21 targets.


Imperforate Anus and Rectourethral Fistula in a Female.
Anorectal malformations (ARM) are complex, heterogeneous disorders and in females the most common anomaly is imperforate anus with a rectovestibular fistula. We describe a malformation not previously encountered in the literature: imperforate anus associated with a normal urethra, normal vagina, but with a recto urethral fistula. Rectourethral fistula in a female is an extremely rare ARM. Precise workup is required to clarify the anatomy for operative planning.


Evaluation of fasciocutaneous perforators using color duplex imaging.
Technological improvements in conventional ultrasound, including color duplex imaging, have greatly facilitated the evaluation of vascular-related problems for virtually every specialty. Higher-frequency transducers now permit the scanning of superficial depths beneath the skin surface with high sensitivity for an analysis specific to the microcirculation. This attribute has already been recognized as a valuable tool for the preoperative mapping of musculocutaneous perforators. A logical extension of this capability would be for the localization and calibration of deep fascial perforators, which may have even greater clinical significance because anomalies at this level are more the rule rather than the the exception. Over the preceding 10-month period, all eight elective fasciocutaneous flaps performed in eight patients had initial scans using color duplex imaging to identify and calibrate all relevant cutaneous perforators. All fasciocutaneous flap subtypes were included. If feasible at the time of flap elevation, all identified perforators were dissected and measured. All were found at the exact site as marked preoperatively, and their diameter closely approximated that predicted. The occasional unanticipated presence in vivo of minor perforators suggests that color duplex imaging may not be reliable for fascial perforators less than 0.5 mm in diameter. Since perforator caliber qualitatively is a major determinant of flow, color duplex imaging can then objectively establish a hierarchy of the importance of perforators in a given region. From such data, the definition of new and more reliable fasciocutaneous flap donor territories should be forthcoming.(ABSTRACT TRUNCATED AT 250 WORDS)


Identifying the challenges and opportunities of PCOS awareness month by analysing its global digital impact.
Although significant resources are invested each September for PCOS Awareness Month campaign, there are no studies measuring its impact. We evaluated the digital impact of PCOS Awareness Month, common themes and associated topics, top influencers, and global equity of influence during the PCOS Awareness month. In this serial cross-sectional analysis, we studied the outputs from Symplur® to study the total impressions of #PCOS on Twitter®. We tracked the hashtags-#PCOS, #PCOSawarenessmonth, #PCOSawareness-and a search query- "#PCOS OR #PCOSawarenessmonth OR #PCOSawareness"-using Sproutsocial® to study the total number of tweets related to PCOS Awareness Month. Network analysis was done using SocioViz® to identify common themes and associated topics. Using SymplurRank® machine learning algorithm, the top 10 #PCOS influencers were identified based on the number of mentions received. Google® Trends was used to study the web and news search popularity over the last 10 years beyond social media platforms. An overall upward trend in the digital impact of PCOS awareness was noted since 2017. While the top themes associated with PCOS (insulin resistance, depression, anxiety, menopause, hormones, infertility) remained the same in 2021 and 2022, newer themes emerged in the latter year suggesting the need for ongoing review. News outlets were the most influential organisations during PCOS Awareness Month in both years of study. Seven of the top 10 users were the same in both years. Limited engagement from African, Asian, South American, and non-English speaking European countries was seen on Google Trends analysis. Active involvement from various stakeholders of PCOS Awareness Month has shaped it into an effective strategy to raise awareness with social media playing a crucial role in amplifying the message. Our findings also provide an opportunity to understand the current perceptions and expectations amongst the public, which can influence future healthcare investment and research.


Narrow-Band Imaging: Clinical Application in Gastrointestinal Endoscopy.
Narrow-band imaging is an advanced imaging system that applies optic digital methods to enhance endoscopic images and improves visualization of the mucosal surface architecture and microvascular pattern. Narrow-band imaging use has been suggested to be an important adjunctive tool to white-light endoscopy to improve the detection of lesions in the digestive tract. Importantly, it also allows the distinction between benign and malignant lesions, targeting biopsies, prediction of the risk of invasive cancer, delimitation of resection margins, and identification of residual neoplasia in a scar. Thus, in expert hands it is a useful tool that enables the physician to decide on the best treatment (endoscopic or surgical) and management. Current evidence suggests that it should be used routinely for patients at increased risk for digestive neoplastic lesions and could become the standard of care in the near future, at least in referral centers. However, adequate training programs to promote the implementation of narrow-band imaging in daily clinical practice are needed. In this review, we summarize the current scientific evidence on the clinical usefulness of narrow-band imaging in the diagnosis and characterization of digestive tract lesions/cancers and describe the available classification systems.


Salmonella typhi rpoS mutant is less cytotoxic than the parent strain but survives inside resting THP-1 macrophages.
Transcription of the stationary-phase sigma factor RpoS of Salmonella typhi increased in the macrophage. A single rpoS mutant of S. typhi was constructed to analyze the role of RpoS in intracellular multiplication of the bacterium and host cell killing. This mutant was sensitive to starvation, low pH and hydrogen peroxide; however, it could still multiply inside resting macrophages and was less cytotoxic than the wild-type strain. Therefore, S. typhi might produce RpoS-dependent factors which could contribute to host cell death.


