Targeting signal transduction pathways of cancer stem cells for therapeutic opportunities of metastasis.
Tumor comprises of heterogeneous population of cells where not all the disseminated cancer cells have the prerogative and "in-build genetic cues" to form secondary tumors. Cells with stem like properties complemented by key signaling molecules clearly have shown to exhibit selective growth advantage to form tumors at distant metastatic sites. Thus, defining the role of cancer stem cells (CSC) in tumorigenesis and metastasis is emerging as a major thrust area for therapeutic intervention. Precise relationship and regulatory mechanisms operating in various signal transduction pathways during cancer dissemination, extravasation and angiogenesis still remain largely enigmatic. How the crosstalk amongst circulating tumor cells (CTC), epithelial mesenchymal transition (EMT) process and CSC is coordinated for initiating the metastasis at secondary tissues, and during cancer relapse could be of great therapeutic interest. The signal transduction mechanisms facilitating the dissemination, infiltration of CSC into blood stream, extravasations, progression of metastasis phenotype and angiogenesis, at distant organs, are the key pathologically important vulnerabilities being elucidated. Therefore, current new drug discovery focus has shifted towards finding "key driver genes" operating in parallel signaling pathways, during quiescence, survival and maintenance of stemness in CSC. Understanding these mechanisms could open new horizons for tackling the issue of cancer recurrence and metastasis-the cause of ~90% cancer associated mortality. To design futuristic & targeted therapies, we propose a multi-pronged strategy involving small molecules, RNA interference, vaccines, antibodies and other biotechnological modalities against CSC and the metastatic signal transduction cascade.


[Difference analysis on proteome of Helicobacter pylori in patients with peptic ulcer, gastritis, and gastric cancer].
To identify the different proteins of Helicobacter pylori (H. pylori) in gastric cancer, peptic ulcer, and gastritis initially. H. pylori in the endoscopic biopsy specimens of gastric mucosa of patients with gastric cancer, peptic ulcer, or gastritis, 3 specimens for each disease, were separated and cultured. The whole-cell protein of the H. pylori was extracted by lysis buffer and sonication. The protein concentration of the bacteria cell lysates was measured by the Bradford method. The protein maps of H. pylori were obtained by two-dimensional gel electrophoresis (2-DE) and the different proteins in gastric cancer, peptic ulcer and gastritis were analyzed by Image Master v 5.0. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-Q-TOF-MS) were performed to identify the different proteins. The differential proteins were searched by the Mascot database at www.matrixscience.com. Four protein spots of H. pylori were over-expressed in the protein maps from gastric cancer in comparison with those from peptic ulcer and gastritis. Mass identification showed that the 4 proteins were thioredoxin, adenylate kinase, single-stranded DNA-binding protein, and ribosomal protein 50S L7/L12, with the Mowse scores of 94, 286, 139 and 132, and with the sequence coverage rates of 77%, 33%, 33%, and 28% respectively. Anti-oxidant and inhibiting apoptosis, thioredoxin may be related to gastric carcinogenesis induced by H. pylori. Proteomics technology has a widespread perspective in the field of relationship between pathogenic bacteria and gastric cancer.


Sevoflurane Inhibits Traumatic Brain Injury-Induced Neuron Apoptosis via EZH2-Downregulated KLF4/p38 Axis.
Traumatic brain injury (TBI) is characterized by physical damage to the brain tissues, ensuing transitory or permanent neurological dysfunction featured with neuronal loss and subsequent brain damage. Sevoflurane, a widely used halogenated anesthetic in clinical settings, has been reported to alleviate neuron apoptosis in TBI. Nevertheless, the underlying mechanism behind this alleviation remains unknown, and thus was the focus of the current study. First, Feeney models were established to induce TBI in rats. Subsequently, evaluation of the modified neurological severity scores, measurement of brain water content, Nissl staining, and TUNEL assay were employed to investigate the neuroprotective effects of sevoflurane. Immunofluorescence and Western blot analysis were further applied to detect the expression patterns of apoptosis-related proteins as well as the activation of the p38-mitogen-activated protein kinase (MAPK) signaling pathway within the lesioned cortex. Additionally, a stretch injury model comprising cultured neurons was established, followed by neuron-specific enolase staining and Sholl analysis. Mechanistic analyses were performed using dual-luciferase reporter gene and chromatin immunoprecipitation assays. The results demonstrated sevoflurane treatment brought about a decrease blood-brain barrier (BBB) permeability, brain water content, brain injury and neuron apoptosis, to improve neurological function. The neuroprotective action of sevoflurane could be attenuated by inactivation of the p38-MAPK signaling pathway. Mechanistically, sevoflurane exerted an inhibitory effect on neuron apoptosis by up-regulating enhancer of zeste homolog 2 (EZH2), which targeted Krüppel-like factor 4 (KLF4) and inhibited KLF4 transcription. Collectively, our findings indicate that sevoflurane suppresses neuron apoptosis induced by TBI through activation of the p38-MAPK signaling pathway via the EZH2/KLF4 axis, providing a novel mechanistic explanation for neuroprotection of sevoflurane in TBI.


Development and validation of RP-HPLC method to determine anti-allergic compound in Thai traditional remedy called Benjalokawichien.
Benjalokawichien (BLW) or Ya-Ha-Rak (HR) is a traditional remedy in the Nationaldrug list of herbal medicinal products AD 2012 of Thailand. For traditional use, BLW is used as antipyretic agent. It also has anti-allergic effect, particularly treating allergic rash. The ethanolic extract of BLW exhibited anti-allergic activity via inhibitory effect against a release ofbeta-hexosaminidase in RBL-2H3 cell line. Pectolinarigenin has been identified as the active compound ofBLW extract. In this study, a reversed-phase high performance liquid chromatography (RP-HPLC) method was developed in order to control quality ofpreparation in three aspects such as chemical fingerprint, quantification and stability of the ethanolic extract. The RP-HPLC was performed with a gradient mobile phase composed of 0.1% ortho phosphoric acid and acetronitrile, and peaks were detected at 331 nm. Based on validation results, this analytical method is precise, accurate and stable for quantitative determination ofpectolinarigenin. The amount ofpectolinarigenin in Benjalokawichien extract determined by this method was 18.50 mg/g ofextract. Therefore, this method could be consideredfor quality control ofBLWextract.


[Acute myocardial infarction with ST-segment elevation: Code I].
Code infarction is a timely strategy for the treatment of acute myocardial infarction (AMI) with elevation of the ST segment. This strategy has shown an increase in survival and quality of life of patients suffering from this event around the world. The processes of management and disposition aimed at the reduction of time for effective and timely reperfusion are undoubtedly a continuous challenge. In the Instituto Mexicano del Seguro Social (IMSS) the mortality due to AMI has been reduced more than 50%, which is a historical situation that deserves much attention. Nonetheless, the continuous improvement and a wider coverage of this strategy in our country are the key factors that will outline a change in the natural history of the leading cause of death in Mexico. This review focuses on current strategies for the management of patients with acute myocardial infarction.


Developmental programming of obesity by maternal exposure to concentrated ambient PM2.5 is maternally transmitted into the third generation in a mouse model.
Obesity is an uncontrolled global epidemic and one of the leading global public health challenges. Maternal exposure to ambient fine particulate matter (PM2.5) may adversely program offspring's adiposity, suggesting a specialized role of PM2.5 pollution in the global obesity epidemic. However, the vulnerable window for this adverse programming and how it is cross-generationally transmitted have not been determined. Therefore, in the present study, female C57Bl/6 J mice were exposed to filtered air (FA) or concentrated ambient PM2.5 (CAP) during different periods, and the development and adulthood adiposity of their four-generational offspring were assessed. Our data show that the pre-conceptional but not gestational exposure to CAP was sufficient to cause male but not female offspring's low birth weight, accelerated postnatal weight gain, and increased adulthood adiposity. These adverse developmental traits were transmitted into the F2 offspring born by the female but not male F1 offspring of CAP-exposed dams. In contrast, no adverse development was noted in the F3 offspring. The present study identified a pre-conceptional window for the adverse programming of adiposity by maternal exposure to PM2.5, and showed that it was maternally transmitted into the third generation. These data not only call special attention to the protection of women from exposure to PM2.5, but also may facilitate the development of intervention to prevent this adverse programming.


Recent developments in federal reimbursement for home health-care services and products.
The current status of reimbursement for home health-care (HHC) products and services is described, and the influence of competition and consolidation on the HHC industry is discussed. Despite inadequate financing and reimbursement pressures, the demand for HHC services continues to grow. The degree of competition in the HHC industry is reflected in bundling of services (gathering payments for services into a single per-capita rate), prospective price negotiations, and competitive bidding. This competition within the home-care industry and pressure on operating margins have spawned a flurry of recent mergers, acquisitions, and corporate restructuring. HHC agencies and suppliers, particularly durable medical equipment suppliers, have been squeezed by inadequate Medicare cost-finding methods, low reimbursement rates, and a high number of denials of Medicare coverage. Three important recent federal measures revised definitions of Medicare coverage, established minimum and maximum payment periods for Medicare reimbursement, reduced payments for services and products covered under Medicare Parts A and B, resurrected prospective-pricing demonstration projects, reduced payments for durable medical equipment and home oxygen supplies, and expanded coverage of services for AIDS patients. State Medicaid program budgets are threatened by recurring administration proposals to cap federal matching payments and by the adoption of a competitive-bid approach to health-care contracting. To survive over the next few years, home health agencies and home-care suppliers will need to monitor operating costs even more closely and pay attention to the patient (payer) mix.


Two-dimensional echocardiographic demonstration of acute myocardial depression in septic shock.
A 50-yr-old woman exhibiting streptococcal neck cellulitis developed severe septic shock with low cardiac output, which was reversed by infusion of dopamine plus dobutamine. Two-dimensional echocardiography performed at the bedside demonstrated severe myocardial failure. The patient's condition remained dependent on inotropic drug support for 2 days and ultimately improved. Two-dimensional echocardiography repeated on the fourth day corroborated the disappearance of transient myocardial failure.


Well-Being in Highly Hypnotizable Persons.
Both hypnotizability and well-being are relevant to health. This study aimed to investigate whether high hypnotizability was positively associated with well-being and whether the latter was related to the activity of the behavioral inhibition/approach system (BIS/BAS). ANOVA revealed significantly higher scores on the General Well-Being Index (PGWBI) in highly hypnotizable (highs, n = 31) compared with low hypnotizable participants (lows, n = 53), with medium hypnotizable participants (mediums, n = 41) exhibiting intermediate values. This finding was discussed in relation to other hypnotizability-related traits, such as morpho-functional brain characteristics, equivalence between imagery and perception, and interoceptive sensitivity. A secondary finding was a nonsignificant gender difference in scores on the PGWBI. The highs' higher well-being could be considered a favorable prognostic factor for physical and mental health.


