Long-Term Athlete Development: Seasonal and Longitudinal Fitness Changes in Female University Rugby Players.
Falk Neto, JH, Parent, E, and Kennedy, MD. Long-term athlete development: Seasonal and longitudinal fitness changes in female university rugby players. J Strength Cond Res 35(12): 3459-3465, 2021-The Long-Term Athlete Development model is used by organizations to determine the expected improvements from athletes at different stages of their careers. For female rugby athletes, university sports should provide continued support for athlete development during the Training to Perform stage (18-21 years old). However, little evidence exists for longitudinal changes across years of participation in university sports in this group. The purpose of this study was to assess changes in anthropometric and fitness characteristics in female university rugby players across different seasons. Seventeen players were divided into forwards (n = 9, 21.1 ± 2.6 years) and backs (n = 8, 19.62 ± 0.9 years) and assessed across 5 points over 3 years: preseason 1, postseason 1, preseason 2, postseason 2, and preseason 3. Anthropometric (height, body mass, and body mass index) and performance measurements (grip strength, flexibility, trunk muscular endurance, upper-body muscular endurance, 40-m sprint, vertical jump, and 20-m shuttle run) were collected. V̇o2max was higher at preseason 2 compared with postseason 1 (p = 0.02), postseason 2 (p = 0.01), and preseason 3 (p = 0.015), and trunk muscular endurance was higher at preseason 3 (p = 0.02). Performance in the first 5 m of the sprint test decreased at postseason 1 (p = 0.018) and preseason 2 (p = 0.016) when compared with preseason 1. The results indicate that these female athletes did not improve their fitness across the Training to Perform stage when participating in university sports. These female rugby players likely developed their fitness at earlier stages and, at this stage, already possessed well-developed fitness levels, which were merely maintained throughout years.


Degradation behavior of composite pins made of tricalcium phosphate and poly(L,DL-lactide).
Combining a bioactive ceramic with a resorbable polymer may improve the biocompatibility and the osseointegration of degradable fracture fixation devices. This study reports on the mechanical properties and degradation behavior of two composite pins made of poly(L,DL-lactide) and 10 and 30% beta-tricalcium phosphate (TCP), respectively. The pins were compared to a pin made of 100% poly(L,DL-lactide). The failure force, bending strength, and molecular weight were determined during in vitro degradation at 37 degrees C up to 78 weeks. The blending with 10 or 30% beta-TCP decreased the initial mechanical properties and led to an accelerated degradation rate. The pins with 30% TCP lost half of their strength after 16 weeks, i.e. faster than the unmodified pin (40 weeks). The pins with 10% TCP, however, showed a decreased initial strength (128+/-9 MPa) compared to the unmodified pin (152+/-9 MPa) but very similar degradation characteristics. The drop of the molecular weight was not significantly different between the three types of pins. It was concluded that the mechanical requirements for a pin for the fixation of small bony fragments with improved biocompatibility were fulfilled by the composite pin with 10% TCP but not by the pin with 30% TCP.


Family history and socioeconomic factors as predictors of myocardial infarction, unstable angina and stroke in an Italian population. PROGETTO 3A Investigators.
A comprehensive case-control study was conducted in an Italian region in order to compare the influence of family history of cardiovascular events, socioeconomic factors, social networks, and their joint associations with major risk factors, on the risk, of myocardial infarction (MI), unstable angina (UA) and ischemic stroke (IS). A total of 513 patients with MI, 178 with UA, 237 with IS, and 928 hospitalised controls were recruited. The odds ratio (OR) of MI for two or more relatives with a positive history of MI was 3.6 (95% CI: 1.8-7.3). Family history of MI was predictive for UA (OR = 5.8; 95% CI: 1.2-28.7), but not for IS. A family history of stroke was more associated with the risk of MI than of IS. After adjustment for known risk factors, the OR of MI for more educated people was 2.1 (1.3-3.6) compared with less-educated people. Large family size seemed to be protective for MI. The effect of major risk factors on MI ranged from additive (diabetes) to multiplicative jointly with high education and family history of MI. A family history of stroke increased IS risk threefold jointly with smoking and hyperlipidemia, and eightfold with diabetes. Besides a family history of MI and IS, in this community a higher educational status seems to better identify groups at increased risk of MI. The joint associations have important preventive implications since by identifying high-risk individuals (for MI and IS) a more careful assessment and control of risk factors amenable to intervention may be performed.


Biventricular pacing therapy for congestive heart failure: a review of the literature.
Biventricular pacing is a new therapy for patients with congestive heart failure and mechanical dyssynchrony. Its therapeutic intent is to activate both ventricles simultaneously, thus improving the mechanical efficiency of the ventricles. Preliminary evidence indicates improvement in hemodynamics, quality of life, and exercise capacity in patients in sinus rhythm as well as in patients with atrial fibrillation. An improvement in diastolic filling, a decrease in mitral regurgitation, and more efficient systolic ejection are proposed as the mechanisms behind these benefits. In addition, some evidence indicates that the frequency of ventricular arrhythmias is decreased. All clinicians involved in the management of patients with congestive heart failure eagerly await the results of ongoing trials. The results of these trials will define which patients are eligible for this therapy, which patients will derive the most benefit from it, and its effect on morbidity and mortality.


Automated Segmentation of the Mouse Body Language to Study Stimulus-Evoked Emotional Behaviors.
Understanding the neural basis of emotions is a critical step to uncover the biological substrates of neuropsychiatric disorders. To study this aspect in freely behaving mice, neuroscientists have relied on the observation of ethologically relevant bodily cues to infer the affective content of the subject, both in neutral conditions or in response to a stimulus. The best example of that is the widespread assessment of freezing in experiments testing both conditioned and unconditioned fear responses. While robust and powerful, these approaches come at a cost: they are usually confined within selected time windows, accounting for only a limited portion of the complexity of emotional fluctuation. Moreover, they often rely on visual inspection and subjective judgment, resulting in inconsistency across experiments and questionable result interpretations. To overcome these limitations, novel tools are arising, fostering a new avenue in the study of the mouse naturalistic behavior. In this work we developed a computational tool [stimulus-evoked behavioral tracking in 3D for rodents (SEB3R)] to automate and standardize an ethologically driven observation of freely moving mice. Using a combination of machine learning-based behavioral tracking and unsupervised cluster analysis, we identified statistically meaningful postures that could be used for empirical inference on a subsecond scale. We validated the efficacy of this tool in a stimulus-driven test, the whisker nuisance (WN) task, where mice are challenged with a prolonged and invasive whisker stimulation, showing that identified postures can be reliably used as a proxy for stimulus-driven fearful and explorative behaviors.


Autoantibodies against M5-muscarinic and beta1-adrenergic receptors in periodontitis patients.
Autoantibodies against muscarinic and beta1-adrenergic receptors are considered a potential cause and/or risk factor for chronic heart failure. Association of periodontitis with such autoantibodies and with impaired heart function has been observed in patients exposed to endemic Chagas' disease, which triggers by itself cardiomyopathy and receptor immunization.Here we studied the association between periodontitis, markers of cardiac injury and receptor autoimmunization in periodontitis patients (n = 147) not exposed to Chagas' disease. The autoantibodies were determined by IgG binding to native intact muscarinic and beta1-adrenergic receptors or to a cyclic peptide mimicking the disease-relevant conformational autoepitope presented by the active beta1-adrenergic receptor. Possible cardiac injury and inflammatory status were judged by serum levels of proBNP/Troponin I and CRP/IL-6, respectively. These parameters were analysed in healthy and periodontally diseased individuals as well as before and after periodontal therapy.Patients with periodontitis had significantly (p < 0.001) higher levels of autoantibodies against M5-muscarinic and beta1-adrenergic receptors, which further increased following periodontal therapy. Receptor autoantibodies were associated with increased inflammatory status but not with increased markers of cardiac injury. Thus, our data indicate that periodontitis triggers systemic inflammation, which is associated with receptor autoimmunization, and, independently thereof, with cardiac injury.


Whole-body exposure to cigarette smoke alters oocyte miRNAs expression in C57BL/6 mice.
Cigarette smoke is toxic for the female reproductive system with particular reference to the ovary. The purpose of the study was to investigate if the microRNAs (miRNAs) pattern could be altered by cigarette smoke exposure in mouse oocytes. For this purpose, C57BL/6 mice were whole-body exposed to three cigarettes daily, 7 days/week, for 2 or 4 months by a specific rodent ventilator. Mice were then superovulated and oocytes collected. MII oocytes pools obtained by single animals were deprived of cumulus cells and used to extract total RNA including miRNAs. TaqMan™ Rodent MicroRNA A Array v2.0 was used to analyze the miRNAs expression profile. The biological functions and the functional networks of the identified up- and downregulated miRNAs were analyzed by ingenuity pathway analysis software. The gene expression of deregulated-miRNAs targets was evaluated. For the first time, the global miRNAs changes in mouse oocyte in response to cigarette smoke exposure were disclosed. Our results revealed significant modulation of miRNAs mainly involved in inflammatory processes, cellular proliferation, and apoptosis. miRNAs expression was altered in a time-dependent manner. Smoke exposure induced an early downregulation of Dicer1. Transcriptional alterations of the modulated miRNAs major targets, estrogen receptor 1, peroxisome proliferator-activated receptor-alpha, and tumor protein 53, as well as that of other key regulatory genes, were evidenced. Cigarette smoke represents a stimulus able to alter miRNAs pattern in mouse oocyte. This study increases our understanding of the ovarian toxicity profile of cigarette smoke, and open new roads toward the identification of biomarkers of oocyte toxicity and dysregulation.


[Terbinafine resistance explains treatment failure in a patient with tinea corporis].
Tinea corporis is a superficial fungal infection of the limbs, chest or back caused by dermatophytes. Local antifungal treatment is often sufficient to treat tinea corporis. Systemic treatment may be needed in more severe cases, in immunocompromised patients or when treatment failure is documented. Treatment failure is relative common and frequent causes are low compliance, low systemic antifungal drug concentrations, reduced penetration of topical agents or an immunocompromised status. Recently, antifungal resistance has been documented in dermatophytes. We describe a patient with terbinafine treatment failure caused by antifungal drug resistance. The frequency of terbinafine resistance in the Netherlands is unknown as no surveillance is performed. Recent reports from both India and European countries indicate that antifungal resistance should be considered in patients with terbinafine treatment failure.