Tuning the Phenotype of Cartilage Tissue Mimics by Varying Spheroid Maturation and Methacrylamide-Modified Gelatin Hydrogel Characteristics.
In hybrid bioprinting of cartilage tissue constructs, spheroids are used as cellular building blocks and combined with biomaterials for dispensing. However, biomaterial intrinsic cues can deeply affect cell fate and to date, the influence of hydrogel encapsulation on spheroid viability and phenotype has received limited attention. This study assesses this need and unravels 1) how the phenotype of spheroid-laden constructs can be tuned through adjusting the hydrogel physico-chemical properties and 2) if the spheroid maturation stage prior to encapsulation is a determining factor for the construct phenotype. Articular chondrocyte spheroids with a cartilage specific extracellular matrix (ECM) are generated and different maturation stages, early-, mid-, and late-stage (3, 7, and 14 days, respectively), are harvested and encapsulated in 10, 15, or 20 w/v% methacrylamide-modified gelatin (gelMA) for 14 days. The encapsulation of immature spheroids do not lead to a cartilage-like ECM production but when more mature mid- or late-stage spheroids are combined with a certain concentration of gelMA, a fibrocartilage-like as well as a hyaline cartilage-like phenotype can be induced. As a proof of concept, late-stage spheroids are bioprinted using a 10 w/v% gelMA-Irgacure 2959 solution with the aim to test the processing potential of the spheroid-laden bioink.


From cognitive networks to seizures: stimulus evoked dynamics in a coupled cortical network.
Epilepsy is one of the most common neuropathologies worldwide. Seizures arising in epilepsy or in seizure disorders are characterized generally by uncontrolled spread of excitation and electrical activity to a limited region or even over the entire cortex. While it is generally accepted that abnormal excessive firing and synchronization of neuron populations lead to seizures, little is known about the precise mechanisms underlying human epileptic seizures, the mechanisms of transitions from normal to paroxysmal activity, or about how seizures spread. Further complication arises in that seizures do not occur with a single type of dynamics but as many different phenotypes and genotypes with a range of patterns, synchronous oscillations, and time courses. The concept of preventing, terminating, or modulating seizures and/or paroxysmal activity through stimulation of brain has also received considerable attention. The ability of such stimulation to prevent or modulate such pathological activity may depend on identifiable parameters. In this work, firing rate networks with inhibitory and excitatory populations were modeled. Network parameters were chosen to model normal working memory behaviors. Two different models of cognitive activity were developed. The first model consists of a single network corresponding to a local area of the brain. The second incorporates two networks connected through sparser recurrent excitatory connectivity with transmission delays ranging from approximately 3 ms within local populations to 15 ms between populations residing in different cortical areas. The effect of excitatory stimulation to activate working memory behavior through selective persistent activation of populations is examined in the models, and the conditions and transition mechanisms through which that selective activation breaks down producing spreading paroxysmal activity and seizure states are characterized. Specifically, we determine critical parameters and architectural changes that produce the different seizure dynamics in the networks. This provides possible mechanisms for seizure generation. Because seizures arise as attractors in a multi-state system, the system may possibly be returned to its baseline state through some particular stimulation. The ability of stimulation to terminate seizure dynamics in the local and distributed models is studied. We systematically examine when this may occur and the form of the stimulation necessary for the range of seizure dynamics. In both the local and distributed network models, termination is possible for all seizure types observed by stimulation possessing some particular configuration of spatial and temporal characteristics.


Quality control of Harpagophytum procumbens and its related phytopharmaceutical products by means of NIR-FT-Raman spectroscopy.
NIR-FT-Raman spectroscopy was used for identification and quantification of harpagoside in secondary roots of Harpagophytum procumbens as well as in related phytopharmaceutical products, e.g., ethanolic extracts and tablets. Applied Raman mappings reveal the spatial distribution of this valuable iridoid glycoside within the different samples. The same technique can be used for quality control purposes beginning from the plant to its final products. Based on the obtained spectral data and reference HPLC values of harpagoside, a reliable multivariate calibration model was developed.


Type I autoimmune hepatitis: clinical course and outcome in an Italian multicentre study.
Many reports of autoimmune hepatitis (AIH) were written in the 'pre-Hepatitis C era' and data on the natural history are still incomplete. To evaluate the clinical presentation and the natural history of type I AIH. Seventy-three consecutive patients with a regular follow-up of at least 2 years were prospectively included in the study. The mean follow-up was 91 +/- 61 months. Patients with 'acute' onset at presentation were significantly older than patients with 'chronic' onset (P < 0.05) and had significantly higher serum levels of transaminase, gamma-glutamyltransferase and bilirubin; Prothrombin time was significantly lower in the said group compared with AIH patients with 'chronic' onset. In 4 of 63 (6.3%) female patients, AIH had the onset during pregnancy; in all of them the outcome of pregnancy was favourable. The major events during the follow-up included oesophageal varices (n = 9) and ascites (n = 4), and 60 patients remained in remission while receiving immunosuppression. None of the patients died during the follow-up, but seven patients were transplanted. The cumulative transplant-free probability of survival was 73.5% at 280 months. Elderly patients have more frequently an acute onset at presentation. Survival in AIH is apparently good; with early diagnosis, and improved medical therapy, liver transplantation for AIH will become a rare event in future.