[TRADITIONAL CHINESE MEDICINE IN TREATMENT OF ATOPIC DERMATITIS].
Atopic dermatitis is a common chronic inflammatory skin disease, affecting up to 15-30% of children in industrialized countries. As there is no definitive cure for atopic dermatitis, patients often seek other complementary therapeutic options, such as traditional Chinese medicine (TCM). TCM comprises numerous treatment modalities for the management of atopic dermatitis including acupuncture and herbal medicine. We report a case of a two and a half year old child with atopic dermatitis exacerbation treated successfully with TCM. During the treatment, we observed gradual decreases in symptoms with complete disappearance of dermatological complaints following 4 months of treatment. There is considerable evidence suggesting a benefit in the use of TCM for the treatment of atopic dermatitis. As the current state of evidence of TCM treatment for atopic dermatitis remains unknown, further studies should be conducted before definite guidelines can be published. The use of TCM has become increasingly popular among children with atopic dermatitis, as clinical evidence report efficacy in improving quality of life and symptoms severity, along with reduction of topical corticosteroid use. Yet, this data is inconclusive, as studies are not randomized double blind controlled.


Direct eye gaze enhances the ventriloquism effect.
The "ventriloquism effect" describes an illusory phenomenon where the perceived location of an auditory stimulus is pulled toward the location of a visual stimulus. Ventriloquists use this phenomenon to create an illusion where an inanimate puppet is perceived to speak. Ventriloquists use the expression and suppression of their own and the puppet's mouth movements as well the direction of their respective eye gaze to maximize the illusion. While the puppet's often exaggerated mouth movements have been demonstrated to enhance the ventriloquism effect, the contribution of direct eye gaze remains unknown. In Experiment 1, participants viewed an image of a person's face while hearing a temporally synchronous recording of a voice originating from different locations on the azimuthal plane. The eyes of the facial stimuli were either looking directly at participants or were closed. Participants were more likely to misperceive the location of a range of voice locations as coming from a central position when the eye gaze of the facial stimuli were directed toward them. Thus, direct gaze enhances the ventriloquist effect by attracting participants' perception of the voice locations toward the location of the face. In an exploratory analysis, we furthermore found no evidence for an other-race effect between White vs Asian listeners. In Experiment 2, we replicated the effect of direct eye gaze on the ventriloquism effect, also showing that faces per se attract perceived sound locations compared with audio-only sound localization. Showing a modulation of the ventriloquism effect by socially-salient eye gaze information thus adds to previous findings reporting top-down influences on this effect.


Clearance and Utilization of Dicarbonyl-Modified LDL in Monkeys and Humans.
The kinetics of elimination of various dicarbonyl-modified low-density lipoproteins from the bloodstream of Macaca mulatta monkeys were investigated. The low-density lipoproteins (LDL) in the monkey blood plasma were isolated by density gradient ultracentrifugation and labeled in vitro with the fluorescent dye FITC; thereupon, they were modified with different natural low molecular-weight dicarbonyls: malondialdehyde (MDA), glyoxal, or methylglyoxal. The control native FITC-labeled LDL and dicarbonyl-modified FITC-labeled LDL were injected into the monkey's ulnar vein; thereafter, blood samples were taken at fixed time intervals during 24 h. The plasma level of FITC-labeled LDL was determined with spectrofluorimetry. The study established that glyoxal- and monkeysglyoxal-labeled LDL circulated in monkey virtually at the same time as native (non-modified) LDL. In contrast, MDA-modified LDL disappeared from the blood extremely rapidly. Administration of the PCSK9 inhibitor involocumab (which increases LDL utilization) to patients with coronary heart disease (CHD) was found to significantly reduce levels of MDA-modified LDL.


Enhancing Cementitious Composites with Functionalized Graphene Oxide-Based Materials: Surface Chemistry and Mechanisms.
Graphene oxide-based materials (GOBMs) have been widely explored as nano-reinforcements in cementitious composites due to their unique properties. Oxygen-containing functional groups in GOBMs are crucial for enhancing the microstructure of cementitious composites. A better comprehension of their surface chemistry and mechanisms is required to advance the potential applications in cementitious composites of functionalized GOBMs. However, the mechanism by which the oxygen-containing functional groups enhance the response of cementitious composites is still unclear, and controlling the surface chemistry of GOBMs is currently constrained. This review aims to investigate the reactions and mechanisms for functionalized GOBMs as additives incorporated in cement composites. A variety of GOBMs, including graphene oxide (GO), hydroxylated graphene (HO-G), edge-carboxylated graphene (ECG), edge-oxidized graphene oxide (EOGO), reduced graphene oxide (rGO), and GO/silane composite, are discussed with regard to their oxygen functional groups and interactions with the cement microstructure. This review provides insight into the potential benefits of using GOBMs as nano-reinforcements in cementitious composites. A better understanding of the surface chemistry and mechanisms of GOBMs will enable the development of more effective functionalization strategies and open up new possibilities for the design of high-performance cementitious composites.


Reflections on IDEAL: What we have learnt from a unique calf cohort study.
The year 2020 marks a decade since the final visit was made in the 'Infectious Diseases of East African Livestock' (IDEAL) project. However, data generation from samples obtained during this ambitious longitudinal study still continues. As the project launches its extensive open-access database and biobank to the scientific community, we reflect on the challenges overcome, the knowledge gained, and the advantages of such a project. We discuss the legacy of the IDEAL project and how it continues to generate evidence since being adopted by the Centre for Tropical Livestock Genetics and Health (CTLGH). We also examine the impact of the IDEAL project, from the authors perspective, for each of the stakeholders (the animal, the farmer, the consumer, the policy maker, the funding body, and the researcher and their institution) involved in the project and provide recommendations for future researchers who are interested in running longitudinal field studies.


Extravascular closure for patients with high-risk femoral anatomy.
Vascular closure devices (VCDs) improve patient comfort and decrease time to ambulation. However, VCD studies have excluded patients with high-risk femoral artery anatomy; we examined the safety and efficacy of clip-based extravascular closure in this high-risk group. We performed a prospective registry enrolling 98 consecutive patients undergoing diagnostic coronary angiography. Inclusion criteria were femoral artery calcification, moderate femoral artery stenosis, or non-femoral arterial sheath insertion. All patients underwent immediate vessel closure with the Starclose device (Abbott Vascular). Patients with severe femoral arterial disease or femoral arterial diameter < or = 4.0 mm were excluded. Hospital outcomes were assessed prospectively and femoral arterial stenosis was determined by quantitative angiography. Inclusion was mainly related to at least one of 3 main high-risk characteristics: moderate femoral arterial stenosis (30%), femoral arterial calcification (24%) or nonfemoral sheath insertion (46%). The average femoral stenosis was 35.3 +/- 5.1% among patients included for a significant femoral disease. There was a 100% procedural and 94% device success: 1 patient required manual compression for greater than or equal to 30 minutes. The average time from sheath removal to hemostasis was 0.76 +/- 1.3 minutes. Despite the higher-risk anatomy, there were no major vascular complications and only one minor vascular complication. The average time to ambulation was 78.1 +/- 47.3 minutes. In this prospective registry, the Starclose VCD was safe and effective for early ambulation of patients despite the presence of high-risk femoral arterial anatomy.


Vestibular Migraine.
The co-occurrence between migraine and vertigo has been noticed for a long time ago. In recent years, however, growing numbers of epidemiological and clinical studies have definitely shown the significant relation between these two diseases. Recently, the term "vestibular migraine" is used commonly in studies. Vestibular migraine has taken place in appendix in the latest International Headache Society Classification. In this review, epidemiology, clinical features, diagnostic criteria and treatment of vesti-bular migraine will be discussed.


Bio-behavioural research in a rare disease population: a doctoral student's experience.
Novice researchers who aspire to contribute to the body of knowledge concerning rare diseases face unique challenges in developing and conducting studies. These include unknown effect sizes in previous research, limitations in recruitment and enrolment, and managing data from a multi-site sample. To describe the challenges in researching rare diseases and possible solutions using a doctoral student exemplar from a cross-sectional correlational study of fatigue. The authors discuss the lessons learned from the study, including the challenges in recruitment, communication, collecting biological data and managing data in general. They posit possible solutions, including improving multi-site coordination, feasible methods for exploring sleep and stress, and measures to prevent equipment and data loss. Rare populations, such as young survivors of childhood brain tumours, deserve a voice in building the body of knowledge needed for more precise, personalised healthcare. It is possible with foresight for the novice researcher to make such a contribution. Improved knowledge and assessment of symptoms during childhood will improve the detection of health risk factors and enable earlier intervention.


A Rat Tibial Growth Plate Injury Model to Characterize Repair Mechanisms and Evaluate Growth Plate Regeneration Strategies.
A third of all pediatric fractures involve the growth plate and can result in impaired bone growth. The growth plate (or physis) is cartilage tissue found at the end of all long bones in children that is responsible for longitudinal bone growth. Once damaged, cartilage tissue within the growth plate can undergo premature ossification and lead to unwanted bony repair tissue, which forms a "bony bar." In some cases, this bony bar can result in bone growth deformities, such as angular deformities, or it can completely halt longitudinal bone growth. There is currently no clinical treatment that can fully repair an injured growth plate. Using an animal model of growth plate injury to better understand the mechanisms underlying bony bar formation and to identify ways to inhibit it is a great opportunity to develop better treatments for growth plate injuries. This protocol describes how to disrupt the rat proximal tibial growth plate using a drill-hole defect. This small animal model reliably produces a bony bar and can result in growth deformities similar to those seen in children. This model allows for investigation into the molecular mechanisms of bony bar formation and serves as a means to test potential treatment options for growth plate injuries.


Poverty-related factors associated with obesity prevention policies in Utah secondary schools.
To address the childhood obesity epidemic, numerous national agencies have outlined specific school policy recommendations for nutrition and physical activity. The extent to which current policies differ by socioeconomic status and geographic location is yet to be determined. This cross-sectional study examined select school nutrition and physical activity policies by markers for poverty among 209 middle and high schools in Utah (82% response rate). The results show that students' opportunities to establish healthful dietary and physical activity patterns differed by economic circumstances and geographic location. Schools with the highest percentage of free and reduced-price lunch enrollment and schools in rural areas were both less likely to offer a variety of healthful foods outside of the school meal program (ie, competitive foods and drinks) and intramural activities or physical activity clubs. Schools with highest free and reduced-price lunch enrollment were more likely to allow the purchase of unhealthful snacks during lunchtimes than schools with low enrollment (28.4% vs 7.6%, P=0.01). Schools in rural communities were less likely to promote walking and bicycling to school compared with other locations (47.4% rural vs 67.1% urban and 63.6% suburban, P=0.06). Current school policies related to nutrition and physical activity may not be conducive to reducing the childhood overweight problem among children attending schools in areas with increased risk factors due to poverty or rural location in Utah.