Better access, quality, and cost for clinically complex veterans with home-based primary care.
In successfully reducing healthcare expenditures, patient goals must be met and savings differentiated from cost shifting. Although the Department of Veterans Affairs (VA) Home Based Primary Care (HBPC) program for chronically ill individuals has resulted in cost reduction for the VA, it is unknown whether cost reduction results from restricting services or shifting costs to Medicare and whether HBPC meets patient goals. Cost projection using a hierarchical condition category (HCC) model adapted to the VA was used to determine VA plus Medicare projected costs for 9,425 newly enrolled HBPC recipients. Projected annual costs were compared with observed annualized costs before and during HBPC. To assess patient perspectives of care, 31 veterans and caregivers were interviewed from three representative programs. During HBPC, Medicare costs were 10.8% lower than projected, VA plus Medicare costs were 11.7% lower than projected, and combined hospitalizations were 25.5% lower than during the period without HBPC. Patients reported high satisfaction with HBPC team access, education, and continuity of care, which they felt contributed to fewer exacerbations, emergency visits, and hospitalizations. HBPC improves access while reducing hospitalizations and total cost. Medicare is currently testing the HBPC approach through the Independence at Home demonstration.


An evaluation of the construct validity of the Adult Rejection Sensitivity Questionnaire.
Rejection sensitivity (RS), the predisposition to defensively expect, readily perceive, and react strongly to interpersonal rejection (Downey & Feldman, 1996; Feldman & Downey, 1994), may be a transdiagnostic trait associated with a range of psychiatric symptoms and psychosocial dysfunction. Valid and reliable assessment of vulnerability factors is essential for individualized treatment and improving clinical outcomes. Limited research has examined the factor structure of the predominantly used self-report measure of RS, the Adult Rejection Sensitivity Questionnaire (A-RSQ; Berenson et al., 2009). Across two studies (Study 1: N = 346, 57.2% female, 76.6% White; 16.8% Hispanic/Latinx; Study 2: N = 540; 43.7% female, 80.2% White; 16.7% Hispanic/Latinx), we examined the factor structure of the A-RSQ in samples of adult U.S. residents and investigated associations with mental health correlates, including neuroticism, social anxiety, anxiety, depression, anhedonia, somatic arousal, and psychological distress. Study 2 also evaluated relations with interpersonal correlates, including introversion, submissiveness, and anxious and avoidant attachment. A two-factor solution with rejection expectancy and rejection concern representing separate factors consistently fit the data best. Distinct patterns of associations emerged suggesting that concern was more strongly associated with indicators of negative affect while expectancy was uniquely associated with diminished positive affect. Both concern and expectancy were associated with indicators of interpersonal dysfunction. Findings suggest that the current operationalization, and perhaps conceptualization, of RS as measured by the A-RSQ requires revision. Additionally, RS may be a clinically relevant transdiagnostic phenotype that influences symptom manifestation and psychosocial functioning. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Determinants of compulsive buying behavior among young adults: The mediating role of materialism.
This research seeks to determine what makes young adults materialistic. The study examines the mediating role of materialism between the contextual factors and compulsive buying. Data was gathered from 219 Pakistani undergraduate university students. Partial Least Square (PLS) technique was used to analyze the data. The study confirms the intuition that more materialistic young adults are more likely to be involved in compulsive buying than are less materialistic young adults. The results were similar with the previous literature conducted in the western culture, indicating that also applies in a modern Islamic society. The findings of the study reveal that materialism mediated the relationship between certain sociological factors (i.e., group, media Celebrity endorsement, and TV advertisement) and compulsive buying. The study highlights the importance of understanding young adults' materialistic attitudes and consumption decisions and provides key knowledge for researchers, policymakers, and managers of leading brands.


Whole slide image registration via multi-stained feature matching.
In the recent decade, medical image registration and fusion process has emerged as an effective application to follow up diseases and decide the necessary therapies based on the conditions of patient. For many of the considerable diagnostic analyses, it is common practice to assess two or more different histological slides or images from one tissue sample. A specific area analysis of two image modalities requires an overlay of the images to distinguish positions in the sample that are organized at a similar coordinate in both images. In particular cases, there are two common challenges in digital pathology: first, dissimilar appearances of images resulting due to staining variances and artifacts; second, large image size. In this paper, we develop algorithm to overcome the fact that scanners from different manufacturers have variations in the images. We propose whole slide image registration algorithm where adaptive smoothing is employed to smooth the stained image. A modified scale-invariant feature transform is applied to extract common information and a joint distance helps to match keypoints correctly by eliminating position transformation error. Finally, the registered image is obtained by utilizing correct correspondences and the interpolation of color intensities. We validate our proposal using different images acquired from surgical resection samples of lung cancer (adenocarcinoma). Extensive feature matching with apparently increasing correct correspondences and registration performance on several images demonstrate the superiority of our method over state-of-the-art methods. Our method potentially improves the matching accuracy that might be beneficial for computer-aided diagnosis in biobank applications.


Enhanced Sampling of Coarse-Grained Transmembrane-Peptide Structure Formation from Hydrogen-Bond Replica Exchange.
Protein structure formation in the membrane highlights a grand challenge of sampling in computer simulations, because kinetic traps and slow dynamics make it difficult to find the native state. Exploiting increased fluctuations at higher temperatures can help overcome free-energy barriers, provided the membrane's structure remains stable. In this work, we apply Hamiltonian replica-exchange molecular dynamics, where we only tune the backbone hydrogen-bond strength to help reduce the propensity of long-lived misfolded states. Using a recently developed coarse-grained model, we illustrate the robustness of the method by folding different WALP transmembrane helical peptides starting from stretched, unstructured conformations. We show the efficiency of the method by comparing to simulations without enhanced sampling, achieving folding in one example after significantly longer simulation times. Analysis of the bilayer structure during folding provides insight into the local membrane deformation during helix formation as a function of chain length (from 16 to 23 residues). Finally, we apply our method to fold the 50-residue-long major pVIII coat protein (fd coat) of the filamentous fd bacteriophage. Our results agree well with experimental structures and atomistic simulations based on implicit membrane models, suggesting that our explicit CG folding protocol can serve as a starting point for better-refined atomistic simulations in a multiscale framework.


Indolent nonfollicular lymphomas: characteristics, treatment, and outcome.
Indolent lymphomas are defined by their low aggressiveness at diagnosis compared with large-cell or T-cell lymphomas: small lymph nodes or blood involvement usually existing for months or years, no B symptoms, and good performance status. However, except in mucosa-associated lymphoid tissue (MALT) lymphoma, the disease is usually disseminated and this indolent presentation does not preclude a good outcome. Indolent lymphomas consist of follicular lymphoma, small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), marginal-zone lymphoma (MZL), and mantle-cell lymphoma (MCL) as defined in the World Health Organization (WHO) classification. A review of morphologic characteristics, clinical presentation, prognostic factors, and outcome is presented here for each of these entities. Despite the absence of good prospective or retrospective studies in the literature, some orientations for the treatment of these patients are given, as well as some ideas for future studies.


The PiZ gene of alpha 1-antitrypsin as a determinant of outcome in PR3-ANCA-positive vasculitis.
We have previously demonstrated that a strong correlation exists between systemic vasculitis with proteinase 3-anti-neutrophil cytoplasm antibodies (PR3-ANCA) and heterozygosity for alpha 1-antitrypsin (alpha 1-AT) deficiency, PiZ. In the present study we characterized the PiZ-positive subgroup by laboratory findings, clinical features and outcome. The series studied consisted of 18 PiZ-positive and 81 PiZ-negative PR3-ANCA patients, comparable in sex ratio, age, C-reactive protein concentrations and renal function at diagnosis, and treatment. PiZ-positive patients had a more disseminated disease as reflected by the number of affected organs (P < 0.01). We found no group differences in relapse tendency. Overall mortality was 39% (7 of 18) in the PiZ-positive and 16% (13 of 81) in the non-PiZ group (P = 0.048). When survival analysis was restricted to 66 patients included in the study at disease onset, the group difference was significant (P = 0.016). The results suggest that the subnormal response of plasma alpha 1-AT seen in PiZ-heterozygotes enhances the risk of dissemination of the vasculitic process and the risk of a fatal outcome. We consider alpha 1-AT phenotyping to be justified in cases of PR3-ANCA-positive vasculitis. Treatments decreasing plasma alpha 1-AT (such as plasmapheresis without plasma replacement) may be deleterious.


A tris(benzyltriazolemethyl)amine-based cage as a CuAAC ligand tolerant to exogeneous bulky nucleophiles.
The archetypal tris(benzyltriazolemethyl)amine (TBTA) ligand was equipped with a bowl-shaped cap in the cage Hm-TBTA. Hm-TBTA accelerates CuAAC reactions without suffering from product inhibition. Furthermore, this shielded ligand efficiently protects the copper center from deactivation by the CuI-chelator glutathione, opening the way to novel approaches for efficient CuAAC reactions in complex media.


Senotherapeutic Drugs: A New Avenue for Skincare?
Skin aging is an outward manifestation of other cellular and molecular aging processes occurring elsewhere in the body. These processes are known collectively as the "hallmarks" of aging, which are a series of basic health maintenance mechanisms that fail over time. Cellular senescence is one of the most studied of the hallmarks of aging; senescent cells accumulate over time and are major drives of the aging process. Here, we discuss the impact of cellular senescence in the context of skin aging, and discuss the emerging landscape of interventions designed for their selective removal by targeted cell death (senolytics) or rejuvenation (senomorphics). We discuss the serotherapeutic strategies that are currently under investigation for systemic aging, which may bring eventual benefits for skin health. Next, we discuss a newly discovered hallmark of aging, dysregulated mRNA processing, which can be targeted for the senomorphic effect. Finally, we highlight a new modality for manipulation of disrupted mRNA processing, oligonucleotide therapeutics. The emerging field of senotherapeutics is set to revolutionize how we view and treat skin aging, and senotherapies are now poised to become a new class of skincare interventions.


Disseminated infection with Trichosporon beigelii.
Two cases of systemic infection with Trichosporon beigelii are reported. Both patients had acute leukemia and were receiving cytotoxic and antibiotic drug therapy, which included amphotericin B, at the time of sepsis. Although clinical isolates of the organisms were found to be sensitive to amphotericin B in vitro, both patients died from severe, widespread fungal infection. The pathologic findings in these two cases suggest that the host response to trichosporon infection is a granulomatous inflammation. Trichosporon is a virulent opportunistic pathogen that may originate from the gastrointestinal tract damaged by cytotoxic therapy in the patient with aplasia. Despite aggressive antifungal therapy, survival is most closely related to recovery of the host's hematopoietic system.