Can Preoperative Magnetic Resonance Imaging Predict the Reparability of Massive Rotator Cuff Tears?
Numerous studies have shown preoperative fatty infiltration of rotator cuff muscles to be strongly negatively correlated with the successful repair of massive rotator cuff tears (RCTs). To assess the association between factors identified on preoperative magnetic resonance imaging (MRI), especially infraspinatus fatty infiltration, and the reparability of massive RCTs. Case-control study; Level of evidence, 3. We analyzed a total of 105 patients with massive RCTs for whom MRI was performed ≤6 months before arthroscopic procedures. The mean age of the patients was 62.7 years (range, 46-83 years), and 46 were men. Among them, complete repair was possible in 50 patients (48%) and not possible in 55 patients (52%). The tangent sign, fatty infiltration of the rotator cuff, and Patte classification were evaluated as predictors of reparability. Using the receiver operating characteristic curve and the area under the curve (AUC), the prediction accuracy of each variable and combinations of variables were measured. Reparability was associated with fatty infiltration of the supraspinatus ( P = .0045) and infraspinatus ( P < .001) muscles, the tangent sign ( P = .0033), and the Patte classification ( P < .001) but not with fatty infiltration of the subscapularis and teres minor ( P = .425 and .132, respectively). The cut-off values for supraspinatus and infraspinatus fatty infiltration were grade >3 and grade >2, respectively. The examination of single variables revealed that infraspinatus fatty infiltration showed the highest AUC value (0.812; sensitivity: 0.86; specificity: 0.76), while the tangent sign showed the lowest AUC value (0.626; sensitivity: 0.38; specificity: 0.87). Among 2-variable combinations, the combination of infraspinatus fatty infiltration and the Patte classification showed the highest AUC value (0.874; sensitivity: 0.54; specificity: 0.96). The combination of 4 variables, that is, infraspinatus and supraspinatus fatty infiltration, the tangent sign, and the Patte classification, had an AUC of 0.866 (sensitivity: 0.28; specificity: 0.98), which was lower than the highest AUC value (0.874; sensitivity: 0.54; specificity: 0.96) among the 2-variable combinations. The tangent sign or Patte classification alone was not a predictive indicator of the reparability of massive RCTs. Among single variables, infraspinatus fatty infiltration was the most effective in predicting reparability, while the combination of Goutallier classification <3 of the infraspinatus and Patte classification ≤2 of the rotator cuff muscles was the most predictive among the combinations of variables. This information may help predict the reparability of massive RCTs.


Selective inhibition of the citrate-to-isocitrate reaction of cytosolic aconitase by phosphomimetic mutation of serine-711.
Iron-regulatory protein 1 (IRP1) is a dual-function protein with mutually exclusive roles as a posttranscriptional regulator of animal-cell iron metabolism or as the cytosolic isoform of the iron-sulfur enzyme aconitase (c-acon). Much effort has focused on the role of IRP1 in posttranscriptional gene regulation and in factors that influence its interconversion with c-acon, but little is known about the metabolic function and regulation of c-acon. The role of PKC-dependent phosphorylation of S711 on IRP1/c-acon function was examined. Phosphorylation state-specific antibodies revealed that S711 is phosphorylated by PKC in vitro and in human embryonic kidney cells treated with a PKC activator. In aco1 yeast, the phosphomimetic mutants S711D and S711E exhibited severely impaired aconitase function, whereas S711A and S711T were unaffected relative to the WT protein. Aconitase activity in yeast extracts displayed a similar pattern when assayed for capacity to convert citrate to isocitrate: WT, S711A, and S711T were active, but S711D and S711E activity was undetectable. In contrast, when measured by the conversion of isocitrate to cis-aconitate, S711D and S711E displayed substantial activity, indicating that phosphorylation impairs the citrate but not isocitrate mode of aconitase function. This possibility was confirmed in vivo by demonstrating that S711D and S711E specifically antagonized the requirement for isocitrate in two metabolic scenarios. Iron-responsive element RNA-binding affinity was unaffected by S711 mutations. Our results show that S711 is a target of phosphorylation capable of conferring distinct effects on c-acon function potentially dictating changes in cytosolic citrate/isocitrate metabolism.


Outcomes in Pediatric Autoimmune Hepatitis and Significance of Azathioprine Metabolites.
Autoimmune hepatitis (AIH) is a common pediatric liver disease and long-term remission is usually maintained with azathioprine (AZA). There is no consensus on the target range for AZA active metabolite 6-thioguanine (6-TGN) levels in pediatric AIH. The aim of the present study was to characterize the outcomes of pediatric patients with AIH and determine correlations between AZA dosing or 6-TGN metabolite levels and biochemical remission. A retrospective chart review was performed and data on presentation, laboratories including AZA metabolite levels, medication use, and outcomes were collected. Between 2002 and 2013, 66 children with AIH were identified (mean age at diagnosis 9.6 ± 5.1 years) with a mean follow-up period of 2.9 ± 3.2 years. Common presenting symptoms included jaundice, fatigue, and abdominal pain. The majority of subjects received steroids for induction and AZA for maintenance of remission. Seventy-nine percent achieved biochemical remission (mean time to remission 6.2 ± 9.2 months), 14% were in the induction phase of therapy, 6% required liver transplantation, and 18% were weaned off immunosuppression and remained in remission. 6-TGN levels ranging from 50 to 250 pmol/8 × 10 red blood cell count were associated with biochemical remission (alanine aminotransferase levels of ≤50 U/L). The vast majority of children with AIH maintain a sustained remission with AZA monotherapy. Biochemical remission was maintained with 6-TGN levels much lower than that recommended for inflammatory bowel disease. These findings suggest that patients should be maintained at the lowest AZA dose possible that is associated with biochemical remission.