Resolution time of amoebic liver abscess by micro-opaque barium sulphate.
Resolution time of amoebic liver abscess in 20 males aged 20-80 yrs. as studied by intra-cavitary micro-opaque barium sulphate ranged from 24-284 days (mean 74.8 S.D. +/- 8.4). Sic of these patients also underwent Indium11m scanning. The resolution time by scanning varied from 24-114 days (Mean 58.3 days S.D. +/- 4.6). No correlation was found between the size of abscess and resolution time. Resolution time studied by two methods was statistically significant. Instillation of micro-opaque barium sulphate is an inexpensive, reliable and a safe method which does not require sophisticated equipment.


Ferromagnetic interaction in mu1,3-cyanamido-derived copper(II) cryptates.
The reaction of dinuclear copper(II) cryptates with calcium cyanamide, CaNCN, and sodium dicyanamide, Na[N(CN)(2)] results in dinuclear compounds of formulae [Cu(2)(HNCN)(R3Bm)](ClO(4))(3) (1), [Cu(2)(dca)(R3Bm)](ClO(4))(3)4H(2)O (2), and [Cu(2)(NCNCONH(2))(R3Bm)](CF(3)SO(3))(3) (3), in which R3Bm=N[(CH(2))(2)NHCH(2)(C(6)H(4)-m)CH(2)NH(CH(2))(2)](3)N and dca=dicyanamido ligand (NCNCN(-)). The X-ray diffraction analysis reveals for both 1 and 3 a dinuclear entity in which the copper atoms are bridged by means of the -NCN- unit. The molar magnetic susceptibility measurements of 1-3 in the 2-300 K range indicate ferromagnetic coupling. The calculated J values, by using theoretical methods based on density functional theory (DFT) are in excellent agreement with the experimental data. Catalytic hydration of a nitrile to an amide functional group is assumed responsible for the formation of 3 from a mu(1,3)-dicyanamido ligand.


RNA memory model: a RNA-mediated transcriptional activation mechanism involved in cell identity.
I propose a new model, called the "RNA memory" model, for the possible role of RNAs in the maintenance and establishment of cell identity. This is cytoplasmic memory obtained by the transmission of mother noncoding (nc) RNAs to daughter cells. These RNAs are able to activate transcription via sequence homology in daughter cells. Regulation of RNA memory is strictly linked to the regulation of ncRNAs with repressive features, such as the RNAs involved in RNA interference (RNAi). Misregulation of this system could lead to misidentity, and thus it could be involved in cancer transformation, progression of viral or genetic diseases, and progression of senescence.


Pathophysiology of Lung Disease and Wound Repair in Cystic Fibrosis.
Cystic fibrosis (CF) is an autosomal recessive, life-threatening condition affecting many organs and tissues, the lung disease being the chief cause of morbidity and mortality. Mutations affecting the CF Transmembrane Conductance Regulator (CFTR) gene determine the expression of a dysfunctional protein that, in turn, triggers a pathophysiological cascade, leading to airway epithelium injury and remodeling. In vitro and in vivo studies point to a dysregulated regeneration and wound repair in CF airways, to be traced back to epithelial CFTR lack/dysfunction. Subsequent altered ion/fluid fluxes and/or signaling result in reduced cell migration and proliferation. Furthermore, the epithelial-mesenchymal transition appears to be partially triggered in CF, contributing to wound closure alteration. Finally, we pose our attention to diverse approaches to tackle this defect, discussing the therapeutic role of protease inhibitors, CFTR modulators and mesenchymal stem cells. Although the pathophysiology of wound repair in CF has been disclosed in some mechanisms, further studies are warranted to understand the cellular and molecular events in more details and to better address therapeutic interventions.


Intravenous nitroglycerin to relieve intrapartum fetal distress related to uterine hyperactivity: a prospective observational study.
During a 1-yr period, we evaluated prospectively the use of nitroglycerin (NTG) to relieve severe intrapartum fetal distress related to uterine hyperactivity. Sixty to ninety micrograms of NTG were injected intravenously (i.v.) within 2-5 min after onset of severe fetal distress after oxygen administration, left lateral decubitus, and discontinuation of any ongoing oxytocin infusion (62%) had failed to resolve the fetal heart rate abnormality. A second dose (60 or 90 micrograms) was used 2-3 min later as required. NTG was completely effective in 22 cases (fetal distress resolution within 4-5 min with restoration of normal uterine activity) and partially but sufficiently effective in the remaining 2 cases (fetal distress resolution within 4-5 min with residual mild uterine hyperactivity). However, a second dose was required for nine parturients (38%). Six parturients (25%) developed hypotension 2 min after the first NTG injection, with a mean nadir of 93.2 mm Hg (minimum 85 mm Hg). Hypotension was always rapidly reversed with a small single dose of ephedrine (4.5-6 mg). In conclusion, we found small doses (60-180 micrograms) of IV NTG to be associated with resolution of severe fetal distress related to uterine hyperactivity along with negligible side effects.


Growth of Word and Pseudoword Reading Efficiency in Alphabetic Orthographies: Impact of Consistency.
Word and pseudoword reading are related abilities fundamental to reading development in alphabetic orthographies. They are respectively assumed to index children's orthographic representations of words, which are in turn acquired through the underlying "self-teaching mechanism" of alphabetic pseudoword decoding. Little is known about concurrent growth trajectories of these skills in the early grades among children learning different alphabetic orthographies. In the present study, between- and within-group latent growth models of word and pseudoword reading efficiency were tested on data spanning Grades 1 and 2 from learners of the inconsistent English and consistent Czech and Slovak orthographies. Several language-general patterns emerged. Significant growth was observed for both skills in all languages. Growth was faster for word than pseudoword reading efficiency, and strong lexicality effects that increased over time were obtained across languages. Language-specific patterns were also found. In line with predictions about the costs of learning lower-consistency orthographies, readers of English experienced relatively slower growth on both reading skills. However, their lag was smaller, and evident only at the latter two time points for word reading. In contrast, on pseudoword reading, the English group performed considerably less well than their Czech and Slovak peers at every time point. Thus, weaker decoding skills were the main contributor to the larger lexicality effects of the English group. These findings are considered within the frame of recent theorizing about the effect of orthographic consistency on decoding as a self-teaching mechanism in alphabetic reading acquisition.


PulseNet USA standardized pulsed-field gel electrophoresis protocol for subtyping of Vibrio parahaemolyticus.
PulseNet is a national molecular subtyping network for foodborne disease surveillance composed of public health and food regulatory agencies. Participants employ molecular subtyping of foodborne pathogens using a standardized method of pulsed-field gel electrophoresis (PFGE) for conducting laboratory-based surveillance of foodborne pathogens. The PulseNet standardized PFGE protocols are developed through a comprehensive testing process. The reproducibility of the protocol undergoes an internal evaluation at the Centers for Disease Control and Prevention and an external evaluation in multiple PulseNet laboratories. Here we describe the development and evaluation of a rapid PFGE protocol for subtyping Vibrio parahaemolyticus for use in PulseNet activities. The protocol was derived from the existing standardized PulseNet protocols for Escherichia coli O157:H7 and Vibrio cholerae. An external evaluation of this protocol was undertaken in collaboration with three PulseNet USA participating public health laboratories. Comparative analysis of the PFGE fingerprints generated by each of these laboratories demonstrated that the protocol is both reliable and reproducible in the hands of multiple users.


Reduced polymorphism of Plasmodium vivax early transcribed membrane protein (PvETRAMP) 11.2.
ETRAMP11.2 (PVX_003565) is a well-characterized protein with antigenic potential. It is considered to be a serological marker for diagnostic tools, and it has been suggested as a potential vaccine candidate. Despite its immunological relevance, the polymorphism of the P. vivax ETRAMP11.2 gene (pvetramp11.2) remains undefined. The genetic variability of an antigen may limit the effectiveness of its application as a serological surveillance tool and in vaccine development and, therefore, the aim of this study was to investigate the genetic diversity of pvetramp11.2 in parasite populations from Amazonian regions and worldwide. We also evaluated amino acid polymorphism on predicted B-cell epitopes. The low variability of the sequence encoding PvETRAMP11.2 protein suggests that it would be a suitable marker in prospective serodiagnostic assays for surveillance strategies or in vaccine design against P. vivax malaria. The pvetramp11.2 of P. vivax isolates collected from Brazil (n = 68) and Peru (n = 36) were sequenced and analyzed to assess nucleotide polymorphisms, allele distributions, population differentiation, genetic diversity and signature of selection. In addition, sequences (n = 104) of seven populations from different geographical regions were retrieved from the PlasmoDB database and included in the analysis to study the worldwide allele distribution. Potential linear B-cell epitopes and their polymorphisms were also explored. The multiple alignments of 208 pvetramp11.2 sequences revealed a low polymorphism and a marked geographical variation in allele diversity. Seven polymorphic sites and 11 alleles were identified. All of the alleles were detected in isolates from the Latin American region and five alleles were detected in isolates from the Southeast Asia/Papua New Guinea (SEA/PNG) region. Three alleles were shared by all Latin American populations (H1, H6 and H7). The H1 allele (reference allele from Salvador-1 strain), which was absent in the SEA/PNG populations, was the most represented allele in populations from Brazil (54%) and was also detected at high frequencies in populations from all other Latin America countries (range: 13.0% to 33.3%). The H2 allele was the major allele in SEA/PNG populations, but was poorly represented in Latin America populations (only in Brazil: 7.3%). Plasmodium vivax populations from Latin America showed a marked inter-population genetic differentiation (fixation index [Fst]) in contrast to SEA/PNG populations. Codon bias measures (effective number of codons [ENC] and Codon bias index [CBI]) indicated preferential use of synonymous codons, suggesting selective pressure at the translation level. Only three amino acid substitutions, located in the C-terminus, were detected. Linear B-cell epitope mapping predicted two epitopes in the Sal-1 PvETRAMP11.2 protein, one of which was fully conserved in all of the parasite populations analyzed. We provide an overview of the allele distribution and genetic differentiation of ETRAMP11.2 antigen in P. vivax populations from different endemic areas of the world. The reduced polymorphism and the high degree of protein conservation supports the application of PvETRAMP11.2 protein as a reliable antigen for application in serological assays or vaccine design. Our findings provide useful information that can be used to inform future study designs.


