A clinical perspective of obesity, metabolic syndrome and cardiovascular disease.
The metabolic syndrome is a condition characterized by a special constellation of reversible major risk factors for cardiovascular disease and type 2 diabetes. The main, diagnostic, components are reduced HDL-cholesterol, raised triglycerides, blood pressure and fasting plasma glucose, all of which are related to weight gain, specifically intra-abdominal/ectopic fat accumulation and a large waist circumference. Using internationally adopted arbitrary cut-off values for waist circumference, having metabolic syndrome doubles the risk of cardiovascular disease, but offers an effective treatment approach through weight management. Metabolic syndrome now affects 30-40% of people by age 65, driven mainly by adult weight gain, and by a genetic or epigenetic predisposition to intra-abdominal/ectopic fat accumulation related to poor intra-uterine growth. Metabolic syndrome is also promoted by a lack of subcutaneous adipose tissue, low skeletal muscle mass and anti-retroviral drugs. Reducing weight by 5-10%, by diet and exercise, with or without, anti-obesity drugs, substantially lowers all metabolic syndrome components, and risk of type 2 diabetes and cardiovascular disease. Other cardiovascular disease risk factors such as smoking should be corrected as a priority. Anti-diabetic agents which improve insulin resistance and reduce blood pressure, lipids and weight should be preferred for diabetic patients with metabolic syndrome. Bariatric surgery offers an alternative treatment for those with BMI ≥ 40 or 35-40 kg/m(2) with other significant co-morbidity. The prevalence of the metabolic syndrome and cardiovascular disease is expected to rise along with the global obesity epidemic: greater emphasis should be given to effective early weight-management to reduce risk in pre-symptomatic individuals with large waists.


Predictors of urinary continence recovery after modified radical prostatectomy for clinically high-risk prostate cancer.
To retrospectively determine predictors of urinary continence (UC) recovery in clinically high-risk prostate cancer (PCa) patients treated with modified radical prostatectomy (RP). A total of 184 patients with clinically high-risk PCa who underwent modified RP in a single Chinese center were retrospectively reviewed. Pelvic floor muscle training with biofeedback was routinely performed after catheter removal. UC was defined as wearing 0 or 1 protective pad daily. Univariate and multivariate Cox regression analyses were performed to determine the predictors of UC recovery. The median age at surgery was 69.5 years (range 48-82), and the median follow-up duration was 40 months (range 12-111). Only 40 patients (21.7%) received a nerve-sparing procedure. For patients with restored UC, the median time to continence was 1 month (range 1-24). UC recovery at 1 month, 6 months, 12 months and the most recent follow-up was observed in 99 (53.8%), 158 (85.9%), 171 (92.9%) and 174 (94.6%) patients, respectively. Multivariate Cox regression analysis showed that patient age < 70 years (hazard ratio 1.684, P = .003) and smaller prostate volume (hazard ratio 0.989, P = .036), but not the surgical approach or treatment with a nerve-sparing procedure, independently predicted UC recovery. Age < 70 years and smaller prostate volume were independent predictors of UC recovery in clinically high-risk PCa patients. The adverse factors of high-risk disease were not significantly associated with UC recovery. These results may help surgeons preoperatively counsel patients regarding expected UC outcomes following RP.


Exploring Support for 100% College Tobacco-Free Policies and Tobacco-Free Campuses Among College Tobacco Users.
Tobacco-free campus policy is identified as an effective means to address tobacco use on college campuses; however, the prevalence of tobacco-free policies (TFPs) in the United States remains low. This study explores college tobacco users' support for a university's TFP and tobacco-free campuses (TFCs) in general. A standardized and structured questionnaire was administered to 790 college tobacco users recruited in a university located in a tobacco-growing region of the United States, during April-May 2011, to collect information on support for TFPs and TFCs and sociodemographic-political characteristics. Descriptive and multivariable logistic regression analyses were conducted to identify key factors associated with support for TFPs and TFCs. Approximately 2 of 5 tobacco users favored TFPs and TFCs. Multivariable logistic regression models showed that demographic factors were mostly not significantly associated with attitudes of the college tobacco users. Instead, while knowledge about harmful effects of exposure to secondhand tobacco smoke significantly increased support for both TFPs and TFCs, parental and peer smoking and exposure to tobacco industry promotions significantly decreased the likelihoods of support compared with respective referent groups. Study findings suggest that campus advocacy and education campaigns for campus tobacco policies to pay attention to tobacco use behavior of familial relations, tobacco industry activities, and other political determinants of tobacco users' attitudes. Thus, this study should inform national initiatives to promote TFPs nationwide such as the Tobacco-Free College Campus Initiative.