Radiosurgery of residual and recurrent vestibular schwannomas.
Radiosurgery is either a primary or an adjunctive management approach used to treat patients with vestibular schwannomas. We sought to determine outcomes measuring the potential benefits against the neurological risks in patients who underwent radiosurgery after previous microsurgical subtotal resection or recurrence of the tumour after total resection. Gamma Knife radiosurgery was applied as an adjunctive treatment modality for 86 patients with vestibular schwannomas from April 1992 to August 2001. We evaluated the results of 50 patients who had a follow-up of at least 3.5 years (median 75 months, range 42-114 months). In 16 patients a recurrence of disease was observed after previous total resection. The median treatment volume was 3.4 ccm with a median dose to the tumour margin of 13 Gy. Tumour control rate was 96%. Two tumours progressed after adjunctive radiosurgery. Useful hearing (Gardner-Robertson II) (4 patients (8%)) and residual hearing (Gardner-Roberson III) (10 patients (20%)) remained unchanged in all patients, who presented with it before radiosurgery, respectively. Clinical neurological improvement was observed in 24 patients (46%). Adverse effects comprised transient neurological symptoms and signs (incomplete facial palsy, House-Brackman II/III) in five cases (recovered completely), mild trigeminal neuropathy in four cases, and morphological changes displaying rapid enlargement of a pre-existing macrocyst in one patient and tumour growth in another one. No permanent new cranial nerve deficit was observed. Radiosurgery appears to be an effective adjunctive method for growth control of vestibular schwannomas and is associated with both a low mortality rate and a good quality of life. Accordingly, radiosurgery is a rewarding therapeutic approach for the preservation of cranial nerve function in the management of patients with vestibular schwannoma in whom prior microsurgical resection failed.


Dentinal Microcrack Development after Canal Preparation: A Longitudinal in Situ Micro-computed Tomography Study Using a Cadaver Model.
The purpose of this study was to evaluate the development of dentinal microcracks after root canal preparation with Reciproc and ProTaper Universal systems using an in situ cadaver model by means of a micro-computed tomography (micro-CT) imaging system. At autopsy, 8 maxillary bone blocks having at least the first and second premolar teeth (n = 16) were excised, scanned at a resolution of 13.18 μm, and randomly distributed into 2 groups (n = 8) according to the preparation protocol: Reciproc and ProTaper Universal systems. Root canals were prepared up to R25 and F2 instruments in the Reciproc and ProTaper Universal groups, respectively. After the preparation procedures, the specimens were scanned again, and the registered preoperative and postoperative cross-section images of the roots (n = 19,060) were screened to identify the presence of dentinal defects. In the Reciproc group, 9176 cross-section images were analyzed, and no crack was observed. In the ProTaper Universal group, 244 of 9884 cross-section slices (2.46%) had dentinal defects; however, all defects were already present in the corresponding preoperative images, indicating that no new microcrack was created after canal preparation. In situ root canal preparation of maxillary premolars with Reciproc and ProTaper Universal systems did not induce the formation of dentinal microcracks in a cadaver model as observed by micro-CT.


[Gene expression profile of medullary thyroid carcinoma--preliminary results].
Medullary thyroid carcinoma occurs both as a sporadic and a familial disease. Inherited MTC (iMTC) patients usually exhibit better prognosis than patients with sporadic form of MTC (sMTC), however, in both subtypes the outcome is unpredictable. No molecular markers contributing to the prognosis or predicting the type of therapy have been introduced to clinical practice until now. The aim of this study was to analyze gene expression pattern of MTC by high density oligonucleotide microarray. 24 samples were studied: 12 MTC and 12 corresponding normal tissues, (Affymetrix HG-U 133A). Among MTC patients there were half inherited cases and half sporadic ones. First, the differences between MTC and thyroid tissue were analyzed by Singular Value Decomposition (SVD) which indicated three main modes determining the variability of gene expression profile: the first two were related to the tumor/normal tissue difference and the third one was related to the immune response. The characteristic expression pattern, beside of numerous changes within cancer- related genes, included many up-regulated genes specific for thyroid C cells. Further analysis of the second component revealed two subgroups of MTC, but the subdivision was not related to the iMTC/sMTC difference. Recursive Feature Replacement (RFR) confirmed the very similar expression profile in both forms of MTC. With subsequent ANOVA analysis some genes with differential expression could be specified, among them monoamine oxidase B (MAOB) and gamma-aminobutyric acid receptor (GABRR1) which were consistently up-regulated in sMTC. In contrary, some genes involved in regulation of cell proliferation: opioid growth factor receptor(OGFR) and synaptotagmin V (SYT 5) were up-regulated in iMTC. The obtained data indicate a very similar gene expression pattern in inherited and sporadic MTC. Minor differences in their molecular profile require further analysis.