Carcinogenicity of low doses of N-ethyl-N-nitrosourea in F344 rats; a dose-response study.
The threshold level of minimum carcinogenic dose of N-ethyl-N-nitrosourea (ENU) and the effect of dose on organ specificity were examined by continuous oral administration to both sexes of F344 rats of low doses of ENU at four concentrations (0.3, 1, 3 and 10 ppm) in the drinking water. ENU at 10 ppm selectively induced neurogenic tumors and tumors of the digestive tract, including duodenal tumors. Even at lower doses it enhanced the spontaneous development of some other tumors. A high dose of ENU (400 ppm) was previously found to induce duodenal tumors selectively. These results indicate that the organ specificity of ENU is influenced by the dose and that ENU has multi-potent carcinogenic activity in many organs and/or tissues. In this study, some specific tumors, such as those of the nervous system and digestive tract, seemed to require a minimum carcinogenic level of ENU (10 ppm) for their appearance. However, it seems that ENU is carcinogenic at much lower dose levels than 10 ppm because ENU enhanced the spontaneous development of some other tumors in many experimental groups. The so-called virtually safe doses inducing these specific tumors at a risk level of 10(-6) were calculated.


Correlation between IRGM genetic polymorphisms and Crohn's disease risk: a meta-analysis of case-control studies.
This meta-analysis was performed to evaluate the relationships between single-nucleotide polymorphisms (SNPs) in the immunity-related GTPase M (IRGM) gene and the risk of Crohn's disease (CD). Eleven case-control studies were included, for a total of 5183 CD patients and 5571 healthy controls. Three common SNPs (rs13361189 C>T, rs10065172 C>T, and rs4958847 A>G) in the IRGM gene were assessed. We found that the IRGM rs13361189 polymorphism was significantly associated with an increased risk of CD [C allele vs T allele: odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.05-1.61, P = 0.017; CC + CT vs TT: OR = 1.32, 95%CI = 1.06-1.64, P = 0.013]. However, we observed no correlation between the rs10065172 and rs4958847 polymorphisms in the IRGM gene with susceptibility to CD (all P > 0.05). Subgroup analysis by ethnicity revealed significant associations between IRGM genetic polymorphisms and an increased risk of CD among Caucasian populations (C allele vs T allele: OR = 1.22, 95%CI = 1.07-1.40, P = 0.004; CC + CT vs TT: OR = 1.22, 95%CI = 1.05-1.41, P = 0.009), but not among Asian populations (all P > 0.05). Meta-regression analysis also confirmed that ethnic differences may be an important source of heterogeneity (P = 0.003). Our meta-analysis results indicate that the IRGM rs13361189 polymorphism contributes to the susceptibility to CD. Thus, the IRGM rs13361189 polymorphism is promising as a biomarker for early diagnosis of CD. However, the IRGM rs10065172 and rs4958847 polymorphisms may not be the major determinants of CD risk.


Laser-assisted tympanomastoidectomy for active mucosal chronic otitis media.
Laser-assisted tympanomastoidectomy for active mucosal chronic otitis media. Achieving disease control in the context of active granulating mucosal chronic otitis media (COM) is typically challenging. Adjuvant laser use in cholesteatomatous COM surgery enhances disease clearance, yet its role in mucosal COM remains unexplored. The purpose of this study is to present the outcomes and our experience of the latter, and to attempt to define the role of this approach in managing mucosal COM. Patients that underwent primary laser-assisted tympanomastoidectomy (2007-2012) for active granulating mucosal COM with at least six months follow-up were studied. Disease control was defined by successful tympanic membrane repair and resolution of otorrhoea. Time-to-event analysis using the Kaplan-Meier method was used to gain a temporal estimate of disease control. Seventy ears (66 patients) were included with mean follow-up of 22 months (6-50 months). Disease control was achieved in 94.3% of cases at latest follow-up, while one- and two-year temporal estimates of control were 97.1% and 91.8% respectively. A mean post-operative four-frequency air-bone gap of 20 dB was achieved in 52 cases (74.3%). Surgical complications included transient vertigo (n = 2), wound infection (n = 2), and temporary facial nerve palsy (n = 1). We present disease control rates favourable to other published series of active mucosal COM, supporting the use of the laser as an efficacious adjunct to tympanomastoid surgery in this context. This initial report should foster further appraisal of this approach in larger prospective studies.


The PFA-100: a potential rapid screening tool for the assessment of platelet dysfunction.
The PFA-100 is a device that simulates high shear dependent platelet function in vitro and thus is particularly useful for screening for von Willebrand's disease (VWD). The aim of this study was to assess the overall potential of the PFA-100 as a primary clinical screening tool using the wide spectrum of clinical samples assessed for platelet function within our institution. The PFA-100 test was performed using both collagen/ADP (CADP) and collagen/epinephrine (CEPI) cartridges on samples from 337 patients with a wide variety of haemostatic defects. One hundred and eighty-two patients were defined as having normal platelet function based on classical laboratory tests and von Willebrand factor levels. The overall clinical sensitivity of the PFA-100 for platelet abnormalities (including VWD) was 81% for CADP and 86% for CEPI. The overall specificity was found to be 82% for CADP and 80% for CEPI. When utilizing both cartridges in combination (with both results either higher or lower than the upper cutoff of the normal ranges), the overall false positive and false negative rates were 12% and 6%, respectively. The PFA-100 proved to be sensitive in detecting classical defects by giving prolonged closure times in samples from patients with major platelet function defects (e.g. von Willebrand's disease, Glanzmann's thrombasthenia and Bernard Soulier syndrome). However, there were a small number of false negative results (6%) obtained with various milder platelet defects (e.g. Hermansky Pudlak syndrome, storage pool and release defects, type I VWD and macrothrombocytopenia). The PFA-100 test provides a useful rapid screening tool and should increase the efficiency and reduce the cost of the routine diagnosis of platelet dysfunction.


Magnetic field control of the ordering of two-component suspension of hard rods.
The Onsager theory of hard rod dispersion in a neutral solvent is extended to a case of two-component dispersion consisting of both non-magnetic and magnetic rods. It was found that the alignment of magneto-sensitive dispersion component by a magnetic field leads to the alignment of non-magnetic component in the dispersion and to an elimination of the isotropic phase. This effect is significant even at low relative concentrations of magnetic rods and leads to a magnetically induced anisotropy in a non-magnetic dispersion of rods mixed with the magnetic ones.


Enhancement of IgE-mediated histamine release from human basophils by immune-specific lymphokines.
Human leucocytes (basophils) release histamine when exposed to ragweed antigen E or anti-IgE. The present study shows that when leucocytes from BCG-positive donors are first incubated with PPD and then challenged with anti-IgE, histamine release is enhanced. In contrast, when leucocytes from BCG-negative donors are incubated with PPD and then challenged with anti-IgE there is no enhancement of histamine release. The enhancement of histamine release was detected within 24 hr after addition of PPD, but was maximal at 48 to 72 hr. Supernatant fluids collected from these leucocyte cultures revealed the presence of a soluble mediator(s) which, when incubated with leucocytes from BCG-negative donors, enhanced the release of histamine. Examination of the supernatant fluids from BCG-positive leucocyte cultures stimulated with PPD showed a correlation between histamine-release enhancing activity and interferon. Treatment of the culture fluids at pH 2.0 abolished the anti-viral activity, indicating that the interferon was of the type II or 'immune' class. The same treatment only partly abolished the histamine-release enhancing activity. It is concluded that immune-specific stimulation of leucocytes results in the release of soluble mediators that are capable of enhancing IgE-mediated histamine release.


Effect of coherence of nonthermal reservoirs on heat transport in a microscopic collision model.
We investigate the heat transport between two nonthermal reservoirs based on a microscopic collision model. We consider a bipartite system consisting of two identical subsystems, and each subsystem interacts with its own local reservoir, which consists of a large collection of initially uncorrelated ancillas. Then a heat transport is formed between two reservoirs by a sequence of pairwise collisions (intersubsystem and subsystem-local reservoir). In this paper we consider two kinds of the reservoir's initial states: the thermal state and the state with coherence whose diagonal elements are the same as that of the thermal state and the off-diagonal elements are nonzero. In this way, we define the effective temperature of the reservoir with coherence according to its diagonal elements. We find that for two reservoirs having coherence the direction of the steady current of heat is different for different phase differences between the two initial states of two reservoirs, especially the heat can transfer from the "cold reservoir" to the "hot reservoir" in the steady regime for particular phase difference. In the limit of the effective temperature difference between the two reservoirs ΔT→0, for most of the phase differences, the steady heat current increases with the increase of effective temperature until it reaches the high effective temperature limit, while for the thermal state or particular phase difference the steady heat current decreases with the increase of temperature at high temperatures, and in this case the conductance can be obtained.


Phospholipase C-independent activation of glycogen synthase kinase-3beta and C-terminal Src kinase by Galphaq.
It is generally thought that activation of phospholipase Cbeta (PLCbeta) by Galphaq accounts for most of the effects of Gq-coupled receptors. Here we describe a novel effect of Galphaq that is independent of the PLCbeta pathway. Expression of the constitutively active Galphaq mutant Galphaq(Q209L) promoted an increase in glycogen synthase kinase-3beta (GSK-3beta) activity that was associated with increased phosphorylation of Tyr216 on GSK-3beta. Galphaq(Q209L)-AA, a mutant that cannot activate PLCbeta, also induced GSK-3beta activation and phosphorylation of Tyr216. We speculate that the protein-tyrosine kinase Csk (C-terminal Src kinase), which is also activated by Galphaq(Q209L) and Galphaq(Q209L)-AA, acts upstream of GSK-3beta. Expression of Csk accentuated the activation of GSK-3beta by Galphaq(Q209L), whereas catalytically inactive Csk blocked GSK-3beta activation by Galphaq(Q209L). Recombinant Csk phosphorylated and activated GSK-3beta in vitro, and GSK-3beta coprecipitated with Csk from cell lysates. These results suggest that activation of Csk and GSK-3beta by Galphaq may contribute to the physiological and pathological effects of Gq-coupled receptors.