[Cardiovascular response to mental and physical stress in hyper-reactive normotensive subjects. Beta blockade effect].
The aim of our study was to evaluate the cardiovascular reactivity in healthy normotensive subjects without medication, using mental and physical stress techniques: Stroop color word conflict test (SCWCT), anticipatory blood pressure response to exercise (ARE) and stress testing (ST). We analized the effects of a selective beta 1 betablocker: bisoprolol (B) on cardiovascular reactivity in our subjects (s). We studied 42 s, but only 30 (21 females and 9 males) were included who were hyperreactives. The mean age was 42.5 years. The higher values of systolic (SBP) and diastolic blood pressure (DBP) during the mental stress (MS) were taken as a measure of reactivity considering hyperreactive response an increase of 30 mm Hg or more and/or 15 mm Hg or more respectively. A prospective, randomized and double blind study on the effects of an oral daily doses of B (5 mg) vs placebo (P) was performed. Statistical analysis was realized with the Fisher exact test. In the results, we could observed a lower sensitivity of ARE and ST vs SCWCT. The 15 s who recieved P followed hyperreactives but 6 of 15 s treated with B were non reactives (p<0.017). B showed a beneficial effect on the hyperreactivity in a significant number of s in relation with P and it could be useful for the prevention of a future hypertension.


Multidetector computed tomography and 3-dimensional imaging: preoperative evaluation of thoracic vascular and tracheobronchial anomalies and abnormalities in pediatric patients.
In the past decade, rapid technical developments and advancements of multidetector computed tomography (MDCT) have revolutionized the preoperative imaging evaluation of thoracic vascular and tracheobronchial anomalies and abnormalities in infants and children. Multidetector computed tomography enables noninvasive, rapid, high-resolution, and 3-dimensional (3D) imaging of the thorax in pediatric patients that provides comprehensive preoperative surgical guidance for pediatric surgeons. With the increasing availability of MDCT and 3D imaging, a practical review is needed for the pediatric surgeon of the evolving role of these techniques in the preoperative evaluation of surgical lesions in infants and children. This article focuses on the review of advantages and disadvantages of MDCT in comparison to other imaging modalities, 2D and 3D imaging postprocessing techniques, and MDCT and 3D imaging appearance of various thoracic vascular and tracheobronchial anomalies and abnormalities in pediatric patients. The primary aim of this article was to facilitate the pediatric surgeons' ability to successfully incorporate MDCT and 3D imaging as a routine preoperative imaging tool for the evaluation of thoracic surgical lesions in infants and children.


A prospective study of venous hemodynamics and quality of live at least five years after varicose vein stripping.
To assess venous hemodynamics and quality of life at lest five years after varicose vein stripping. We conducted a prospective study with 39 patients (63 limbs) with primary lower limbs varicose veins. Preoperatively, all patients were subjected to clinical evaluation, duplex ultrassound, air plethysmography (APG), and CIVIQ questionnaire of quality of life. By APG, venous filling index (VFI), ejection fraction (EF), and residual volume fraction (RVF) were determined. CIVIQ addresses four domains in course of 20 questions, including states of physical, social, and psychological well-being, and pain level. Varicose veins were treated by standard venous stripping. At least five years after surgery (77.9 ± 10.9 months), patients were reassessed and had clinical examination, duplex ultrasound, APG, and CIVIQ repeated. No late follow-up data was available for 24 patients. Preoperative and late postoperative VFI levels were similar, whereas EF (P=0.05) and RVF (P=0.01), as hemodynamic variables, significantly improved following surgery. In the late postoperative period, overall CIVIQ scores were significantly lower (P=0.005), as were scores in all four domains: pain (P=0.001), physical (P=0.007), social (P=0.008), and psychological (P= 0.05). In a small prospective cohort, improvements in venous hemodynamics and in quality of life of patients submitted to standard varicose veins stripping were maintained five years after the procedure.