The effect of ascorbic acid supplementation on the blood lead levels of smokers.
The study subjects were 75 adult men (20 to 30 years of age), who smoked one pack of cigarettes per day (minimum) and had no clinical signs of ascorbic acid deficiency or lead toxicity. None had a history of industrial exposure to lead, and the blood-lead levels were anticipated to be below 1.45 micromol/L, the minimum blood level associated with toxicity symptoms. The men were randomly assigned to three study groups of 25, and each group was provided a four-week supply of one level of daily ascorbic acid supplements (placebo, 200 mg or 1000 mg of ascorbic acid). We measured baseline and weekly serum and urine ascorbic-acid levels as well as blood and urine lead levels. The weekly group means and variations of the measured data were statistically compared by means of ANOVA and Pearson's correlation. The serum ascorbic-acid levels of the groups receiving ascorbic acid increased significantly after one week (p< or =.001). There was no effect of placebo or 200 mg ascorbic-acid supplementation on the blood or urine lead levels. However, there was a 81% decrease in blood-lead levels in the 1000 mg ascorbic acid group after one week of supplementation (p< or =.001). Daily supplementation with 1000 mg of ascorbic acid results in a significant decrease of blood-lead levels associated with the general population. Ascorbic acid supplementation may provide an economical and convenient method of reducing blood-lead levels, possibly by reducing the intestinal absorption of lead.


Role of exponential apparent diffusion coefficient in characterizing breast lesions by 3.0 Tesla diffusion-weighted magnetic resonance imaging.
To evaluate the role of exponential apparent diffusion coefficient (ADC) as a tool for differentiating benign and malignant breast lesions. This prospective observational study included 88 breast lesions in 77 patients (between 18 and 85 years of age) who underwent 3T breast magnetic resonance imaging (MRI) including diffusion-weighted imaging (DWI) using b-values of 0 and 800 s/mm2 before biopsy. Mean exponential ADC and ADC of benign and malignant lesions obtained from DWI were compared. Receiver operating characteristics (ROC) curve analysis was undertaken to identify any cut-off for exponential ADC and ADC to predict malignancy. P value of <0.05 was considered statistically significant. Histopathology was taken as the gold standard. According to histopathology, 65 lesions were malignant and 23 were benign. The mean ADC and exponential ADC values of malignant lesions were 0.9526 ± 0.203 × 10-3 mm2/s and 0.4774 ± 0.071, respectively, and for benign lesions were 1.48 ± 0.4903 × 10-3 mm2/s and 0.317 ± 0.1152, respectively. For both the parameters, differences were highly significant (P < 0.001). Cut-off value of ≤0.0011 mm2/s (P < 0.0001) for ADC provided 92.3% sensitivity and 73.9% specificity, whereas with an exponential ADC cut-off value of >0.4 (P < 0.0001) for malignant lesions, 93.9% sensitivity and 82.6% specificity was obtained. The performance of ADC and exponential ADC in distinguishing benign and malignant breast lesions based on respective cut-offs was comparable (P = 0.109). Exponential ADC can be used as a quantitative adjunct tool for characterizing breast lesions with comparable sensitivity and specificity as that of ADC.


The role of iron in the activation of mannonic and altronic acid hydratases, two Fe-requiring hydro-lyases.
D-Altronate hydratase and D-mannonate hydratase belong to a class of Fe2+-requiring enzymes, but the function of iron in these enzymes is largely unknown. Methods are described for the convenient preparation of both these hydratases from Escherichia coli and studies related to metal activation are presented. The enzymes are inactive in the absence of a bivalent metal and a reducing agent such as dithiothreitol. Fe2+ at low concentrations activates the enzymes efficiently, but inhibits them over 2 mM. Furthermore Mn2+ is also capable of activating aldonic acid hydratases and appears to be a constituent of the enzyme active center. A marked synergistic activation is observed in the presence of both ions, raising the possibility that the enzyme has two binding sites for ions. Upon activation, the two aldonic acid hydratases incorporate a single Fe atom and contain no Fe-S core, in contrast to other characterized Fe-hydratases, such as aconitase or maleic acid hydratase. The incorporated iron is losely bound (with Kd about 4.5 mM and 20 mM for mannonate and altronate hydratase, respectively) and can be readily removed with EDTA. The enzymes exhibit no requirement for sulphide ions and are insensitive to thiol reagents. A first-order inhibition is observed with iron chelators and can be removed by competition with excess metal ions. No change in the absorption spectra is observed upon oxidation-reduction or activation with metals. The activated enzymes exhibit no electron paramagnetic (EPR) spectrum under anaerobic conditions; in the presence of oxygen, an intense EPR spectrum develops in Fe2+-activated samples with signal at g = 1.98, which upon reaction of the enzyme with the substrate moves into a species with signals at g = 4.15 and g = 9.07, with EPR parameters very similar to those of oxidized rubredoxins.


Fifty years of language maintenance and language dominance in bilingual Hispanic immigrants.
Spanish language tests of 801 Cuban and Mexican immigrants showed no evidence of language loss during 50 years of U.S. residence; a few years after immigration, their English vocabulary approximated that of English monolinguals. The critical-age hypothesis was not supported for the acquisition of English vocabulary when English schooling and language usage were controlled by multiple regression. Most Ss continued to speak about as much Spanish as English; but read, wrote, and heard (on television and radio) far more English than Spanish. Under these conditions, Ss maintained Spanish dominance on tests of vocabulary recognition, lexical decision, and oral comprehension. Dominance was task specific and shifted to English on a category generation task about 12 years after immigration. No evidence of bilingual language interference was found; this is attributed to the strong Spanish foundation of the participants.