Podocyte-specific knockin of PTEN protects kidney from hyperglycemia.
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has proven to be downregulated in podocytes challenged with high glucose (HG), and knockout of PTEN in podocytes aggravated the progression of diabetic kidney disease (DKD). However, whether podocyte-specific knockin of PTEN protects the kidney against hyperglycemia in vivo remains unknown. The inducible podocyte-specific PTEN knockin (PPKI) mice were generated by crossing newly created transgenic loxP-stop- loxP-PTEN mice with podocin-iCreERT2 mice. Diabetes mellitus was induced in mice by intraperitoneal injection of streptozotocin at a dose of 150 mg/kg. In vitro, small interfering RNA and adenovirus interference were used to observe the role of PTEN in HG-treated podocytes. Our data demonstrated that PTEN was markedly reduced in the podocytes of patients with DKD and focal segmental glomerulosclerosis, as well as in those of db/db mice. Interestingly, podocyte-specific knockin of PTEN significantly alleviated albuminuria, mesangial matrix expansion, effacement of podocyte foot processes, and incrassation of glomerular basement membrane in diabetic PPKI mice compared with wild-type diabetic mice, whereas no alteration was observed in the level of blood glucose. The potential renal protection of overexpressed PTEN in podocytes was partly attributed with an improvement in autophagy and motility and the inhibition of apoptosis. Our results showed that podocyte-specific knockin of PTEN protected the kidney against hyperglycemia in vivo , suggesting that targeting PTEN might be a novel and promising therapeutic strategy against DKD.


Tumour necrosis factor-alpha-induced glucose-stimulated insulin secretion inhibition in INS-1 cells is ascribed to a reduction of the glucose-stimulated Ca2+ influx.
The present study was undertaken to determine how tumour necrosis factor-alpha (TNF-alpha) elicits the inhibition of glucose-stimulated insulin secretion (GSIS) in rat insulinoma cells (INS)-1 beta-cells. TNF-alpha pretreatment did not change the expression levels of insulin, PDX-1, glucose transporter 2, glucokinase, K(ATP) channels, Ca(2)(+) channels, and exocytotic molecules and, furthermore, did not reduce the glucose-stimulated ATP level. On the other hand, TNF-alpha reduced the glucose-stimulated influx of Ca(2)(+). The TNF-alpha treatment was thought to activate c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and NF-kappaB inflammatory signals, since TNF-alpha increased phospho-JNK and phospho-p38 and reduced I kappaB levels. Inhibitors of these signaling pathways prevented the TNF-alpha-induced reduction of the Ca(2)(+) influx and GSIS. Overexpression of MEKK3, a possible mediator from the TNF-alpha receptor to the JNK/p38 and NK-kappaB signaling cascade, increased the levels of phospho-JNK, phospho-p38, and NF-kappaB, and reduced the glucose-stimulated Ca(2)(+) influx and GSIS. The reduction of the Ca(2)(+) influx and GSIS in MEKK3-overexpressing INS-1 cells was also prevented by inhibitors of JNK, p38, and NF-kappaB. These data demonstrate that TNF-alpha inhibits GSIS by reducing the glucose-stimulated Ca(2)(+) influx, possibly through the activation of JNK and p38 MAPK and NF-kappaB inflammatory signals. Thus, our findings suggest that the activation of stress and inflammatory signals can contribute to the inhibition of GSIS in the development of diabetes.


Exercise hemodynamics and myocardial metabolism during long-term beta-adrenergic blockade in severe heart failure.
Hemodynamics and myocardial metabolism at rest and during exercise were investigated in 21 patients with heart failure. The patients were evaluated before and after long-term treatment (14 +/- 7 months) with the beta-adrenergic blocking agent metoprolol. Clinical improvement with increased functional capacity occurred during treatment. Maximal work load increased by 25% (104 to 130 W; p less than 0.001). Hemodynamic data showed an increased cardiac index (3.8 to 4.6 liters/min per m2; p less than 0.02) during exercise. Pulmonary capillary wedge pressure decreased at rest (20 to 13 mm Hg; p less than 0.01) and during exercise (32 to 28 mm Hg; p = NS). Stroke volume index (30 to 39 g.m/m2; p less than 0.006) and stroke work index (28 to 46 g.m/m2; p less than 0.006) increased during exercise and long-term metoprolol treatment. The arterial norepinephrine concentration decreased at rest (3.72 to 2.19 nmol/liter; p less than 0.02) but not during exercise (13.2 to 11.1 nmol/liter; p = NS). The arterial-coronary sinus norepinephrine difference suggested a decrease in myocardial spillover during metoprolol treatment (-0.28 to -0.13 nmol/liter; p = NS at rest and -1.13 to -0.27 nmol/liter; p less than 0.05 during exercise). Coronary sinus blood flow was unchanged during treatment. Four patients produced myocardial lactate before the study, but none produced lactate after beta-blockade (p less than 0.05). There was no obvious improvement in a subgroup of patients with ischemic cardiomyopathy. In summary, there were signs of increased myocardial work load without higher metabolic costs after treatment with metoprolol.


Prognostic value of indeterminable anaerobic threshold in heart failure.
In patients with heart failure (HF), during maximal cardiopulmonary exercise test, anaerobic threshold (AT) is not always identified. We evaluated whether this finding has a prognostic meaning. We recruited and prospectively followed up, in 14 dedicated HF units, 3058 patients with systolic (left ventricular ejection fraction <40%) HF in stable clinical conditions, New York Heart Association class I to III, who underwent clinical, laboratory, echocardiographic, and cardiopulmonary exercise test investigations at study enrollment. We excluded 921 patients who did not perform a maximal exercise, based on lack of achievement of anaerobic metabolism (peak respiratory quotient ≤1.05). Primary study end point was a composite of cardiovascular death and urgent cardiac transplant, and secondary end point was all-cause death. Median follow-up was 3.01 (1.39-4.98) years. AT was identified in 1935 out of 2137 patients (90.54%). At multivariable logistic analysis, failure in detecting AT resulted significantly in reduced peak oxygen uptake and higher metabolic exercise and cardiac and kidney index score value, a powerful prognostic composite HF index (P<0.001). At multivariable analysis, the following variables were significantly associated with primary study end point: peak oxygen uptake (% pred; P<0.001; hazard ratio [HR]=0.977; confidence interval [CI]=0.97-0.98), ventilatory efficiency slope (P=0.01; HR=1.02; CI=1.01-1.03), hemoglobin (P<0.05; HR=0.931; CI=0.87-1.00), left ventricular ejection fraction (P<0.001; HR=0.948; CI=0.94-0.96), renal function (modification of diet in renal disease; P<0.001; HR=0.990; CI=0.98-0.99), sodium (P<0.05; HR=0.967; CI=0.94-0.99), and AT nonidentification (P<0.05; HR=1.41; CI=1.06-1.89). Nonidentification of AT remained associated to prognosis also when compared with metabolic exercise and cardiac and kidney index score (P<0.01; HR=1.459; CI=1.09-1.10). Similar results were obtained for the secondary study end point. The inability to identify AT most often occurs in patients with severe HF, and it has an independent prognostic role in HF.


Ab initio study of the RbSr electronic structure: potential energy curves, transition dipole moments, and permanent electric dipole moments.
Excited states and the ground state of the diatomic molecule RbSr were calculated by post Hartree-Fock molecular orbital theory up to 22 000 cm(-1). We applied a multireference configuration interaction calculation based on multiconfigurational self-consistent field wave functions. Both methods made use of effective core potentials and core polarization potentials. Potential energy curves, transition dipole moments, and permanent electric dipole moments were determined for RbSr and could be compared with other recent calculations. We found a good agreement with experimental spectra, which have been obtained recently by helium nanodroplet isolation spectroscopy. For the lowest two asymptotes (Rb (5s (2)S) + Sr (5s4d (3)P°) and Rb (5p (2)P°) + Sr (5s(2) (1)S)), which exhibit a significant spin-orbit coupling, we included relativistic effects by two approaches, one applying the Breit-Pauli Hamiltonian to the multireference configuration interaction wave functions, the other combining a spin-orbit Hamiltonian and multireference configuration interaction potential energy curves. Using the results for the relativistic potential energy curves that correspond to the Rb (5s (2)S) + Sr (5s4d (3)P°) asymptote, we have simulated dispersed fluorescence spectra as they were recently measured in our lab. The comparison with experimental data allows to benchmark both methods and demonstrate that spin-orbit coupling has to be included for the lowest states of RbSr.


[Rapid immunoenzyme diagnosis of influenza in patients with various allergoses and bronchial asthma].
In an investigation carried out in the allergological clinic of the Tbilisi State Medical Institute in the period between two outbreaks of influenza, the presence of influenza antigen was determined in nasal washings taken from 127 patients with different allergoses and bronchial asthma by means of the enzyme immuno-assay with the use of the type-specific virion antigen of M1-protein. This method was found to be highly sensitive and to have some advantages over traditional methods used for the diagnosis of influenza. In patients with preasthma and different forms of bronchial asthma elevated susceptibility to influenza infection and its unfavorable influence on the clinical course of these pathological conditions were established.


Influence of patellar ligament insertion angle on quadriceps usage during walking in anterior cruciate ligament reconstructed subjects.
Reduced quadriceps contraction has been suggested as an adaptation to prevent anterior tibial translation in anterior cruciate ligament (ACL)-deficient knees. This theory has been supported by a recent study that peak knee flexion moment (thought to be created by a decrease of quadriceps contraction) during walking was negatively correlated with patellar ligament insertion angle (PLIA) in ACL-deficient knees, but not in contralateral, uninjured knees. In addition, the PLIA was significantly smaller in ACL-deficient knees than in contralateral, uninjured knees. However, it is unknown whether ACL reconstruction restores the PLIA or whether the relationship between the PLIA and knee flexion moments previously observed in ACL-deficient knees disappears. This study tested the following hypotheses: (1) The PLIA of ACL-reconstructed knees is significantly smaller than the PLIA of uninjured contralateral knees; (2) Peak knee flexion moment (balanced by net quadriceps moment) during walking is negatively correlated with the PLIA in ACL-reconstructed knees. The PLIA of 24 ACL-reconstructed and contralateral knees were measured using MRI, and peak knee flexion moments during walking were measured. Results showed that the PLIA of ACL-reconstructed (22.9 +/- 4.4 degrees) knees was not significantly smaller (p = 0.09, power = 0.99) than the PLIA of contralateral (24.1 +/- 4.8 degrees) knees. Peak knee flexion moment was not correlated with the PLIA following ACL reconstruction (R2 = 0.016, power = 0.99). However, the magnitude of the knee flexion moment remained significantly lower in ACL-reconstructed knees. In summary, this study has shown that the PLIA of ACL-reconstructed knees returned to normal and that patients no longer adapt their gait in response to the PLIA, though quadriceps function did not return to normal levels.