Awake craniotomy. A patient`s perspective.
To report the personal experiences of patients undergoing awake craniotomy for brain tumor resection. We carried out a qualitative descriptive survey of patients` experiences with awake craniotomies for brain tumor resection. The survey was conducted through a standard questionnaire form after the patient was discharged from the hospital. Of the 9 patients who met the inclusion criteria and underwent awake craniotomy, 3 of those patients reported no recollection of the operation. Five patients had auditory recollections from the operation. Two-thirds (6/9) reported that they did not perceive pain. Five patients remembered the head clamp fixation, and 2 of those patients classified the pain from the clamp as moderate. None of the patients reported that the surgery was more difficult than anticipated. Awake craniotomy for surgical resection of brain tumors was well tolerated by patients. Most patients reported that they do not recall feeling pain during the operation. However, we feel that further work and exploration are needed in order to achieve better control of pain and discomfort during these types of operations.


Generation and pathogenicity of anti-platelet factor 4 antibodies: diagnostic implications.
Recent studies have elucidated the target antigens for heparin-dependent antibodies. The major one is generated in the presence of platelet factor 4 (PF4) and heparin at a well-defined concentration that allows formation of heparin-PF4 complexes and induces an alteration of the PF4 molecule. It then exposes neoepitopes, which bind the heparin-dependent antibodies. These antibodies are generated only in some heparin-treated patients, and only a subgroup of them develops thrombocytopenia (HIT) sometimes associated with thrombosis (HITT). The major challenge is to understand how antibodies can be generated and why only some of them are pathogenic. The presence of the IgG isotype at a high concentration is an important factor for developing HIT/HITT. The clinical context, which induces accumulation and activation of platelets at pathological sites, is also important for disease occurrence. The presence of antibodies (mainly the IgG isotype) enhances cell-cell interactions and platelet activation followed by platelet accumulation at these sites. Generation and expression of the autoantigen, HPF4 complexes, is a key feature for triggering antibody binding and pathogenicity. Factors contributing to antibody generation and its persistence, and factors contributing to the expression of the autoantigen triggering the disease development are discussed.


Phenotypic variation of a virulent Candida albicans strain and two spontaneous, relatively avirulent mutant strain derivatives.
The effect of media and temperature of incubation on colony phenotype of Candida albicans strain 4918, and two relatively avirulent mutant strains, designated 4918-2 and 4918-10, has been investigated. In addition, the strains were characterized on the basis of morphotyping pattern. Colony phenotypes were determined for cultures grown on either Lee's medium supplemented with arginine and zinc, or M63 medium supplemented with casamino acids. Incubation was at either 24 or 37 degrees C for 7 days. The results demonstrated that the predominant colony phenotype observed at 24 degrees C was different from that at 37 degrees C for all three strains, irrespective of the medium. While the growth medium influenced the specific colony phenotypes observed, as well as their categorical distribution, no significant medium effect on switching frequency was apparent. The switching repertoire of strain 4918-10 was consistently more varied than either the parental strain or 4918-2 under the conditions examined. However, categorization of the colony phenotypes shown by the three strains suggested that the pattern exhibited by strain 4918-2 was distinct from that of the other two strains. In addition, individual primary colonies of each phenotype observed were clonally plated in order to examine further the switching frequencies. The results established that all three strains were capable of high frequency switching. Other experiments demonstrated that morphotypes of all three strains were different from one another as expected from the differences in their virulence reported previously.


Crystal structure of activated ribulose-1,5-bisphosphate carboxylase complexed with its substrate, ribulose-1,5-bisphosphate.
The three-dimensional structure of the complex of ribulose-1,5-bisphosphate carboxylase from Rhodospirillum rubrum, CO2, Mg2+, and ribulose bisphosphate has been determined with x-ray crystallographic methods to 2.6-A resolution. Ribulose-1,5-bisphosphate binds across the active site with the two phosphate groups in the two phosphate binding sites of the beta/alpha barrel. The oxygen atoms of the carbamate and the side chain of Asp-193 provide the protein ligands to the bound Mg2+ ion. The C2 and the C3 or C4 oxygen atoms of the substrate are also within the first coordination sphere of the metal ion. At the present resolution of the electron density maps, two slightly different conformations of the substrate, with the C3 hydroxyl group "cis" or "trans" to the C2 oxygen, can be built into the observed electron density. The two different conformations suggest two different mechanisms of proton abstraction in the first step of catalysis, the enolization of the ribulose 1,5-bisphosphate. Two loop regions, which are disordered in the crystals of the nonactivated enzyme, could be built into their respective electron density. A comparison with the structure of the quaternary complex of the spinach enzyme shows that despite the different conformations of loop 6, the positions of the Mg2+ ion, and most atoms of the substrate are very similar when superimposed on each other. There are, however, some significant differences at the active site, especially in the metal coordination sphere.


Influence of premolar extractions on tooth size discrepancy. Part two: Analysis of Bolton values.
The purpose of this study is to investigate whether the extraction of four premolars as a requirement of orthodontic therapy is a factor in the creation of tooth size discrepancies (TSD) (Bolton value (BV)), and to determine whether any tooth extraction combinations create more severe discrepancies comparing our result with the results from analogical studies. Hypothetical tooth extractions were performed in all cases by the following combinations: all first premolars, all second premolars, upper first and lower second premolars, and upper second and lower first premolars, estimating extraction influence on TSD frequency and size. 148 pretreatment dental casts were examined. It has been determined that in normal TBI group the smallest discrepancies were created after the second (1.087 mm) and fourth types of combinations have been chosen (1.174 mm). In a low TBI group, the smallest discrepancies occur after first (1.544 mm) and third (1.568 mm) types of removal. In high TBI group the smallest discrepancies appear after type two (3.379 mm) and type four (3.586 mm) have been chosen.


Reduction in NO(x) emission trends over China: regional and seasonal variations.
We analyzed satellite observations of nitrogen dioxide (NO2) columns by the Ozone Monitoring Instrument (OMI) over China from 2005 to 2010 in order to estimate the top-down anthropogenic nitrogen oxides (NOx) emission trends. Since NOx emissions were affected by the economic slowdown in 2009, we removed one year of abnormal data in the analysis. The estimated average emission trend is 4.01 ± 1.39% yr(-1), which is slower than the trend of 5.8-10.8% yr(-1) reported for previous years. We find large regional, seasonal, and urban-rural variations in emission trends. The average NOx emission trend of 3.47 ± 1.07% yr(-1) in warm season (June-September) is less than the trend of 5.03 ± 1.92% yr(-1) in cool season (October-May). The regional annual emission trends decrease from 4.76 ± 1.61% yr(-1) in North China Plain to 3.11 ± 0.98% yr(-1) in Yangtze River Delta and further down to -4.39 ± 1.81% yr(-1) in Pearl River Delta. The annual emission trends of the four largest megacities, Shanghai, Beijing, Guangzhou, and Shenzhen are -0.76 ± 0.29%, 0.69 ± 0.27%, -4.46 ± 1.22%, and -7.18 ± 2.88% yr(-1), considerably lower than the regional averages or surrounding rural regions. These results appear to suggest that a number of factors, including emission control measures of thermal power plants, increased hydro-power usage, vehicle emission regulations, and closure or migration of high-emission industries, have significantly reduced or even reversed the increasing trend of NOx emissions in more economically developed megacities and southern coastal regions, but their effects are not as significant in other major cities or less economically developed regions.


Groundwater and surface-water exchange and resulting nitrate dynamics in the Bogue Phalia basin in northwestern Mississippi.
During April 2007 through September 2008, the USGS collected hydrogeologic and water-quality data from a site on the Bogue Phalia to evaluate the role of groundwater and surface-water interaction on the transport of nitrate to the shallow sand and gravel aquifer underlying the Mississippi Alluvial Plain in northwestern Mississippi. A two-dimensional groundwater/surface-water exchange model was developed using temperature and head data and VS2DH, a variably saturated flow and energy transport model. Results from this model showed that groundwater/surface-water exchange at the site occurred regularly and recharge was laterally extensive into the alluvial aquifer. Nitrate was consistently reported in surface-water samples (n = 52, median concentration = 39.8 μmol/L) although never detected in samples collected from in-stream piezometers or shallow monitoring wells adjacent to the stream (n = 46). These two facts, consistent detections of nitrate in surface water and no detections of nitrate in groundwater, coupled with model results that indicate large amounts of surface water moving through an anoxic streambed, support the case for denitrification and nitrate loss through the streambed.


[Hepatitis C virus (Flaviviridae: Hepacivirus: Hepacivirus C): regulation of signaling reactions of innate immunity].
Studying the regulation of signaling reactions of innate immunity by the hepatitis C virus (HCV) will help to reveal the causes of the transition of the acute form of the disease to a chronic course. The molecular mechanisms of activation by HCV RNA of innate immunity receptors TLR and RLR and signal transduction processes leading to the synthesis of IFN and inflammatory cytokines are considered. The inhibitory effects of non-structural and structural HCV proteins on immune signaling reactions are analyzed in detail. The information presented is the result of an analysis of literature data published in international databases mainly over the past 5 years. In conclusion, signaling receptors are proposed as targets for the development of new antiviral drugs with immunotherapeutic activity.


Microbiology of peritonitis in peritoneal dialysis patients with multiple episodes.
Peritoneal dialysis (PD)-associated peritonitis clusters within patients. Patient factors contribute to peritonitis risk, but there is also entrapment of organisms within the biofilm that forms on PD catheters. It is hypothesized that this biofilm may prevent complete eradication of organisms, predisposing to multiple infections with the same organism. Using data collected in the Canadian multicenter Baxter POET (Peritonitis, Organism, Exit sites, Tunnel infections) database from 1996 to 2005, we studied incident PD patients with 2 or more peritonitis episodes. We determined the proportion of patients with 2 or more episodes caused by the same organism. In addition, using a multivariate logistic regression model, we tested whether prior peritonitis with a given organism predicted the occurrence of a subsequent episode with the same organism. During their time on PD, 558 patients experienced 2 or more peritonitis episodes. Of those 558 patients, 181 (32%) had at least 2 episodes with the same organism. The organism most commonly causing repeat infection was coagulase-negative Staphylococcus (CNS), accounting for 65.7% of cases. Compared with peritonitis caused by other organisms, a first CNS peritonitis episode was associated with an increased risk of subsequent CNS peritonitis within 1 year (odds ratio: 2.1; 95% confidence interval: 1.5 to 2.8; p < 0.001). Among patients with repeat CNS peritonitis, 48% of repeat episodes occurred within 6 months of the earlier episode. In contrast to previous data, we did not find a high proportion of patients with multiple peritonitis episodes caused by the same organism. Coagulase-negative Staphylococcus was the organism most likely to cause peritonitis more than once in a given patient, and a prior CNS peritonitis was associated with an increased risk of CNS peritonitis within the subsequent year.