The aesthetic unit principle of facial aging.
In youth, facial aesthetic units flow together without perceptible division. The face appears as a single dynamic structure with a smooth contour and very little if any shadowing between different anatomical regions. As one ages, facial aesthetic units slowly become distinct. This process may be a consequence of differences in skin thickness, composition of subcutaneous tissue, contour of the facial skeleton, and location of facial ligaments. Although the impact of aesthetic unit separation is clinically apparent, its fundamental role in perceived facial aging has not yet been defined empirically. To evaluate and define the effect of aesthetic unit separation on facial aging and to empirically validate the rationale for the blending of aesthetic units as a principle for facial rejuvenation. We prepared the photographs of 7 women for experimental evaluation of the presence or absence of facial aesthetic unit separation. Photographic stimuli were then presented to 24 naive observers in a blinded paired comparison. For each stimulus pair, observers were asked to select the facial photograph that they considered to be more youthful in appearance. Each stimulus was compared with all others. We calculated a preference score for the total number of times any photograph was chosen to be more youthful compared with all others. Paired t tests were used to compare the preference scores between the facial stimuli with and without aesthetic unit separation. We generated 4032 responses for analysis. Photographs without facial aesthetic unit separation were consistently judged to be more youthful than their aged original or modified counterparts, with mean preference scores of 0.66 and 0.33, respectively (P ≤ .047). When we selected the paired stimulus that directly compared one photograph with aesthetic unit separation with another with blended aesthetic units (2015 pairs), observers indicated that the photograph with the blended aesthetic unit was younger 95% of the time. Within-rater reliability was found to be very good (r = 0.88). Our data support the hypothesis that facial aesthetic unit separation influences perceived facial youthfulness among photographs of women. The presence of facial aesthetic unit separation results in a less youthful appearance. Based on these empirical data, the concept of facial aesthetic unit separation appears to play a significant role in perceived facial aging. NA.


The Relationship Between Autophagy and Brain Plasticity in Neurological Diseases.
Autophagy, a catabolic degradation system, is utilized for destroying and recycling the damaged or unnecessary cellular components. Brain plasticity refers to the remarkable characteristics of brain neurons that change their structure and function according to previous experience. This review was performed by searching the relevant articles in databases of SCIENCEDIRECT, PUBMED, and Web of Science, from respective inception to January 2019. Here, we review the neuroprotective effect of autophagy in neurological diseases and the mechanism of autophagy in brain plasticity. Moreover, the mechanism of autophagy in the process of brain plasticity can provide the possibility for the development of new treatment methods in the future, thus benefiting patients with neurological diseases. In summary, autophagy and brain plasticity play important roles in neurological diseases.


Heteropolyacid-Containing Ionic Liquid-Catalyzed Multicomponent Synthesis of Bridgehead Nitrogen Heterocycles: Mechanisms and Mitochondrial Staining.
The current manuscript describes the use of a heteropolyacid-containing task-specific ionic liquid, supported in imidazolium-based ionic liquids, as the catalyst for an efficient multicomponent synthesis of hexahydroimidazo[1,2-α]pyridine derivatives. The reactions conditions were fully optimized, and the bridgehead nitrogen heterocycle derivatives could be obtained in just 1 h exclusively as a single isomer ( trans). Single crystal X-ray analysis confirmed the trans derivative as the only isomer. The mechanism of the reaction was investigated by ESI(+)-MS(/MS), and the use of the elegant charge-tag strategy allowed a catalytic cycle to be proposed for the current transformation and revealed the possibility of at least two reaction pathways. One derivative bearing a coumarin scaffold was synthesized, and its fluorescent properties allowed it to be tested as a probe for live-cell imaging experiments with a preference for mitochondria.


Susceptibility of Meningococcal Strains Responsible for Two Serogroup B Outbreaks on U.S. University Campuses to Serum Bactericidal Activity Elicited by the MenB-4C Vaccine.
In 2013 and 2014, two U.S. universities had meningococcal serogroup B outbreaks (a total of 14 cases) caused by strains from two different clonal complexes. To control the outbreaks, students were immunized with a serogroup B meningococcal vaccine (Novartis) that was not yet licensed in the United States. The vaccine (referred to as MenB-4C) contains four components capable of eliciting bactericidal activity. Both outbreak strains had high expression levels of two of the vaccine antigens (subfamily B factor H binding protein [FHbp] and neisserial heparin binding antigen [NHba]); the university B outbreak strain also had moderate expression of a third antigen, NadA. We investigated the bactericidal activity of sera from mice immunized with FHbp, NHba, or NadA and sera from MenB-4C-immunized infant macaques and an adult human. The postimmunization bactericidal activity of the macaque or human serum against isolates from university B with FHbp identification (ID) 1 that exactly matched the vaccine FHbp sequence variant was 8- to 21-fold higher than that against isolates from university A with FHbp ID 276 (96% identity to the vaccine antigen). Based on the bactericidal activity of mouse antisera to FHbp, NadA, or NHba and macaque or human postimmunization serum that had been depleted of anti-FHbp antibody, the bactericidal activity against both outbreak strains largely or entirely resulted from antibodies to FHbp. Thus, despite the high level of strain expression of FHbp from a subfamily that matched the vaccine antigen, there can be large differences in anti-FHbp bactericidal activity induced by MenB-4C vaccination. Further, strains with moderate to high NadA and/or NHba expression can be resistant to anti-NadA or anti-NHba bactericidal activity elicited by MenB-4C vaccination.