Cabazitaxel, a novel chemotherapeutic alternative for drug-resistant hepatocellular carcinoma.
The prognosis of advanced hepatocellular carcinoma (HCC) patients remains extremely poor, partially due to the development of acquired resistance to sorafenib and chemotherapy. Cabazitaxel, a semisynthetic taxane, has been approved for the therapy of docetaxel-resistant prostate cancer. However, no studies have been performed on the effect of cabazitaxel on HCC, and whether cabazitaxel remains sensitive in chemotherapy-resistant and sorafenib-resistant HCC cells is not clear. Our results demonstrate that cabazitaxel is highly toxic to HCC cell lines in a time- and dose-dependent manner by inducing G2/M phase arrest and apoptosis in vitro. Cabazitaxel also significantly suppresses HCC tumor growth in vivo. In chemotherapy-resistant HCC cell Huh-TS-48 with P-gp-overexpression, cabazitaxel shows less cross-resistant to other chemotherapeutic agents. The resistance fold of cabazitaxel, doxorubicin, paclitaxel, docetaxel and vinorelbine is 1.53, 8.60, 38.58, 15.53 and 18.06 respectively. Furthermore, sorafenib-resistant HCC cell SK-sora-5 is still sensitive to cabazitaxel. The IC50 values of cabazitaxel after 72 h exposure for parental cell SK-hep-1 and resistant cell SK-sora-5 are 0.84 and 0.73 nM. The results indicate that cabazitaxel is a potential agent to treat HCC after developing chemotherapy resistance caused by overexpression of P-gp and acquired resistance to sorafenib, and might improve prognosis in advanced HCC patients.


Cholesterol granuloma.
The "idiopathic haemotympanum" is in reality a persistent secretory otitis media. Histologically it demonstrates a chronic granular mastoiditis associated with a cholesterol granuloma. This, however, is not a very specific finding and may be frequently found in other types of the 'underaerated middle ear syndrome', wuch as ears with central perforations or indeed with cholesteatoma. In these granulomas, iron deposits are found, as well as the iron-chelating agent--lactoferin, which is known to be part of the defence mechanism of all mucosas. Lactoferrin is specifically secreted by the exocrine glands and it is not surprising to find much of it in the middle ear in a situation where mucus is being abundantly synthesized--as the case may be in any otitis media. There is no real clinical or histological evidence, so far, that neither the iron deposits nor the cholesterol crystals of these granulomas emanate from a previous hemorrhage.


Heritable colorectal cancer and cancer genes: systemic expressions.
Epidemiological studies of heritable cancer have demonstrated that cancer predisposition is a dominant trait; these studies have also predicted the recessive outcome of the neoplastic process. Biochemical studies of dominantly heritable cancer have demonstrated the relevance of systemic effects. The systemic effects are presumably due to a dominant mutation at the "initiator locus." Collectively they define cancer initiation at the cellular level (as described in this review). Molecular biological studies have demonstrated that cancer progression and the appearance of clinical cancer occur through an accumulation of recessive mutations at critical loci. We must continue to try to define not only the inherited and acquired gene defects that initiate the neoplastic state but also the subsequent genetic alterations and biomarkers involved in tumor progression. These genetic defects are already proving useful in diagnosis and prognostication. The hope is that these biomarkers may be useful for designing specific differentiation therapy.


[Study on the level changes of obesity-associated factors and puberty-associated hormones and their relationship between obese and normal 13 years old children].
To investigate the level changes of obesity-associated factors and puberty-associated hormones and their relationship between obese and normal Children. The concentrations of orexins, leptin, insulin, testosterone (T), estradiol (E), luteotrophic hormone (LH), as well as follicle stimulating hormone (FSH) in blood were measured respectively in 78 cases of 13 years old obesity children and 84 normal children as a control group by the means of RIA methods. The bone ages were evaluated with "bone age standard of hundred percent scale". The leptin and insulin concentrations were significantly higher in obesity children as compared with the control group (P < 0.01). The concentrations of plasma orexinA were significantly lower in obesity children as compared with the control group (P < 0.01). The concentrations of T were significantly lower in obesity boys as compared with the control group (P < 0.01). The concentrations of E2 and LH were significantly higher in obesity girls as compared with the control group (P < 0.01). The bone age of the obese children was significantly older than that of the control group. Along with the bone age of children became older, the concentration of leptin and LH in blood were significantly increased. There was a positive correlation between LH and FSH in two groups of either boys and girls and so did between leptin and insulin, C-peptide, E2 (P < 0.01). In the group of normal boys, the positive correlations between LH, FSH and E2 were shown (r = 0.373, 0.314, P <0.05), and a negative correlations between leptin and T were shown as( r = -0.423, P < 0.01), a positive correlation between leptin and FSH was also shown as (r = 0.308, P < 0.05). In the control group of girls, there were positive correlations between leptin, LH and E2 (r = 0.585, 0.647, P < 0.01). Any correlations between LH, FSH T and E2 were not shown in the two obese groups of boys and girls. The leptin, orexinA, insulin, T, E2, and LH concentrations had been changed significantly in blood among those obesity children, and so as their interactions. The high level of leptin in obesity children may change the concentrations of T, E2 and LH and affect the development of puberty.


Microfinance for women at high risk for HIV in Kazakhstan: study protocol for a cluster-randomized controlled trial.
Among women at high risk for HIV and other sexually transmitted diseases (STIs), gender and economic issues limit the impact of behavioral prevention strategies. Women in Kazakhstan with dual risks of sex trading and drug use face elevated risk for HIV and STIs and may benefit from an economic empowerment intervention which combines HIV-risk reduction (HIVRR) education with financial skills-building and asset-building to promote reduced reliance on sex trading for income. The study employs a two-arm, cluster-randomized controlled trial (c-RCT) design. We will use cluster randomization to assign 350 women in approximately 50 cohorts to a traditional four-session HIV-risk-reduction intervention combined with a six-session financial literacy intervention, enrollment in a 24-session vocational training program and receipt of matched savings (HIVRR+MF); or to the four-session HIV-risk-reduction intervention alone (HIVRR). Repeated behavioral and biological assessments will be conducted at baseline, then at 6, 9, and 15 months post randomization/session 1. This study responds to an identified need in the academic literature for rigorous testing of structural interventions, including combination microfinance and HIV-prevention interventions. ClinicalTrials.gov, ID: NCT02406482 . Registered on 30 March 2015.


Diagnostics of inflammaging in relation to sarcopenia.
One of the theories about aging focuses on the immune response and relates to the activation of subclinical and chronic inflammation. This study was designed to investigate the relationship between inflammation and sarcopenia and to evaluate the influence of lifestyle on the inflammatory profile. Finally, therapeutic strategies to counteract the pathophysiological effect of skeletal muscle aging were also indicated. One hundred seventy-three individuals aged 71.5 ± 6.8 years were divided into two groups: sarcopenia and probable sarcopenia (n = 39) and no sarcopenia (n = 134). Sarcopenia was assessed according to the algorithm of the European Working Group on Sarcopenia in the older adults 2. C-reactive protein (CRP) (p = 0.011) and CRP/albumin ratio (p = 0.030) as well as IL-1β (p = 0.002), cfDNA (p < 0.001) and bilirubin levels (p = 0.002) were significantly higher in the sarcopenia group as opposed to the no sarcopenia group. No significant differences were observed between groups in the concentration of TNFα (p = 0.429) and IL-6 (p = 0.300). An inverse correlation was found between gait speed and cfDNA (rs = -0.234, p < 0.01) and IL-1β (rs = -0.263, p < 0.01). The ROC analysis of cfDNA, CRP, IL-1β and bilirubin ranged from 0.6 to 0.7, which confirms the association between sarcopenia and inflammatory mediators and indicates high clinical usefulness of cfDNA and bilirubin in sarcopenia prediction. We also indicated a link between inflammation and fitness level in the older adult thereby providing evidence that lifestyle exercise should be a key therapeutic strategy in sarcopenia prevention.


[Interaction between gomizine D and α-glucosidase].
This paper describes a study exploring the interaction between gomizine D and α-glucosidase. The inhibitory activity of α-glucosidase by gomizine D was determined using PNPG as substrates Gomizine D gave the IC₅₀ value of 0.59 mmol•L⁻¹, which was higher than that of acarbose (1.95 mmol•L⁻¹). Gomizine D was a reversible and non-competitiveα-glucosidase inhibitor with an inhibition constant Ki=4.026 g•L⁻¹. The binding mode between gomizine D and α-glucosidase was analyzed by AutoDock Vina molecular docking software. The lowest energy of Gomizine D binding to α-glucosidase was -7.7 kcal•mol⁻¹, which was lower than that of acarbose (-6.6 kcal•mol⁻¹). After binding with gomizine D, UV spectroscopy analysis displayed that the microenvironment of aromatic residue in the secondary structure of α-glucosidase was changed, and the polarity of protein was reduced.


HIV prevalence and the cascade of care in five South African correctional facilities.
South Africa is home to the world's largest HIV epidemic. Throughout the world, incarcerated individuals have a higher prevalence of HIV than the general public, and South Africa has one of the highest rates of incarceration in sub-Saharan Africa. In spite of this, little has been published about the burden of HIV and how care is delivered in South African correctional facilities. To estimate the prevalence of people living with HIV and identify initiation and retention in the HIV cascade of care across five correctional facilities. Cross-sectional retrospective analysis of 30,571 adult inmates who participated in a tuberculosis screening and HIV counseling and testing campaign in South African correctional facilities (January 1, 2014-January 31, 2015). Descriptive statistics were used to estimate the proportion and 95% confidence intervals of HIV. Proportions of persons retained and lost at each step in the HIV cascade of care under this intervention were calculated. Poisson regression with robust variance estimates were used, and clustering by facility was accounted for in all analyses. Results of the screening campaign found previously undiagnosed HIV among 13.0% of those consenting to screening, with a total estimated HIV prevalence of 17.7% (n = 3,184, 95% CI: 17.2-18.3%) in the sample. When examining the overall cascade of care, 48.3% of those with HIV initiated care, and overall 45.6% of persons who entered care qualified for ART initiated treatment. A Poisson regression accounting for clustering by facility found HIV high risk groups within the population such as women (aRR = 1.72, 95% CI: 1.57, 1.89), those over 35 years of age (aRR = 2.43, 95% CI: 1.53, 3.85), and people incarcerated less than one year (aRR = 1.41, 95% CI: 1.19, 1.67). In this setting, routine screening is recommended, and measures are needed to ensure that persons diagnosed are adequately linked to and retained in care.