Cardiovascular protective effects of resveratrol.
Resveratrol (3,4',5-trihydroxy-trans-stilbene), a phytoalexin found in grape skins, peanuts, and red wine, has been reported to have a wide range of biological and pharmacological properties. It has been speculated that at low doses (such as consumed in the common diet) resveratrol may have cardioprotective activity. In this article we describe recent in vitro and in vivo studies in animal models. The results of these studies suggest that resveratrol modulates vascular cell function, inhibits LDL oxidation, suppresses platelet aggregation and reduces myocardial damage during ischemia-reperfusion. Although the reported biological data indicate that resveratrol is a highly promising cardiovascular protective agent, more studies are needed to establish its bioavailability and in vivo cardioprotective effects, particularly in humans.


Two new beta3 integrin mutations in Indian patients with Glanzmann thrombasthenia: localization of mutations affecting cysteine residues in integrin beta3.
New mutations in the beta3 integrin subunit have been identified in two unrelated Glanzmann thrombasthenia patients originating from India and Bangladesh. Both patients had histories of excessive bleeding and were found to have Glanzmann thrombasthenia based on absent ADP-induced platelet aggregation. Immunoblotting of platelet lysates of Patient 1 demonstrated reduced levels of alphaIIb and an unexpected high Mr beta3 band of approximately 260,000, with little or no normal-sized beta3. Upon reduction, a weak beta3 band of normal Mr was observed. Platelet lysates of Patient 2 demonstrated undetectable levels of beta3. Sequence analyses identified homozygous mutations in the beta3 genes of both patients. Patient 1 had a C506Y missense mutation resulting in the expression of an unpaired cysteine; we propose that the Mr approximately 260,000 band is a disulfide-bonded beta3 dimer. Patient 2 had an insertion mutation resulting in a frameshift and premature termination. Both mutations affect biogenesis of platelet alphaIIbbeta3 receptors.


Cancer in survivors of childhood soft tissue sarcoma and their relatives.
One hundred fifty-nine 3-year survivors of childhood soft tissue sarcoma and their relatives were surveyed to determine the frequency of second malignant neoplasms (SMNs) in patients and cancer in their relatives. The cancer experience of the patients, their offspring, siblings, parents, parental siblings, and grandparents was compared to that expected of the general population based on age-, sex- and calendar year-specific rates from the Connecticut Tumor Registry. A significant excess of SMNs was observed in the patients (observed expected = 8:0.38). Among 758 first-degree relatives, a significant cancer excess was observed (34:20.68), attributable largely to cancer of soft tissue and bone (6:0.44) and breast (9:3.39) and to cancers occurring before age 35 years (12:4.14). Overall, a significantly lower than expected cancer incidence was confirmed in the 1,693 second-degree relatives (142:178). To identify patient characteristics associated with higher than expected familial cancer risk, kindreds were partitioned by patient age at diagnosis tumor type, tumor site SMN and other factors. A highly significant cancer excess was observed in the relatives of SMN patients (26:12.78). The tumor types occurring in excess in close relatives were also observed as SMNs in the patients. The findings confirm an association among childhood soft tissue sarcoma and cancers of the breast, bone, joint, or soft tissue as SMN in patients and in close relatives and suggest that the risk of a second tumor is associated with a familial predisposition to cancer.


The role of GnRH agonists plus add-back therapy in the treatment of endometriosis.
Agonistic analogs of GnRH have emerged as effective drugs in the treatment of pelvic pain associated with endometriosis. Iatrogenic hypoestrogenism is the fundamental mechanism through which GnRH agonists induce regression of the exquisitely estrogen-dependent endometriotic lesions. The decrease in bone mass consistently observed in women on long-term GnRH agonist treatment has prompted regulatory agencies such as the FDA to approve the use of these drugs for a maximum of six months in the treatment of endometriosis. The very high recurrence rate of pelvic symptomatology after the interruption of medical therapy underlines the importance of strategies aiming at improving the safety of effective long-term treatments. Data has recently become available suggesting the existence of an ideal range of circulating estradiol levels which would maintain a normal bone metabolism and still cause atrophy of endometriotic lesions. Add-back regimens including estrogen preparations have been therefore studied with variable results. In strict analogy, as oral progestins have been shown to improve bone mass in postmenopausal women, regimens employing progestin add-back have been proposed. Our review describes most of the currently published studies employing these and other substances in association with the commonly used GnRH agonists in patients with symptomatic endometriosis.


National Institutes of Health funding for cardiothoracic surgical research.
Our objective was determine the status of National Institutes of Health (NIH) funding for cardiothoracic surgery research. (1) Funding from the NIH is critical if new procedures and devices are to be developed. (2) The success rate for NIH applications coming from cardiothoracic surgery faculty is thought to be inferior. (3) Per capita numbers of surgical NIH application and awards and application success rate have recently been found to be below the average for the NIH. Application and award data for full-time academic cardiothoracic surgeons were obtained by matching records in the NIH IMPAC II database with membership rosters of The Society of Thoracic Surgeons and The American Association for Thoracic Surgery. Manpower data were obtained from 1999, 2003, and 2005 reports of the STS/AATS Workforce committee. Society membership was used as a surrogate for investigator experience. The number of NIH applications has increased steeply in the past 7 years; however, the number of awards has remained constant. This pattern was observed for surgery and cardiothoracic surgery as well. Until 2003, the cardiothoracic surgery application success rate was actually higher than that of surgery and the NIH as a whole (between 25% and 40%). Since then, however, the cardiothoracic surgery application success rate has declined steeply and is now only 14%. NIH applications and awards per 100 cardiothoracic surgeons, although similar to those of surgery, are very much less than the NIH as a whole. Per capita NIH funding of cardiothoracic surgeons is very much less than that of the NIH as a whole. The primary cause is the low per capita number of applications submitted by cardiothoracic surgeons. Junior cardiothoracic faculty should be encouraged to apply for career development awards. However, since the ability to shift cost from clinical to academic faculty is declining, affirmative action from the NIH may be necessary.


A rating scale for Gilles de la Tourette's syndrome: description, reliability, and validity data.
We developed a rating scale for tic disorders that uses only objective criteria and accommodates the variety of tic manifestations. Using short videotaped recordings with the examiner out of the taping room, we measured five tic variables: number of body areas affected, frequency of motor tics and vocalizations, and severity of motor tics and vocalizations. The rating scale fulfilled tests for inter-rater reliability and temporal stability, and correlated well with scales used to assess global changes over prolonged periods. It objectively detected improvement in tics with neuroleptics, the one pharmacotherapy accepted to abate tics in most patients.


Flexible subunit stoichiometry of functional human P2X2/3 heteromeric receptors.
The aim of the present work was to clarify whether heterotrimeric P2X2/3 receptors have a fixed subunit stoichiometry consisting of one P2X2 and two P2X3 subunits as previously suggested, or a flexible stoichiometry containing also the inverse subunit composition. For this purpose we transfected HEK293 cells with P2X2 and P2X3 encoding cDNA at the ratios of 1:2 and 4:1, and analysed the biophysical and pharmacological properties of the generated receptors by means of the whole-cell patch-clamp technique. The concentration-response curves for the selective agonist α,β-meATP did not differ from each other under the two transfection ratios. However, co-expression of an inactive P2X2 mutant and the wild type P2X3 subunit and vice versa resulted in characteristic distortions of the α,β-meATP concentration-response relationships, depending on which subunit was expressed in excess, suggesting that HEK293 cells express mixtures of (P2X2)1/(P2X3)2 and (P2X2)2/(P2X3)1 receptors. Whereas the allosteric modulators H+ and Zn2+ failed to discriminate between the two possible heterotrimeric receptor variants, the α,β-meATP-induced responses were blocked more potently by the competitive antagonist A317491, when the P2X2 subunit was expressed in deficit of the P2X3 subunit. Furthermore, blue-native PAGE analysis of P2X2 and P2X3 subunits co-expressed in Xenopus laevis oocytes and HEK293 cells revealed that plasma membrane-bound P2X2/3 receptors appeared in two clearly distinct heterotrimeric complexes: a (P2X2-GFP)2/(P2X3)1 complex and a (P2X2-GFP)1/(P2X3)2 complex. These data strongly indicate that the stoichiometry of the heteromeric P2X2/3 receptor is not fixed, but determined in a permutational manner by the relative availability of P2X2 and P2X3 subunits.


Treatment of narcolepsy-cataplexy syndrome with the new selective and reversible MAO-A inhibitor brofaromine-a pilot study.
Eighteen narcoleptic patients were treated in a single-blind study with brofaromine, a new selective and reversible MAO-A-inhibitor. After a drug-free period of seven days, brofaromine was administered for two weeks. Patients were treated with 75 mg brofaromine for the first week and with 150 mg brofaromine for the second week of the study. After an adaptation night nocturnal sleep EEGs were recorded under placebo before brofaromine was given, one week later under 75 mg, and another week later under 150 mg brofaromine. Excessive daytime sleepiness (EDS) was evaluated under placebo at the beginning of the study, under 75 mg at the end of the first week, and under 150 mg brofaromine at the end of the second week by means of the Multiple Sleep Latency Test (MSLT) and the Maintenance of Wakefulness Test (MWT). The number of cataplexies was protocolled by the patients. Compared to placebo the administration of 150 mg brofaromine led to a significant increase of sleep latency in the MLST as well as in the MWT. REM sleep was significantly suppressed in the nocturnal sleep EEG, in the MSLT and in the MWT. The number of cataplexies protocolled by the patient was significantly decreased under 150 mg of brofaromine compared to placebo. Improvement of vigilance and cataplexy occurred in dose-dependent manner. No serious side effects were observed. The results of the present single-blind study indicate that brofaromine seems to be a well-tolerated and effective drug for the treatment of excessive daytime sleepiness and cataplexy in narcoleptic patients.