Fetal behavior assessed in all three trimesters of normal pregnancy by four-dimensional ultrasonography.
To assess fetal behavior in all three trimesters of normal pregnancy and to investigate the continuation of behavior from fetal to neonatal period. One hundred out of 130 pregnant women in all trimesters with singleton pregnancy were assigned for the investigation. All recordings were performed in the morning, after two hours of fasting. Video recordings of newborns were made while the newborns were in bed, separated from other infants in the nursery, dressed, and lying on their backs in a supine position with unrestrained hands. Recording was not performed during prolonged episodes of fussing and crying, during drowsiness, and episodes of hiccupping. All observed facial expressions and movement patterns were presented collectively with maximum, minimum, and median frequencies during 30-minute observation period. We noted a tendency towards decreased frequency of facial expressions and movement patterns with increasing gestational age. In the first trimester, we observed the highest incidence of general movements ranging between 5 and 147, and with a median value of 47. In the second trimester, the number of head and hand movements decreased gradually, compared with the first trimester. The highest range was registered for head retroflexion pattern, ranging from 15 to 42 with a median of 25. The most frequent facial pattern in the second trimester was sucking (3 and 30 movements per infant with a median value of 9). Wilcoxon rank-sum test showed statistically significant differences between the fetuses in the third trimester and the newborns (P<0.05) in hand to head, hand to mouth, hand to eye, hand to ear movement), tongue expulsion, and smiling, whereas the differences between the rest of the movements were not statistically significant. Spearman rank order correlation reached statistical significance (P<0.05) in isolated eye blinking, smiling, grimacing, hand to head, hand to mouth, hand to eye, hand to face, and in hand to ear movement, whereas the differences between the rest of the facial expressions were not statistically significant. Fetal behavioral patterns directly reflect the developmental and maturational processes of the central nervous system. 4D observation of fetal and early neonatal period may add to better understanding of the neurological development of the fetus.


Recombinant interferon-alpha-2b treatment of hairy-cell leukaemia: experience with a low-dose schedule.
50 patients with hairy cell leukaemia (HCL) were treated with recombinant interferon (IFN) alpha-2b 2.0 x 10(6) IU/m2 subcutaneously three times weekly to evaluate the efficacy of low-dose IFN therapy in inducing and maintaining remission of the disease. At the time of this report 48 patients, of whom 22 were splenectomized, had been treated for at least 3 months and were considered evaluable for response. The median observation time on IFN-alpha-2b was 11 months (range 3 to 20). 4 cases with atypical disease (spongy lymphoid myelofibrosis) were also included. All patients responded to IFN. After 3 months 11/48 patients (23%) had achieved a partial remission (PR) with normalization of peripheral blood values. After 6 months 27/43 patients (63%) had achieved a favourable response; complete remission (CR) was recorded in 4 and PR in 23 patients. The proportion of patients with favourable responses (CR + PR) increased with the duration of therapy and after 12 months of therapy 23/28 (82%) patients showed CR or PR, 9 patients (32%) being in CR. Splenectomized patients disclosed a trend towards a more rapid response. It is concluded that IFN-alpha-2b is a highly effective first-line therapy for HCL.


Talon cusp associated with other dental anomalies: a case report.
Talon cusp is an uncommon dental anomaly referring to an accessory cusp projecting from the cingulum area, or cemento-enamel junction of maxillary or mandibular anterior teeth, in both the primary and permanent dentition. This paper reports a rare case of talon cusp affecting the mandibular right central incisor and maxillary right lateral incisor, together with other dental abnormalities, viz. an inverted impacted migrating mandibular right second premolar; complete agenesis of the maxillary and mandibular third molars, the maxillary right second permanent molar, and the mandibular left permanent central incisor; severe crowding; deep bite; hypoplastic teeth; bilateral reverse cross-bite in the premolar region; and a retrognathic mandible. The presence of this number of dental anomalies in a single patient is rare.


Sudden death due to ruptured pancreaticoduodenal artery aneurysm.
Superior pancreaticoduodenal artery aneurysms are rare; their rupture often leads to sudden death. We report a case of a 59-year-old hypertensive man who died of a massive retroperitoneal hemorrhage following rupture of an aneurysm of the superior pancreaticoduodenal artery. We also discuss this unusual vascular lesion and review the pertinent literature.