Structural characterization of the stringent response related exopolyphosphatase/guanosine pentaphosphate phosphohydrolase protein family.
Exopolyphosphatase/guanosine pentaphosphate phosphohydrolase (PPX/GPPA) enzymes play central roles in the bacterial stringent response induced by starvation. The high-resolution crystal structure of the putative Aquifex aeolicus PPX/GPPA phosphatase from the actin-like ATPase domain superfamily has been determined, providing the first insights to features of the common catalytic core of the PPX/GPPA family. The protein has a two-domain structure with an active site located in the interdomain cleft. Two crystal forms were investigated (type I and II) at resolutions of 1.53 and 2.15 A, respectively. This revealed a structural flexibility that has previously been described as a "butterfly-like" cleft opening around the active site in other actin-like superfamily proteins. A calcium ion is observed at the center of this region in type I crystals, substantiating that PPX/GPPA enzymes use metal ions for catalysis. Structural analysis suggests that nucleotides bind at a similar position to that seen in other members of the superfamily.


Finite-temperature local protein sequence alignment: percolation and free-energy distribution.
Sequence alignment is a tool in bioinformatics that is used to find homological relationships in large molecular databases. It can be mapped on the physical model of directed polymers in random media. We consider the finite-temperature version of local sequence alignment for proteins and study the transition between the linear phase and the biologically relevant logarithmic phase, where the free energy grows linearly or logarithmically with the sequence length. By means of numerical simulations and finite-size-scaling analysis, we determine the phase diagram in the plane that is spanned by the gap costs and the temperature. We use the most frequently used parameter set for protein alignment. The critical exponents that describe the parameter-driven transition are found to be explicitly temperature dependent. Furthermore, we study the shape of the (free-) energy distribution close to the transition by rare-event simulations down to probabilities on the order 10(-64). It is well known that in the logarithmic region, the optimal score distribution (T=0) is described by a modified Gumbel distribution. We confirm that this also applies for the free-energy distribution (T>0). However, in the linear phase, the distribution crosses over to a modified Gaussian distribution.


Enediyne natural products: biosynthesis and prospect towards engineering novel antitumor agents.
This review gives a brief account on the current status of enediyne biosynthesis and the prospective of applying combinatorial biosynthesis methods to the enediyne system for novel analog production. Methods for cloning enediyne biosynthetic gene clusters are first reviewed. A unified paradigm for enediyne biosynthesis, characterized with (a) the enediyne PKS, (b) the enediyne PKS accessory enzymes, and (c) tailoring enzymes, is then presented. Strategies and tools for novel enediyne analog production by combinatorial biosynthesis are finally discussed. The results set the stage to decipher the molecular mechanism for enediyne biosynthesis and lay the foundation to engineer novel enediynes by combinatorial biosynthesis for future endeavors.


Synthesis and Characterization of the Inclusion Complex of β-cyclodextrin and Azomethine.
A β-cyclodextrin (β-Cyd) inclusion complex containing azomethine as a guest was prepared by kneading method with aliquot addition of ethanol. The product was characterized by Fourier Transform Infrared (FTIR) spectrometer, 1H Nuclear Magnetic Resonance (1H NMR) and Thermogravimetric Analyzer (TGA), which proves the formation of the inclusion complex where the benzyl part of azomethine has been encapsulated by the hydrophobic cavity of β-Cyd. The interaction of β-Cyd and azomethine was also analyzed by means of spectrometry by UV-Vis spectrophotometer to determine the formation constant. The formation constant was calculated by using a modified Benesi-Hildebrand equation at 25 °C. The apparent formation constant obtained was 1.29 × 104 L/mol. Besides that, the stoichiometry ratio was also determined to be 1:1 for the inclusion complex of β-Cyd with azomethine.


Diagnosis and treatment of child and adolescent anxiety disorders.
The criteria from the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) for anxiety disorders relevant to children and adolescents are reviewed. Empirically supported behavioral and pharmacological therapies specific to separation anxiety disorder, avoidant disorder, overanxious disorder, simple phobia, obsessive compulsive disorder, and sleep terror disorder are discussed. Exposure-based treatments are indicated in most cases in which an anxiety-evoking stimulus can be clearly identified. With respect to the treatment of children and adolescents, pharmacotherapy remains understudied for most disorders. It appears that the behavioral therapies found useful in the treatment of adults with anxiety disorders can be successfully applied to the care of younger persons. Significant lacunae remain in the clinical research literature in these fields, offering many opportunities for both practitioners and scientists.


Weighting improves the information provided by joint counts on the severity of arthritis and its impact on patients' well-being in juvenile idiopathic arthritis.
To develop a scoring system for juvenile idiopathic arthritis (JIA) in which joints are weighted to reflect their relative importance to children's function and to examine whether weighting increases the correlation of joint counts with subjective and laboratory outcome measures. A weighted joint score was devised by a panel of experienced paediatric rheumatologists, who assigned a weight from 1 (not very important) to 10 (essential for key functional activities) to each joint based on its functional importance to children's physical and daily activities. The associations of simple and weighted counts of swollen, tender, limited and active joints with the physician's global assessment of overall disease activity, the parent's global assessment of the child's overall well-being and intensity of pain, the Childhood Health Assessment Questionnaire (C-HAQ), the Child Health Questionnaire (CHQ) and the erythrocyte sedimentation rate were compared using Spearman's correlation analysis in 60 unselected patients seen in the clinic and in 61 consecutive patients with disease duration > or = 5 yr. Weighted counts of swollen and active joints yielded greater correlation with the physician's global assessment than did simple counts. The correlation of weighted counts of swollen, painful and active joints with the parent's assessment of overall well-being and intensity of pain was superior to that provided by simple counts. Weighting increased most of the correlations between joint counts and the C-HAQ score and the physical component of the CHQ. Weighting improves the information provided by joint counts on the severity of arthritis and its impact on patients' well-being.


Granulopoiesis and Neutrophil Homeostasis: A Metabolic, Daily Balancing Act.
Granulopoiesis is part of the hematopoietic hierarchic architecture, where hematopoietic stem cells give rise to highly proliferative multipotent and lineage-committed granulocytic progenitor cells that differentiate into unipotent neutrophil progenitors. Given their short lifespan, neutrophils are rapidly cleared from circulation through specialized efferocytic macrophages. Together with an intrinsic clock, these processes contribute to circadian fluctuations, preserving self-tolerance and protection against invading pathogens. However, metabolic perturbation of granulopoiesis and neutrophil homeostasis can result in low-grade chronic inflammation, as observed with aging. During acute pathogenic infections, hematopoiesis can also be switched into emergency mode, which has been recently associated with significant neutrophil functional heterogeneity. This review focuses on a new reassessment of regulatory mechanisms governing neutrophil production, life-cycle, and diversity in health and disease.


Mobile X-ray Outside the Hospital vs. X-ray at the Hospital Challenges Exposed in an Explorative RCT Study.
For frail patients, it may sometimes be preferable to carry out X-ray examinations at the patients' own home. The general state of such patients may worsen due to transport and change of environment when transported for examination at the hospital. The aim of the randomized controlled trial (RCT) was to investigate if mobile X-ray improves healthcare for fragile patients. The primary outcome was the number of hospitalizations. We collected all data using questionnaires and data from the Electronic Patient Record (ER). Patients referred to a mobile X-ray examination living in nursing homes and homes for the elderly in the Aarhus Municipality (Denmark). mobile X-ray examinations compared to those at the hospital. Study appraisal: Data were collected and stored using the computer programme Redcap. Stata was used for statistical calculations. One hundred and thirty-six patients were included in the RCT. We did not find significant differences between mobile X-ray (intervention) and X-ray at the hospital (control) concerning hospitalizations and number of hospital days. Challenges: We met several challenges when carrying out RCT in the planned study population. Doctors often withdraw the referral when they found out that their patient should go to the hospital instead of mobile X-ray. The nursing home staff often considered the patient too frail to allow the test person to ask questions post X-ray. We also met challenges in the randomization method resulting in bias in the first data collection, so we had to adjust the randomization method. For the fragile patients in the present explorative study, mobile X-ray did not significantly reduce the number of hospitalizations compared to X-ray at the hospital. Yet, mobile X-ray may be a new important diagnostic tool for more precise treatment to the frailest patients for whom transportation to the hospital is too exhausting. We need studies with focus on this aspect. We also recommend future RCT studies in a population for which mobile X-ray has not yet been a possibility.


Chemotherapy principles in the treatment of prostatic cancer.
The efficacy of chemotherapy for prostatic cancer is difficult to evaluate owing to the low incidence of measurable indicator lesions and the resulting need for indirect response criteria. Although complete regressions remain exceptional, a number of agents, eg, doxorubicin and cisplatin have been shown to be effective in the treatment of this disease. So far, combinations of effective agents with or without concomitant hormone therapy have not proven to be more effective than single agents. Androgen priming has considerable theoretical appeal and deserves further consideration. A higher effectiveness of chemotherapeutic agents might be obtained by linkage to various carriers. Estramustine phosphate is an example of such a complex that has a cytotoxic effect in test systems in which estrogen has no effect and in patients with hormone-refractory prostatic cancer. The use of hormonal and other carriers that could increase the specificity of chemotherapeutic agents deserves extensive exploration.