MTHFR-1298 A>C (rs1801131) is a predictor of survival in two cohorts of stage II/III colorectal cancer patients treated with adjuvant fluoropyrimidine chemotherapy with or without oxaliplatin.
Adjuvant treatment based on fluoropyrimidines (FL) improves the prognosis of stage II/III colorectal cancer (CRC). Validated predictive/prognostic biomarkers would spare therapy-related morbidity in patients with a good prognosis. We compared the impact of a set of 22 FL-related polymorphisms with the prognosis of two cohorts of CRC patients treated with adjuvant FL with or without OXA, including a total of 262 cases. 5,10-Methylentetrahydrofolate reductase (MTHFR) MTHFR-1298 A>C (rs1801131) polymorphism had a concordant effect: MTHFR-rs1801131-1298CC genotype carriers had a worse disease free survival (DFS) in both the cohorts. In the pooled population MTHFR-rs1801131-1298CC carriers had also a worse overall survival. We computed a clinical score related to DFS including MTHFR-rs1801131, tumor stage, sex and tumor location, where rs1801131 is the most detrimental factor (hazard ratio=5.3, 95% confidence interval=2.2-12.9; P-value=0.0006). MTHFR-rs1801131 is a prognostic factor that could be used as an additional criteria for the choice of the proper adjuvant regimen in stage II/III colorectal cancer patients.


Trisomy 9 mosaicism diagnosed in utero.
We present three cases of trisomy 9 mosaicism diagnosed by amniocentesis with ongoing pregnancies after referral to our center due to fetal abnormalities. Two cases were associated with severe fetal growth restriction (FGR), each of which resulted in an intrauterine fetal demise (IUFD) in the third trimester. The other case involved mild FGR with a congenital diaphragmatic hernia and resulted in a live birth with severe development delay. A major prenatal finding of trisomy 9 mosaicism is FGR. Fetuses with trisomy 9 mosaicism can rarely survive in the case of severe FGR.


The cytoplasmic sites of the snRNP protein complexes are punctate structures that are responsive to changes in metabolism and intracellular architecture.
Five anti-Sm monoclonal antibodies, Y12, 7.13, KSm4, KSm6, and 128, stain similar discrete punctate structures distributed throughout the cytoplasm of hamster fibroblasts in addition to the expected intense nuclear staining. Several criteria suggest the cytoplasmic staining reflects the cytoplasmic pools of snRNP core proteins. The relative intensity of the cytoplasmic staining is similar to the 30% relative abundance of the cytoplasmic snRNP core proteins compared to the nuclear snRNP core proteins based on cell-fractionation studies. Moreover, the cytoplasmic staining is removed by the same extraction conditions that solubilize the pools of cytoplasmic snRNP core proteins. The cytoplasmic sites of staining are typically spherical but heterogeneous in diameter (0.2-0.5 microm). The larger particles greatly exceed the diameter of individual snRNP core particles and are likely to represent centers of many snRNP proteins or snRNP protein complexes. The staining, though punctate, is evenly dispersed throughout the cytoplasm with no evidence of major compartmentalization. The cytoplasmic staining pattern collapses into larger foci of intensely staining structures when cellular energy levels are depleted or when cells are exposed to hypertonic medium. Unlike the normal sites of snRNP protein cytoplasmic staining, these larger collapsed foci resist detergent extraction. These results suggest that the cytoplasmic staining identified with the anti-Sm monoclonal antibodies represents the large pools of snRNP core proteins in the cytoplasm.


FSCN‑1 increases doxorubicin resistance in hepatocellular carcinoma through promotion of epithelial-mesenchymal transition.
Resistance to chemotherapy drugs remains a significant problem for the treatment of many types of cancer. Fascin‑1 (FSCN‑1) is an actin-bundling protein involved in the invasion and metastasis of a variety of tumors. However, its involvement in drug resistance in hepatocellular carcinoma (HCC) remains unclear. The present study aimed to investigate the function of FSCN‑1 in HCC resistance to doxorubicin (DOX). FSCN‑1 expression was increased in DOX-resistant HCC cell lines (SNU449 and SNU387) compared with DOX-sensitive cell lines (Huh7 and Hep3B). The resistance of HCC cells to DOX was decreased following FSCN‑1 knockdown with small interfering RNA. FSCN‑1 knockdown also significantly altered the expression of key markers of epithelial-mesenchymal transition (EMT). Notably, vimentin expression was reduced and epithelial‑cadherin expression was increased. Furthermore, when EMT was suppressed through knockdown of Twist, an essential pathway of DOX-induced EMT, the viability of HCC cells following treatment with DOX was not affected by FSCN‑1 expression. Furthermore, FSCN‑1 knockdown eliminated hypoxia-induced doxorubicin resistance and EMT. The results of the present study indicated that FSCN‑1 expression increased DOX resistance in HCC cells via the promotion of EMT, and this phenomenon was maintained in a hypoxic environment. FSCN‑1 potentially represents a novel target to overcome resistance to DOX in HCC.


Dietary Cl(-) restriction upregulates pendrin expression within the apical plasma membrane of type B intercalated cells.
Pendrin, encoded by Slc26a4, is a Cl(-)/HCO(3)(-) exchanger expressed in the apical region of type B and non-A, non-B intercalated cells, which regulates renal NaCl excretion. Dietary Cl(-) restriction upregulates total pendrin protein expression. Whether the subcellular expression of pendrin and whether the apparent vascular volume contraction observed in Slc26a4 null mice are Cl(-) dependent, but Na(+) independent, is unknown. Thus the subcellular distribution of pendrin and its role in acid-base and fluid balance were explored using immunogold cytochemistry and balance studies of mice ingesting a NaCl-replete or a Na(+)-replete, Cl(-)-restricted diet, achieved through substitution of NaCl with NaHCO(3). Boundary length and apical plasma membrane pendrin label density each increased by approximately 60-70% in type B intercalated cells, but not in non-A, non-B cells, whereas cytoplasmic pendrin immunolabel increased approximately 60% in non-A, non-B intercalated cells, but not in type B cells. Following either NaCl restriction or Cl(-) restriction alone, Slc26a4 null mice excreted more Cl(-) and had a higher arterial pH than pair-fed wild-type mice. In conclusion, 1) following dietary Cl(-) restriction, apical plasma membrane pendrin immunolabel increases in type B intercalated cells, but not in non-A, non-B intercalated cells; and 2) pendrin participates in the regulation of renal Cl(-) excretion and arterial pH during dietary Cl(-) restriction.


Botulinum toxin in gait dysfunction due to ankle clonus: a case series.
Our purpose is to assess the effectiveness of Botulinum toxin (Btx) on gait dysfunction due to ankle clonus in neurological patients. We use a retrospective case note review of 11 patients attending the Regional Acquired Brain Injury Unit (RABIU), Musgrave Park Hospital, Belfast, Northern Ireland. All patients had received Btx for the treatment of ankle clonus. Demographic data including diagnosis and time since neurological insult was collected. Information regarding walking speed and assistance required to walk before and after Btx treatment was analysed. In 10 of 11 patients, walking speed was significantly improved at 4-6 weeks post Btx injections (P = 0.006) and at 14-16 weeks post Btx injections (P = 0.005). Eight patients reduced their level of dependency on assistance. Subjective improvements in levels of pain, gait pattern and 'toe clawing' were also reported. Our findings suggest that Botulinum toxin has a role in treating ankle clonus in neurological patients, where it interferes in gait. Walking speed and level of dependence on others improved in this group.


[The effect of combined therapy with the use of thymalin and piracetam on the level of middle-molecule peptides in the blood and on the lipid peroxidation activity in patients with diffuse toxic goiter].
The content of medium-weight molecular peptides (MMP), lipid peroxidation (LPO) activity, the profile of blood thyroid hormones, and radioactive iodine absorption by the thyroid were determined in 104 patients with light, moderate and grave diffuse toxic goiter (DTG). The content of MMP in the blood correlated with the gravity of DTG and thus may serve an additional test for its determination. Depending on the treatment 66 patients with DTG of medium gravity were distributed into 5 groups: group I included patients given mercazolyl, group II patients on lithium carbonate, group III patients who received mercazolyl and thymalin, group IV patients on mercazolyl and piracetam, and group V included patients given mercazolyl, thymalin and piracetam. A study was made of the blood content of MMP and LPO activity before therapy and after euthyroidism attainment. The treatment with the use of mercazolyl, thymalin and piracetam was found to produce a beneficial effect on the parameters under study and the clinical course of DTG.


Synthesis and iron sequestration equilibria of novel exocyclic 3-hydroxy-2-pyridinone donor group siderophore mimics.
The synthesis of a novel class of exocyclic bis- and tris-3,2-hydroxypyridinone (HOPO) chelators built on N(2) and N(3) aza-macrocyclic scaffolds and the thermodynamic solution characterization of their complexes with Fe(III) are described. The chelators for this study were prepared by reaction of either piperazine or N,N',N''-1,4,7-triazacyclononane with a novel electrophilic HOPO iminium salt in good yields. Subsequent removal of the benzyl protecting groups using HBr/acetic acid gave bis-HOPO chelators N(2)(etLH)(2) and N(2)(prLH)(2), and tris-HOPO chelator N(3)(etLH)(3) in excellent yields. Solution thermodynamic characterization of their complexes with Fe(III) was accomplished using spectrophotometric, potentiometric, and electrospray ionization-mass spectrometry (ESI-MS) methods. The pK(a)'s of N(2)(etLH)(2), N(2)(prLH)(2), and N(3)(etLH)(3), were determined spectrophotometrically and potentiometrically. The Fe(III) complex stability constants for the tetradentate N(2)(etLH)(2) and N(2)(prLH)(2), and hexadentate N(3)(etLH)(3), were measured by spectrophotometric and potentiometric titration, and by competition with ethylenediaminetetraacetic acid (EDTA). N(3)(etLH)(3) forms a 1:1 complex with Fe(III) with log β(110) = 27.34 ± 0.04. N(2)(prLH)(2) forms a 3:2 L:Fe complex with Fe(III) where log β(230) = 60.46 ± 0.04 and log β(110) = 20.39 ± 0.02. While N(2)(etLH)(2) also forms a 3:2 L:Fe complex with Fe(III), solubility problems precluded determining log β(230); log β(110) was found to be 20.45 ± 0.04. The pFe values of 26.5 for N(3)(etLH)(3) and 24.78 for N(2)(prLH)(2) are comparable to other siderophore molecules used in the treatment of iron overload, suggesting that these hydroxypyridinone ligands may be useful in the development of new chelation therapy agents.


The effect of tilmicosin on cardiac superoxide dismutase and glutathione peroxidase activities.
In this study, the effect of tilmicosin on cardiac superoxide dismutase and glutathione peroxidase activities was investigated. Forty male BALB/c mice were used as material. Ten mice served as a control group, and 30 mice were injected with tilmicosin (25 mg/kg body weight, subcutaneously, with a single injection). After drug administration, they were monitored for 3 days. Tilmicosin caused decreases in cardiac superoxide dismutase and glutathione peroxidase activities.