Comparison of different extraction methods: steam distillation, simultaneous distillation and extraction and headspace co-distillation, used for the analysis of the volatile components in aged flue-cured tobacco leaves.
Steam distillation (SD), simultaneous distillation and extraction (SDE) and headspace co-distillation (HCD) were compared here for their effectiveness in the extraction of volatile compounds from tobacco. The different grades of aged flue-cured tobacco leaves extracted by the three methods respectively were analyzed using GC-MS. Mass spectra or authentic compounds were used to identify around 408 components in various volatile fractions. On the one hand, the qualitative comparison showed that more compounds were detected in HCD extract (391 components) than in SDE extract (377 components), and the approximately quantitative analysis showed that the total amount of volatile components in SDE extract (445.48 microg/g) was much more than that in HCD extract (315.72 microg/g). But on the other hand, HCD was the most efficient for nearly all the highly volatile compounds among the three methods. As to low-volatile compounds such as lactones, long chain aldehydes, ketones, alcohols, and esters, more was detected in SDE extract than in HCD extract. The SD method (322 components, total amount 228.42 microg/g) was the lowest sensitive to all compounds except semi-volatile fatty acids among the three methods.


Ocean acidification reduces sperm flagellar motility in broadcast spawning reef invertebrates.
Ocean acidification is now recognized as a threat to marine ecosystems; however, the effect of ocean acidification on fertilization in marine organisms is still largely unknown. In this study, we focused on sperm flagellar motility in broadcast spawning reef invertebrates (a coral and a sea cucumber). Below pH 7.7, the pH predicted to occur within the next 100 years, sperm flagellar motility was seriously impaired in these organisms. Considering that sperm flagellar motility is indispensable for transporting the paternal haploid genome for fertilization, fertilization taking place in seawater may decline in the not too distant future. Urgent surveys are necessary for a better understanding of the physiological consequences of ocean acidification on sperm flagellar motility in a wide range of marine invertebrates.


The reverse shoulder prosthesis (Delta III) in acute shoulder fractures: technical considerations with respect to stability.
The reverse shoulder prosthesis reverses the relationship between the scapular and humeral component, resulting in a mechanical advantage as the deltoid muscle is able to compensate for the rotator cuff deficiency. Based on this mechanical advantage, the reverse shoulder prosthesis has become an accepted alternative for the treatment of complex proximal humeral fractures. The purpose of this article is to discuss technical considerations related to stability in the use of the reverse shoulder prosthesis in acute shoulder fractures, based on clinical experience.


Myeloid differentiation factor 88 is up-regulated in epileptic brain and contributes to experimental seizures in rats.
Accumulating evidence supports that activation of inflammatory pathways is a crucial factor contributing to the pathogenesis of seizures. In particular, the activation of interleukin-1 beta (IL-1β) system exerts proconvulsant effects in a large variety of seizure models. Myeloid differentiation factor 88 (MyD88) is a critical adaptor protein in the signaling cascade elicited by IL-1β. The present study aimed to investigate the expression pattern of MyD88 in rat models of seizures and in patients with refractory temporal lobe epilepsy (TLE), and to study the role of MyD88 in epileptic seizures. Our results revealed that MyD88 was up-regulated in the hippocampus of rats in the lithium-pilocarpine model of acute seizures. Importantly, MyD88 overexpression was also significantly present in the brain from chronic epileptic rats and the temporal neocortex specimens from drug-resistant TLE patients. In the acute seizure model, both the behavioral and electrographic seizure activities were record and analyzed in rats for 90min, starting immediately after pilocarpine injection. ST2825, a synthetic MyD88 inhibitor, was administered intracerebroventricularly (2.5-5.0-10μg in 2μl) 20min before pilocarpine injection. We found that ST2825 at doses of 5μg and 10μg significantly inhibited the pilocarpine-induced behavioral and electrographic seizures. Moreover, 10μg ST2825 prevented the proconvulsant actions of IL-1β. As previous evidence suggested that IL-1β proconvulsant effects was mediated by enhancing the phosphorylation level of the NR2B subunit of N-methyl-d-aspartate (NMDA) receptor, we then probed whether this molecular was involved in the effect of the pharmacological inhibition. Our results revealed that 10μg ST2825 markedly reversed the increased Tyr1472-phosphorylation of the NR2B subunit of NMDA receptor observed in the proconvulsant conditions of IL-1β and in seizures induced by pilocarpine alone. These findings indicate that altered expression of MyD88 might contribute to the pathogenesis of seizures and targeting of this adaptor protein might represent a novel therapeutic strategy to suppress seizure activities.


ISCL: Interdependent Self-Cooperative Learning for Unpaired Image Denoising.
With the advent of advances in self-supervised learning, paired clean-noisy data are no longer required in deep learning-based image denoising. However, existing blind denoising methods still require the assumption with regard to noise characteristics, such as zero-mean noise distribution and pixel-wise noise-signal independence; this hinders wide adaptation of the method in the medical domain. On the other hand, unpaired learning can overcome limitations related to the assumption on noise characteristics, which makes it more feasible for collecting the training data in real-world scenarios. In this paper, we propose a novel image denoising scheme, Interdependent Self-Cooperative Learning (ISCL), that leverages unpaired learning by combining cyclic adversarial learning with self-supervised residual learning. Unlike the existing unpaired image denoising methods relying on matching data distributions in different domains, the two architectures in ISCL, designed for different tasks, complement each other and boost the learning process. To assess the performance of the proposed method, we conducted extensive experiments in various biomedical image degradation scenarios, such as noise caused by physical characteristics of electron microscopy (EM) devices (film and charging noise), and structural noise found in low-dose computer tomography (CT). We demonstrate that the image quality of our method is superior to conventional and current state-of-the-art deep learning-based unpaired image denoising methods.