Analysis of ABCG2 and other urate transporters in uric acid homeostasis in chronic kidney disease: potential role of remote sensing and signaling.
In the setting of chronic kidney disease (CKD), altered extra-renal urate handling may be necessary to regulate plasma uric acid. The Remote Sensing and Signaling Hypothesis (Nigam S. What do drug transporters really do? Nat Rev Drug Discov 2015; 14: 29-44) suggests that multispecific solute carrier (SLC) and ATP-binding cassette (ABC) drug transporters in different tissues are part of an inter-organ communication system that maintains levels of urate and other metabolites after organ injury. Data from the Chronic Renal Insufficiency Cohort (CRIC; n = 3598) were used to study associations between serum uric acid and single nucleotide polymorphisms (SNPs) on the following uric acid transporters: ABCG2 (BRCP), SLC22A6 (OAT1), SLC22A8 (OAT3), SLC22A10 (OAT5), SLC22A11 (OAT4), SLC22A12 (URAT1), SLC22A13 (OAT10), SLC17A1-A3 (NPTs), SLC2A9 (GLUT9), ABCC2 (MRP2) and ABCC4 (MRP4). Regression models, controlling for principal components age, gender and renal function, were run separately for those of European (EA) and African ancestry (AA), and P-values corrected for multiple comparisons. A twin cohort with participants of EA and normal renal function was used for comparison. Among those of EA in CRIC, statistically significant signals were observed for SNPs in ABCG2 (rs4148157; beta-coefficient = 0.68; P = 4.78E-13) and SNPs in SLC2A9 (rs13125646; beta-coefficient = -0.30; P = 1.06E-5). Among those of AA, the strongest (but not statistically significant) signals were observed for SNPs in SLC2A9, followed by SNPs in ABCG2. In the twin study (normal renal function), only SNPs in SLC2A9 were significant (rs4481233; beta-coefficient=-0.45; P = 7.0E-6). In CRIC, weaker associations were also found for SLC17A3 (NPT4) and gender-specific associations found for SLC22A8 (OAT3), SLC22A11 (OAT4), and ABCC4 (MRP4). In patients of EA with CKD (CRIC cohort), we found striking associations between uric acid and SNPs on ABCG2, a key transporter of uric acid by intestine. Compared with ABCG2, SLC2A9 played a much less significant role in this subset of patients with CKD. SNPs in other SLC (e.g. SLC22A8 or OAT3) and ABC (e.g. ABCC4 or MRP4) genes appear to make a weak gender-dependent contribution to uric acid homeostasis in CKD. As renal urate transport is affected in the setting of declining kidney function, extra-renal ABCG2 appears to play a compensatory role-a notion consistent with animal studies and the Remote Sensing and Signaling Hypothesis. Overall, the data indicate how different urate transporters become more or less important depending on renal function, ethnicity and gender. Therapies focused on enhancing ABCG2 urate handling may be helpful in the setting of CKD and hyperuricemia.


Real-life efficacy and drug continuation of secukinumab in treating moderate to severe plaque psoriasis in Aegean region of Turkey: a multicenter retrospective study and systematic review of the literature.
Secukinumab was demonstrated to be efficient in the treatment of moderate to severe plaque psoriasis in the phase studies. Real-life treatment experiences obtained from patients that do not meet the inclusion criteria of phase studies can provide valuable information on efficacy and safety results. Results may also differ in different ethnic populations. To investigate short and long-term efficacy and drug continuation of secukinumab in Turkish population. The study conducted in three tertiary care psoriasis centers. Patients' demographic characteristics and week 0 / 4th week / 12th week / 1st year PASI values were analyzed. For systematic review of the literature a PubMed search using the keywords "secukinumab and real and psoriasis" from inception to April 2021 was performed. Mean PASI scores improved the compared to baseline at all assessment weeks (p = 0.000). In multivariate model, we found that bioexperience have negative influence on the PASI90 response at week 4. Univariate analysis showed significant relationship only between PASI90 response rate and gender at week 12 and year 1. Approximately 85% of patients remained on secukinumab treatment at the end of one year. Secukinumab seems to be an effective treatment option for plaque psoriasis. According to our knowledge, this is the first study concerning about long-term efficacy and drug continuation of secukinumab from Turkey.


[n-3 Polyunsaturated fatty acid attenuates hyperhomocysteinemia-induced hepatic steatosis by increasing hepatic LXA5 content].
Nonalcoholic fatty liver disease (NAFLD) and hyperhomocysteinemia (HHcy) both are major health problems worldwide, whose incidence are closely related with each other. We previously reported the mechanism of HHcy-caused hepatic steatosis, but the role of n-3 polyunsaturated fatty acid (n-3 PUFA) in HHcy-induced hepatic steatosis remains unclear. In this study, 6-week-old C57BL/6 male mice were given a high methionine diet (HMD, 2% methionine diet), and plasma homocysteine levels were measured by ELISA to confirm the establishment of an HHcy model. Meantime, mice were fed HMD with or without n-3 PUFA supplement for 8 weeks to determine the role and mechanism of n-3 PUFA in hepatic steatosis induced by HHcy. Results showed that n-3 PUFA significantly improved hepatic lipid deposition induced by HHcy. qRT-PCR analysis demonstrated that n-3 PUFA inhibited the upregulation of Cd36, a key enzyme of fatty acid uptake, caused by HHcy. Further, the inhibition of hepatic Cd36 expression was associated with the inactivation of aryl hydrocarbon receptor (Ahr) induced by n-3 PUFA. Of note, mass spectrometry revealed that hepatic content of lipoxin A5 (LXA5) was significantly increased in HMD+n-3 PUFA-fed mice compared with that in HMD-fed mice. In primary cultured hepatocytes, LXA5 treatment markedly reversed homocysteine-evoked Cd36 upregulation and Ahr activation, which resulted in reduced lipid accumulation. In conclusion, we demonstrate that n-3 PUFA inactivates HHcy-induced Ahr-Cd36 pathway by increasing hepatic LXA5 content, which alleviates hepatic steatosis. Thus, our results may provide a potential strategy for treatment of NAFLD.


Postregistration monitoring of pesticides is urgently required to protect ecosystems.
Current admission policies for pesticides follow a controlled experimental tiered risk assessment approach, giving results that are difficult to extrapolate to a real-world situation. Later analyses of compounds such as DDT and neonicotinoid pesticides clearly show that the actual chemical impacts frequently affect many more components of an ecosystem than a priori suggested by risk assessment. Therefore, to manage the actual risks for ecosystems imposed by manufactured compounds, it is proposed that current admission policies for chemicals be enriched by using postregistration monitoring. Such monitoring is essential to identify unexpected direct and indirect impacts on organisms by accounting for multiple propagation routes and exposures. Implementation of postregistration monitoring could build on existing monitoring networks. This approach would tackle the current policy impasse of compartment-based regulations versus exposure-based regulations, and, more importantly, would provide a safety lock for risk assessment across compartments and more likely ensure the protection of our natural environment. Environ Toxicol Chem 2017;36:860-865. © 2017 SETAC.


Using ventricular modeling to robustly probe significant deep gray matter pathologies: Application to cerebral palsy.
Understanding the relationships between the structure and function of the brain largely relies on the qualitative assessment of Magnetic Resonance Images (MRIs) by expert clinicians. Automated analysis systems can support these assessments by providing quantitative measures of brain injury. However, the assessment of deep gray matter structures, which are critical to motor and executive function, remains difficult as a result of large anatomical injuries commonly observed in children with Cerebral Palsy (CP). Hence, this article proposes a robust surrogate marker of the extent of deep gray matter injury based on impingement due to local ventricular enlargement on surrounding anatomy. Local enlargement was computed using a statistical shape model of the lateral ventricles constructed from 44 healthy subjects. Measures of injury on 95 age-matched CP patients were used to train a regression model to predict six clinical measures of function. The robustness of identifying ventricular enlargement was demonstrated by an area under the curve of 0.91 when tested against a dichotomised expert clinical assessment. The measures also showed strong and significant relationships for multiple clinical scores, including: motor function (r2 = 0.62, P < 0.005), executive function (r2 = 0.55, P < 0.005), and communication (r2 = 0.50, P < 0.005), especially compared to using volumes obtained from standard anatomical segmentation approaches. The lack of reliance on accurate anatomical segmentations and its resulting robustness to large anatomical variations is a key feature of the proposed automated approach. This coupled with its strong correlation with clinically meaningful scores, signifies the potential utility to repeatedly assess MRIs for clinicians diagnosing children with CP. Hum Brain Mapp 37:3795-3809, 2016. © 2016 Wiley Periodicals, Inc.


Spectroscopic methods in bioinorganic chemistry: blue to green to red copper sites.
A wide variety of spectroscopic methods are now available that provide complimentary insights into the electronic structures of transition-metal complexes. Combined with calculations, these define key bonding interactions, enable the evaluation of reaction coordinates, and determine the origins of unique spectroscopic features/electronic structures that can activate metal centers for catalysis. This presentation will summarize the contributions of a range of spectroscopic methods combined with calculations in elucidating the electronic structure of an active site using the blue copper site as an example. The contribution of electronic structure to electron-transfer reactivity will be considered in terms of anisotropic covalency, electron-transfer pathways, reorganization energy, and protein contributions to the geometric and electronic structures of blue-copper-related active sites.


Huge multinodular goiter with mid trachea obstruction: indication for fiberoptic intubation.
Goiter or thyromegaly is one of the most common causes of mid tracheal obstruction (external compression or stenosis), which may be associated with difficult larynx visualization and/or difficult airway management, depending on the goiter size, type and ingrowth into the surrounding tissue. Iodine deficiency disorders are still one of the most common causes of goiter in the population of the African continent. These patients with goiter generally present for medical examination at an advanced stage of the disease. Mallampati test, thyromental distance and inter-incisor gap appear to provide the optimal combination for prediction of difficult visualization of the larynx. Video laryngoscopy examination of the subglottic region and inspection of tracheal deviation in the presence of tracheal compression without detected stenosis of the trachea is a standard and preferred technique in comparison with direct laryngoscopy. Intubation can be performed when vocal cords are visualized. The major difficulty on intubation is encountered in only 5.3% of patients with goiter. Large goiter need not always be associated with a higher incidence of difficult endotracheal intubation. Only two predicting factors for difficult airway assessment were identified in these patients: cancerous goiter (especially if compressive signs are present) and Cormack and Lehane grade III/IV. The indication for fiberoptic intubation is tracheal compression or initial tracheal stenosis. Conventional tracheostomy has to be performed in goiter patients with identified tracheomalacia and/or high degree or tracheal stenosis.


Pulp analysis of teeth submitted to different types of forces: a histological study in rats.
The purpose of this study was to histologically evaluate pulp and dentin under induced tooth movement (ITM) with different types of forces. The maxillary right first molars of rats were submitted to movement with continuous (CF), continuous interrupted (CIF) and intermittent (IF) forces during 5, 7 and 9 days with nickel-titanium (NiTi) closed-coil springs exerting 50cN force magnitude. The groups were histologically evaluated as for cellularity pattern, presence of dystrophic, hemodynamic alterations in the pulp as well dentin alterations. The main observed alterations were related to hemodynamic pulp characteristics, such as presence of thrombosis, vascular congestion and hemorrhages. The hemodynamic alterations were statistically evaluated by Shapiro-Wilk normality test and analysis of variance by the Kruskall-Wallis test. There was no significant differences observed between groups in the different types of applied forces and duration of ITM (vascular congestion, p=1.000; hemorrhage, p=0.305; thrombosis, p=1.000). Pulp tissue alterations resulting from ITM were limited to hemodynamic events, without progressing to irreversible degeneration, regardless of the type of force applied.