Adverse events related to the use of peripheral intravenous catheters in children according to dressing regimens.
A randomized, controlled study was implemented to verify reasons to release and adverse events related to the use of peripheral intravenous catheters in children, according to the dressing regimens The sample was set at 150 peripheral intravenous catheters, randomly assigned to three groups: sterile gauze dressings, sterilized transparent film dressings, and non sterile hypoallergenic adhesive tape. The data was collected after consent had been obtained by the Ethics Committee, including children who had been submitted to catheterization with Teflon(R) over the needle catheters. Statistical tests were performed by applying the Pearson Chi-square test, significance level set at p < 0.05. The results showed that dressing regimens influenced the reasons for catheter removal and occurrence of adverse events, mainly due to infiltration (55.3%). The Sterile gauze showed the best performance (p=0.002) in comparison with the other studied groups, once 40.0% of the catheters were removed by release from treatment.


The Sleep of the Bereaved.
OBJECTIVE: Sleep disruption is common in widow(er)s. The objective of this study was to characterize the sleep of Spousally Bereaved (SB) seniors (60y+) studied within 4-19 months of being widowed. METHOD: Subjective (PSQI, 2-weeks diary) and objective (2-weeks actigraphy) baseline sleep measures were obtained in 47 (38f, 9m) Spousally Bereaved (SB) seniors, 33 (25f, 8m) Good Sleeper Controls (GSC), and 47 (38f, 9m) Older Adults with Insomnia (OAI); each group with the same mean age (72y). OAI subjects passed formal diagnostic criteria for primary or co-morbid insomnia. GSC subjects had no diagnosis of insomnia. At baseline (pre-treatment), all subjects completed 2 weeks of detailed sleep diary and wrist actigraphy, and completed the Pittsburgh Sleep Quality Index (PSQI) among other measures. RESULTS: Significant group effects appeared in PSQI (GSC: 2.4, SB: 6.7, OAI: 10.5; Effect Sizes [ES]>1) and diary measures. In diary measures, for Total Sleep Time, Sleep Efficiency and Wake After Sleep Onset, SB were better than OAI and worse than GSC (0.47<ES<1.19). For Sleep Latency, SB were worse than GSC (ES=0.57), but similar to OAI. However, actigraphy results indicated no significant SB vs. GSC, or SB vs. OAI, differences in any of the sleep measures considered. CONCLUSION: The sleep disruption of bereaved seniors appears to be intermediate between GSC and OAI, as reported either retrospectively using the PSQI, or prospectively using a sleep diary. Only in diary sleep latency, were SB and OAI values similar. This pattern was not, however, observed when parallel objective actigraphic measures were considered.


Psychological side-effects of the mass screening on cervical cancer.
The results are reported of a study on the psychological side-effects of mass screening for cervical cancer in Rotterdam. The reactions of participants towards a positive smear and towards the treatment which followed the positive smear were analysed. Women who had problems with a positive smear and with a serious disorder which necessitated an operation and hospitalization had problems with the treatment. However, most women who underwent the operation did not have lasting problems of either a psychological or somatic nature. Women who had been treated by their G.P.s or by a gynaecologist in most cases did not have problems with their treatment. The final conclusion was that mass screening for cervical cancer in Rotterdam caused psychological side-effects to occur among women with a positive smear. However, for the majority of women with a positive smear they were not of a lasting or serious nature.


Single molecule behavior of inhibited and active states of Escherichia coli ATP synthase F1 rotation.
ATP hydrolysis-dependent rotation of the F(1) sector of the ATP synthase is a successive cycle of catalytic dwells (∼0.2 ms at 24 °C) and 120° rotation steps (∼0.6 ms) when observed under V(max) conditions using a low viscous drag 60-nm bead attached to the γ subunit (Sekiya, M., Nakamoto, R. K., Al-Shawi, M. K., Nakanishi-Matsui, M., and Futai, M. (2009) J. Biol. Chem. 284, 22401-22410). During the normal course of observation, the γ subunit pauses in a stochastic manner to a catalytically inhibited state that averages ∼1 s in duration. The rotation behavior with adenosine 5'-O-(3-thiotriphosphate) as the substrate or at a low ATP concentration (4 μM) indicates that the rotation is inhibited at the catalytic dwell when the bound ATP undergoes reversible hydrolysis/synthesis. The temperature dependence of rotation shows that F(1) requires ∼2-fold higher activation energy for the transition from the active to the inhibited state compared with that for normal steady-state rotation during the active state. Addition of superstoichiometric ε subunit, the inhibitor of F(1)-ATPase, decreases the rotation rate and at the same time increases the duration time of the inhibited state. Arrhenius analysis shows that the ε subunit has little effect on the transition between active and inhibited states. Rather, the ε subunit confers lower activation energy of steady-state rotation. These results suggest that the ε subunit plays a role in guiding the enzyme through the proper and efficient catalytic and transport rotational pathway but does not influence the transition to the inhibited state.


Clinical effectiveness of preoperative embolization for cerebellar hemangioblastoma.
The cerebellar hemangioblastoma (CHB) has an abundant blood supply and deep anatomical location. Complete surgical resection is generally very difficult. This study investigated the safety and effectiveness of preoperative embolization followed by surgical resection of CHB in a large cohort of patients. A database of 125 CHB patients with surgical resection in Beijing Tiantan Hospital between July 2006 and July 2012 was reviewed. Of those, 46 cases (experimental group) received preoperative embolization, 79 cases (control group) underwent surgery without embolization. Patient demographics, tumor size, duration of surgery, blood loss, blood transfusion, complications and follow-up results were collected and analyzed retrospectively. In the experimental group, the Kamofsky score (KS) was 80-100 in 40 cases (86.9%), 40-70 in 4 cases (8.7%), and below 40 in 2 cases (4.3%). Among 31 cases with follow-up, KS was 80-100 in 27 cases (87.1%), 40-70 in 2 cases (6.5%), and 0 in 2 cases (6.5%). In control group, KS was 80 -100 in 65 cases (82.2%), 40-70 in 6 cases (7.6%), 10-30 in 3 cases (3.8%), and 0 in 3 cases (3.8%). Among 53 cases with follow-up, KS was 80-100 in 44 cases (83.0%), 40-70 in 4 cases (7.5%), 10-30 in 1 case (1.9%), and 0 in 4 cases (7.5%). There were statistically significant differences between the experimental and control groups in tumor size, duration of surgery, amount of intraoperative blood loss and transfusion (p <0.01). However, complications (p = 0.31) and follow-up results (p = 0.76) showed no significant differences between groups. Selective preoperative embolization of those CHB patients with richer blood supply, higher hemorrhage risk, is safe and effective, and is a reliable adjuvant therapy for complete surgical resection of CHB.


Dysbiosis a risk factor for celiac disease.
Celiac disease remains one of the most challenging pathologies of the small intestine. It involves multiple pathogenic pathways and there are no disease-changing pharmacological agents available against it yet. The term microbiota refers to the community of microorganisms that inhabit a particular region of the body. Normal gut microbiota has a vital role in maintaining the intestinal homeostasis and promoting health. Celiac disease is associated with microbiota alteration, especially with an increase in the number of Gram-negative bacteria and a decrease in the number of Gram-positive bacteria. There is a strong relationship between intestinal dysbiosis and celiac disease, and recent studies are aimed at determining whether the celiac disease is a risk factor for dysbiosis or dysbiosis is for celiac disease. Therefore, the aim of this review was to assess the latest findings regarding the gut microbiota and its impact on the celiac disease, including therapeutic aspects.


Advances in biomarkers for the early diagnosis of prostate cancer.
More and more studies have revealed that the level of serum prostate specific antigen(PSA) has little value for early diagnosis of prostate cancer (PCa). For example, negative prostate biopsies are as high as 70%-80% for patients with serum PSA ranging between 4 ng/mL and 10 ng/mL. However, the negative results cannot exclude the existence of cancer. In the studies of the early diagnosis of PCa, investigators focused on seeking biomarkers that have higher sensitivity and specificity. Recently, PSA derivatives, HPC1, PCA3, TMPRSS2: ETS, GSTP1, AMACR, GOLPH2, EPCA, sarcosine, and the combination of multiple biomarkers are widely discussed. In this article, we have reviewed their recent development and the prospective value of the combination of multiple biomarkers, which may be helpful for the early diagnosis and the prognostic monitoring of patients with PCa.


Allergic contact dermatitis caused by 2-hydroxyethyl methacrylate and ethyl cyanoacrylate contained in cosmetic glues among hairdressers and beauticians who perform nail treatments and eyelash extension as well as hair extension applications: A systematic review.
Current cosmetic regulations primarily focus on protecting consumers, not the professional user who is subjected to a partly different, and certainly more intense exposure to hazardous substances. Against this background, this systematic review aims to compile and appraise evidence regarding skin toxicity of 2-hydroxyethyl methacrylate (HEMA; CAS no. 212-782-2) and ethyl cyanoacrylate (ECA; CAS no. 7085-85-0) contained in cosmetic glues used among hairdressers and beauticians who perform nail treatments and eyelash extension as well as hair extension applications. This systematic review followed the Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) 2020 recommendations for reporting systematic reviews and meta-analysis. In total, six publications from six countries were eligible for this systematic review. A meta-analysis revealed that hairdressers and beauticians have a ninefold increased risk of developing contact allergy to HEMA compared with controls who are not hairdressers and beauticians. Results for ECA are lacking. The results of this systematic review clearly show that-regarding contact allergy to acrylates-it is not appropriate to apply risk assessment for consumers to hairdressers and beauticians who occupationally handle cosmetic glues. The regulations in existence do not adequately address occupational risks for hairdressers and beauticians connected with the use of acrylate-containing cosmetic substances and need reconsideration.


Quantitative estimates of the optimal balance between digestible lysine and the true protein contents of broiler feeds.
Typical poultry feed formulation models have been developed for meeting the minimum specifications of the essential amino acids (EAAs), ignoring the importance of providing precise levels of the non-essential amino acids (NEAAs) that are required for maximum performance. Including true protein (TP) values in these models in relation to EAAs can most accurately account for the requirements of all amino acids (AAs) in the ration (essential, non-essential and excess EAAs). Data from recent research reports on the digestible lysine (dLys) requirements for maximum weight gain and minimum feed conversion ratio (FCR) were compiled from the literature. dLys requirements and the TP contents of the feeds were recalculated based on common ingredient composition values. Broken-line linear (BLL) and broken-line quadratic (BLQ) models were fitted to the data and compared. The dLys requirements of broilers (g/kg diet) for body weight gain (BWG) and FCR were found to increase linearly as a function of the true and crude protein contents of the diet. These relationships were not affected by either age or sex. As chickens aged, the dLys requirements decreased. However, the dLys requirement to TP ratio did not change with age for BWG or FCR. For maximum BWG and minimum FCR, the dLys requirements were estimated from the prediction models to be 4.92% ± 0.51 and 5.58% ± 0.70 of the TP level of the diet, using the BLL models, respectively. The good linear relationship between the dLys requirement and TP level allows the prediction of the variables from each other for use in feed formulation to represent the requirements of both EAAs and NEAAs. The dietary dLys requirements were estimated to be lower using the BLL vs. the BLQ models. TP was a better predictor of dLys requirements than crude protein (higher R(2) values).


Pretreatment Prediction of Individual Rheumatoid Arthritis Patients' Response to Anti-Cytokine Therapy Using Serum Cytokine/Chemokine/Soluble Receptor Biomarkers.
The inability to match rheumatoid arthritis (RA) patients with the anti-cytokine agent most efficacious for them is a major hindrance to patients' speedy recovery and to the clinical use of anti-cytokine therapy. Identifying predictive biomarkers that can assist in matching RA patients with more suitable anti-cytokine treatment was our aim in this report. The sample consisted of 138 RA patients (naïve and non-naïve) who were administered tocilizumab or etanercept for a minimum of 16 weeks as a prescribed RA treatment. Pretreatment serum samples were obtained from patients and clinical measures of their disease activity were evaluated at baseline and 16 weeks after treatment commenced. Using patients' pretreatment serum, we measured 31 cytokines/chemokines/soluble receptors and used multiple linear regression analysis to identify biomarkers that correlated with patients' symptom levels (DAS28-CRP score) at week 16 and multiple logistic analyses for biomarkers that correlated with patients' final outcome. The results revealed that sgp130, logIL-6, logIL-8, logEotaxin, logIP-10, logVEGF, logsTNFR-I and logsTNFR-II pretreatment serum levels were predictive of the week 16 DAS28-CRP score in naïve tocilizumab patients while sgp130, logGM-CSF and logIP-10 were predictive in non-naïve patients. Additionally, we found logIL-9, logVEGF and logTNF-α to be less reliable at predicting the week 16 DAS28-CRP score in naïve etanercept patients. Multiple linear regression and multiple logistic regression analyses identified biomarkers that were predictive of remission/non-remission in tocilizumab and etanercept therapy. Although less reliable than those for tocilizumab, we identified a few possible biomarkers for etanercept therapy. The biomarkers for these two therapies differ suggesting that their efficacy will vary for individual patients. We discovered biomarkers in RA pretreatment serum that predicted their week 16 DAS28-CRP score and clinical outcome to tocilizumab therapy. Most of these biomarkers, especially sgp130, are involved in RA pathogenesis and IL-6 signal transduction, which further suggests that they are highly reliable. UMIN-CTR Clinical Trial UMIN000016298.


Individual variation in the relation between body temperature and energy expenditure in response to elevated ambient temperature.
The question we address here is whether a mild increase in environmental temperature affects body temperature and energy expenditure, focusing on the individual variation in the relation between energy expenditure and body temperature. We studied eight normal weight healthy females, 48 h at an ambient temperature of 22 degrees C, and 48 h at 27 degrees C. Energy expenditure (EE) was measured in a respiration chamber. Subjects' skin temperature was measured continuously from 8:00 a.m. until 12:00 p.m.: forehead, infraclavicular zone, thigh, hand, and foot. Core temperature was determined tympanically. Body composition was determined by under water weighing. Exposure to 27 degrees C caused a significant increase in body temperature (both skin and core), a decrease in temperature gradients, and a decrease in energy expenditure. At 27 degrees C 24 h EE, adjusted for body composition, was significantly related to body tympanic temperature. The decrease in 24 h EE, at 27 degrees C ambient temperature, was significantly, negatively related to the increase in T(tym), indicating individual responses in adaptation to elevated ambient temperature. Changes in temperature gradient (comparing 27 degrees C with 22 degrees C) were negatively related to changes in EE. This shows that individuals differ in their response to an increase in environmental temperature regarding the relative contribution of insulative or metabolic adjustments.


Resistance of cotton rats, Sigmodon hispidus, to primary infection by Nippostrongylus brasiliensis.
The resistance of cotton rats, Sigmodon hispidus to Nippostrongylus brasiliensis infection was examined and compared the response to that of the susceptible Indian soft-furred rat, Millardia meltada. After a primary infection with infective third-stage N. brasiliensis larvae (L3), the number of eggs in feces and adult worm recovery rates from the small intestine of cotton rats were significantly lower than in the controls. To determine whether cotton rat resistance was observed during the migratory phase or the intestinal phase, cotton rats and control animals were challenged subcutaneously with L3 or intraduodenally with adult worms, and larval recovery from lungs and adult worm burden were evaluated. The recovery rate of larvae from the lungs of cotton rats was about five-fold lower than from controls. Adult worm recovery from the small intestine of cotton rats was also lower than that from the controls, but the difference (two-fold lower) was smaller than that observed for lung recovery. Carbon treatment at a dose of 250-500 mg/kg effectively increased larval worm recovery from the lungs of cotton rats. However, this treatment had no effect on worm recovery from the intestine after intraduodenal implantation of adult N. brasiliensis. These results suggest that macrophage function have important role in the expression of strong resistance during the migratory phase of N. brasiliensis infection in cotton rats.


Transforming growth factor-beta 1 (TGF-beta 1) expression and regulation in rat cortical astrocytes.
Transforming growth factor-beta 1 (TGF-beta 1) is a potent modulator of immune and glial cells' functions and thus, could play an important role in neuro-immune interaction. However, published reports disagree on whether or not TGF-beta 1 is expressed in normal brain. We demonstrate here the constitutive expression of TGF-beta 1 mRNA but not protein in both cerebral cortex and primary rat cortical astrocytes. Steady-state TGF-beta 1 mRNA level increased 2-fold in adult compared to neonatal cortex and during proliferation and differentiation of astrocytes in primary culture. This response was not accompanied by the appearance of detectable TGF-beta protein either in vivo or in vitro. However, both intracellular immunoreactive TGF-beta and extracellular TGF-beta 1 activity were detected upon in vitro stimulation of astrocytes with interleukin-1 (IL-1). The extracellular TGF-beta 1 increased with time of exposure to and concentration of IL-1. In contrast, the amount of TGF-beta 1 mRNA remained unchanged during stimulation of astrocytes with IL-1. These results suggest that the production of TGF-beta 1 in astrocytes is regulated at both mRNA and protein levels. The former may occur during astrocytic development, and the latter during astrocytic response to injury in association with elevation of IL-1.


A feasibility study comparing checklists and global rating forms to assess resident performance in clinical skills.
This study evaluated the feasibility of two different scoring forms for assessing the clinical performance of residents in anaesthesiology. One of the forms had a checklist format including task-specific items and the other was a global rating form with general dimensions of competence including 'clinical skills', 'communication skills' and 'knowledge'. Thirty-two clinicians representing 25 (83%) of the 30 training hospitals in the country participated in the study. The clinicians were randomized into two groups, each of which used one of the scoring formats to assess a resident's performance in four simulated clinical scenarios on videotape. Clinicians' opinions about the appropriateness of the scoring forms were rated on a scale of 1-5. The checklist format was rated significantly higher compared with the global rating form (mean 4.6, 0.5 vs. mean 3.5, 1.4, p < 0.001). The inter-rater agreement regarding pass/fail decisions was poor irrespective of the scoring form used. This was explained by clinicians' leniency as assessors rather than by lack of vigilance in the observations or disagreements on standards for good performance.


Hyperuricemia induced by the uricosuric drug probenecid in rats.
Stimulation of uric acid production by the well-known uricosuric drug probenecid was studied using potassium oxonate-treated rats and eviscerated rats subjected to functional hepatectomy. In oxonate-treated rats, probenecid was hyperuricosuric, increasing the glomerular-filtered amounts of uric acid and causing marked hyperuricemia. This could be completely blocked by combination dosing with allopurinol, an inhibitor of xanthine oxidase. In eviscerated rats subjected to functional hepatectomy, probenecid also increased plasma uric acid and urinary uric acid excretion, but when given together with allopurinol, the increase of plasma uric acid was abolished with a remarkable increase of plasma hypoxanthine and xanthine. When probenecid was given by combination dosing with propranolol, a beta adrenoceptor antagonist, the hyperuricemia was also completely blocked. Thus, probenecid is concluded to stimulate uric acid production, probably via some interaction with endogenous catecholamine, resulting in hyperuricemia in rats, although it is a practical hypouricemic drug in humans.


Connexin 26 expression and mutation analysis in epidermal disease.
Gap junctional communication has a key role in the co-ordination of keratinocyte differentiation. Multiple connexins are expressed in the epidermis and mutations in four of these connexins are associated with disorders of keratinisation. Specific autosomal dominant Cx26 mutations have been associated with syndromes of skin disease and hearing loss. Here we describe the characterization of a new Cx26 polyclonal antibody raised against the cytoplasmic region of the protein. It has been used to investigate Cx26 protein localization in epidermal disease and in the study of mutant Cx26 proteins.


Zinc carnosine-based modified bismuth quadruple therapy vs standard triple therapy for Helicobacter pylori eradication: A randomized controlled study.
Helicobacter pylori (H. pylori) infection is a worldwide problem with increasing burden on the health sector due to its increasing rate of resistance. The conventional triple therapy (TT) is becoming obsolete with a high failure rate of eradication, necessitating the need for better alternatives or regimens. To investigate H. pylori eradication rate of TT vs modified bismuth quadruple therapy. Ninety-two patients with dyspepsia symptoms and positive 13C-urea breath test were randomly assigned to two groups. The first group (control group) was treated for 14 d using standard TT protocol: Esomeprazole (40 mg twice daily), amoxicillin (1 g twice daily) and clarithromycin (500 mg twice daily). On the other hand, the second group was prescribed a 10-d course of modified bismuth quadruple therapy fortified with zinc carnosine: TT in addition to bismuth subcitrate (240 mg twice daily) and zinc carnosine (75 mg twice daily). A repeated 13C-urea breath test was done 4 wk after the completion of the eradication therapy. Among the 92 subjects, 67.4% were males and 32.6% were females. There were no differences in demographic characteristics (age, body mass index, smoking history, previous antibiotics use and ethnicity) between the modified bismuth quadruple therapy group and TT group. The eradication rate was higher [93.5% (43/46)] in the modified bismuth quadruple therapy group compared to 69.6% (32/46) in the standard TT group (P = 0.003). Of the tested predictor variables, only nationality, smoking and therapy type were statistically significant. Besides dizziness, which was recorded in modified bismuth quadruple therapy group, there were no significant differences in side effects between the two groups. Ten days of modified bismuth quadruple therapy fortified with zinc carnosine is superior to 14 d of conventional TT in eradicating H. pylori infection, with no additional significant adverse events.


The effects of anxiety on affective learning and serial position recall.
Sixty-five college-aged adults participated in a study that examined the effects of trait and state anxiety on learning positive and negative emotional words from the Affective Auditory Verbal Learning Test (AAVL). Self-reported state and trait anxiety were measured via Speilberger's State-Trait Anxiety Inventory (STAI). Each participant completed the five learning trials and delayed recall trial of the positive and negative word lists; order of administration for the word lists was counterbalanced across participants. Using ANOVA, initial analyses revealed significant effects for order of administration of the positive and negative word lists. ANCOVAs (using state and trait anxiety as covariates) yielded a significant interaction involving serial position, trial, and state anxiety as well as an interaction involving serial position, trial, and trait anxiety. Post hoc analyses did not support a priori hypotheses. However, state anxiety was associated with decreased word recall on the first learning trial. The results of this study indicate that state anxiety is initially associated with decreased performance when learning emotional words. However, these initial effects dissipate with subsequent learning trials. Implications for task performance are discussed.


[A girl with congenital hemifacial hypertrophy].
A girl with congenital hemifacial hypertrophy had been observed and treated by a multidisciplinary team for craniofacial disorders in an academic medical centre since birth. At the age of 8 she was treated on account of considerable facial asymmetry and multiple intraoral problems. The two-step surgery involved reduction of the maxilla and the zygoma, reduction of soft tissues, removal of the teeth on the affected side, correction of the alveolar ridges of the maxilla and the mandible and placement of oral implants. After a healing period of 4 months fixed partial dentures were constructed on the implants.


Association between Type 2 Diabetes Mellitus and Brain Atrophy: A Meta-Analysis.
Type 2 diabetes mellitus (T2DM) is known to be associated with cognitive decline and brain structural changes. This study systematically reviews and estimates human brain volumetric differences and atrophy associated with T2DM. PubMed, PsycInfo and Cochrane Library were searched for brain imaging studies reporting on brain volume differences between individuals with T2DM and healthy controls. Data were examined using meta-analysis, and association between age, sex, diabetes characteristics and brain volumes were tested using meta-regression. A total of 14,605 entries were identified; after title, abstract and full-text screening applying inclusion and exclusion criteria, 64 studies were included and 42 studies with compatible data contributed to the meta-analysis (n=31,630; mean age 71.0 years; 44.4% male; 26,942 control; 4,688 diabetes). Individuals with T2DM had significantly smaller total brain volume, total grey matter volume, total white matter volume and hippocampal volume (approximately 1% to 4%); meta-analyses of smaller samples focusing on other brain regions and brain atrophy rate in longitudinal investigations also indicated smaller brain volumes and greater brain atrophy associated with T2DM. Meta-regression suggests that diabetes-related brain volume differences start occurring in early adulthood, decreases with age and increases with diabetes duration. T2DM is associated with smaller total and regional brain volume and greater atrophy over time. These effects are substantial and highlight an urgent need to develop interventions to reduce the risk of T2DM for brain health.


Fragmentation of Kaolinite Aggregates Induced by Ion-Exchange Reactions within Adsorbed Humic Acid Layers.
Mixing of humic acids and kaolinite clay suspended in aqueous solution containing aluminum ions promotes aggregation of the clay instantaneously. To this fast clay destabilization succeed reversible fragmentation processes which display varying kinetic ranges for which the changes in the average masses of fragments are determined. We show the rate of formation of fragments to decay with the mass i as i(-2) and the maximal rate of aggregate breakup to increase with the fragment mass as i(lambda), where lambda lies between 0.35 and 0.40. At short terms the rate of variation of the average masses of the fragments is lower than expected from the theory. Aggregate fragmentation is attributed to slow progressive modifications in the positive and negative charge distributions within the amphoteric humic acid adsorbed layer, which are induced by the high density of positive charge existing on the clay surface after aluminum ion adsorption. Kaolinite-aluminum ion-humic acid complexes aggregate by forming initially linear small portions of stacked platelets. These portions are connected together to form larger agglomerates of fractal dimension close to 2.5. Copyright 2000 Academic Press.


Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer's disease.
We quantified the amount of amyloid beta-peptide (Abeta) immunoreactivity as well as amyloid deposits in a large cohort of transgenic mice overexpressing the V717F human amyloid precursor protein (APP(V717F+/-) TG mice) with no, one, or two mouse apolipoprotein E (Apoe) alleles at various ages. Remarkably, no amyloid deposits were found in any brain region of APP(V717F+/-) Apoe(-/-) TG mice as old as 22 mo of age, whereas age-matched APP(V717F +/-) Apoe(+/-) and Apoe(+/+) TG mice display abundant amyloid deposition. The amount of Abeta immunoreactivity in the hippocampus was also markedly reduced in an Apoe gene dose-dependent manner (Apoe(+/+) > Apoe(+/-) >> Apoe(-/-)), and no Abeta immunoreactivity was detected in the cerebral cortex of APP(V717F+/-) Apoe(-/-) TG mice at any of the time points examined. The absence of apolipoprotein E protein (apoE) dramatically reduced the amount of both Abeta(1-40) and Abeta(1-42) immunoreactive deposits as well as the resulting astrogliosis and microgliosis normally observed in APP(V717F) TG mice. ApoE immunoreactivity was detected in a subset of Abeta immunoreactive deposits and in virtually all thioflavine-S-fluorescent amyloid deposits. Because the absence of apoE alters neither the transcription or translation of the APP(V717F) transgene nor its processing to Abeta peptide(s), we postulate that apoE promotes both the deposition and fibrillization of Abeta, ultimately affecting clearance of protease-resistant Abeta/apoE aggregates. ApoE appears to play an essential role in amyloid deposition in brain, one of the neuropathological hallmarks of Alzheimer's disease.


Dynamics of the Dictyostelium discoideum mitochondrial proteome during vegetative growth, starvation and early stages of development.
In this study, a quantitative comparative proteomics approach has been used to analyze the Dictyostelium discoideum mitochondrial proteome variations during vegetative growth, starvation and the early stages of development. Application of 2-D DIGE technology allowed the detection of around 2000 protein spots on each 2-D gel with 180 proteins exhibiting significant changes in their expression level. In total, 96 proteins (51 unique and 45 redundant) were unambiguously identified. We show that the D. discoideum mitochondrial proteome adaptations mainly affect energy metabolism enzymes (the Krebs cycle, anaplerotic pathways, the oxidative phosphorylation system and energy dissipation), proteins involved in developmental and signaling processes as well as in protein biosynthesis and fate. The most striking observations were the opposite regulation of expression of citrate synthase and aconitase and the very large variation in the expression of the alternative oxidase that highlighted the importance of citrate and alternative oxidase in the physiology of the development of D. discoideum. Mitochondrial energy states measured in vivo with MitoTracker Orange CM Ros showed an increase in mitochondrial membrane polarization during D. discoideum starvation and starvation-induced development.


Supramolecular Nanostructures for Vaccines.
Although this is an era of pandemics and many devastating diseases, this is also a time when bionanotechnology flourishes, illuminating a multidisciplinary field where vaccines are quickly becoming a balsam and a prevention against insidious plagues. In this work, we tried to gain and also give a deeper understanding on nanovaccines and their way of acting to prevent or cure cancer, infectious diseases, and diseases caused by parasites. Major nanoadjuvants and nanovaccines are temptatively exemplified trying to contextualize our own work and its relative importance to the field. The main properties for novel adjuvants seem to be the nanosize, the cationic character, and the biocompatibility, even if it is achieved in a low dose-dependent manner.


Translocation of malpositioned posterior chamber intraocular lens from anterior to posterior chamber along with fibrin glue-assisted transscleral fixation.
A posterior chamber intraocular lens (PCIOL) wrongly placed in anterior chamber (AC) can lead to progressive endothelial loss and damage to angle structures. We describe a sutureless, closed-chamber translocation technique to maneuver a PCIOL from AC into the PC and fixate it transsclerally with fibrin glue in presence of a large posterior capsular rent. This is a prospective interventional case series. The participants were three cases of PCIOL in AC with high intraocular pressure and poor uncorrected visual acuity who underwent the translocation surgery successfully. All cases showed improvement in uncorrected visual acuity, with lowered intraocular pressure and no loss in best spectacle-corrected visual acuity till 6 months follow-up. This technique prevents a large incision, does not require a special IOL as in transscleral suture fixation, and results in a low endothelial cell loss.


Profiling and bioinformatic analysis of circular RNA expression regulated by c-Myc.
The c-Myc transcription factor is involved in cell proliferation, cell cycle and apoptosis by activating or repressing transcription of multiple genes. Circular RNAs (circRNAs) are widely expressed non-coding RNAs participating in the regulation of gene expression. Using a high-throughput microarray assay, we showed that Myc regulates the expression of certain circRNAs. A total of 309 up- and 252 down-regulated circRNAs were identified. Among them, randomly selected 8 circRNAs were confirmed by real-time PCR. Subsequently, Myc-binding sites were found to generally exist in the promoter regions of differentially expressed circRNAs. Based on miRNA sponge mechanism, we constructed circRNAs/miRNAs network regulated by Myc, suggesting that circRNAs may widely regulate protein expression through miRNA sponge mechanism. Lastly, we took advantage of Gene Ontology and KEGG analyses to point out that Myc-regulated circRNAs could impact cell proliferation through affecting Ras signaling pathway and pathways in cancer. Our study for the first time demonstrated that Myc transcription factor regulates the expression of circRNAs, adding a novel component of the Myc tumorigenic program and opening a window to investigate the function of certain circRNAs in tumorigenesis.


Hyponatremia - A rare complication of Gitelman's syndrome.
Gitelman's syndrome (GS) is a rare autosomal recessive disorder caused by mutations in thiazide-sensitive NaCl cotransporter. We report a 49-year-old, normotensive lady with prolonged hypokalemia since her 20s who was diagnosed with GS at our renal clinic. During follow-up, she was found to have mild, asymptomatic, euvolemic hyponatremia with low serum uric acid, inappropriately high urine osmolality and sodium consistent with syndrome of inappropriate antidiuretic hormone-like presentation. Despite life-long urinary sodium losses, hyponatremia has rarely been reported in GS to be due to the primary disease process. We present relevant clinical data and hypothesize on why this disease per se may be a risk factor for dilutional hyponatremia.