An international study to revise the EORTC questionnaire for assessing quality of life in lung cancer patients.
The European Organization for Research and Treatment of Cancer (EORTC) QLQ-LC13 was the first module to be used in conjunction with the core questionnaire, the QLQ-C30. Since the publication of the LC13 in 1994, major advances have occurred in the treatment of lung cancer. Given this, an update of the EORTC QLQ-LC13 was undertaken. The study followed phases I to III of the EORTC Module Development Guidelines. Phase I generated relevant quality-of-life issues using a mix of sources including the involvement of 108 lung cancer patients. Phase II transformed issues into questionnaire items. In an international multicenter study (phase III), patients completed both the EORTC QLQ-C30 and the 48-item provisional lung cancer module generated in phases I and II. Patients rated each of the items regarding relevance, comprehensibility, and acceptance. Patient ratings were assessed against a set of prespecified statistical criteria. Descriptive statistics and basic psychometric analyses were carried out. The phase III study enrolled 200 patients with histologically confirmed lung cancer from 12 centers in nine countries (Cyprus, Germany, Italy, Israel, Spain, Norway, Poland, Taiwan, and the UK). Mean age was 64 years (39 - 91), 59% of the patients were male, 82% had non-small-cell lung cancer, and 56% were treated with palliative intent. Twenty-nine of the 48 questions met the criteria for inclusion. The resulting module with 29 questions, thus currently named EORTC QLQ-LC29, retained 12 of the 13 original items, supplemented with 17 items that primarily assess treatment side-effects of traditional and newer therapies.


Immunogenicity of an electron beam inactivated Rhodococcus equi vaccine in neonatal foals.
Rhodococcus equi is an important pathogen of foals that causes severe pneumonia. To date, there is no licensed vaccine effective against R. equi pneumonia of foals. The objectives of our study were to develop an electron beam (eBeam) inactivated vaccine against R. equi and evaluate its immunogenicity. A dose of eBeam irradiation that inactivated replication of R. equi while maintaining outer cell wall integrity was identified. Enteral administration of eBeam inactivated R. equi increased interferon-γ production by peripheral blood mononuclear cells in response to stimulation with virulent R. equi and generated naso-pharyngeal R. equi-specific IgA in newborn foals. Our results indicate that eBeam irradiated R. equi administered enterally produce cell-mediated and upper respiratory mucosal immune responses, in the face of passively transferred maternal antibodies, similar to those produced in response to enteral administration of live organisms (a strategy which previously has been documented to protect foals against intrabronchial infection with virulent R. equi). No evidence of adverse effects was noted among vaccinated foals.


Stimulus-dependent EEG activity reflects internal updating of tactile working memory in humans.
Despite recent advances in uncovering the neural signature of tactile working memory processing in animals and humans, the representation of internally modified somatosensory working memory content has not been studied so far. Here, recording EEG in human participants (n = 25) performing a modified delayed match-to-sample task allowed us to disambiguate internally driven memory processing from encoding-related delay activity. After presentation of two distinct vibrotactile frequencies to different index fingers, a visual cue indicated which of the two previous stimuli had to be maintained in working memory throughout a retention interval for subsequent frequency discrimination against a probe stimulus. During cued stimulus maintenance, α activity (8-13 Hz) over early somatosensory cortices was lateralized according to the cued tactile stimulus, even though the location of the stimuli was task irrelevant. The task-relevant memory content, in contrast, was found to be represented in right prefrontal cortex. The key finding was that the visually presented instructions triggered systematic modulations of prefrontal β-band activity (20-25 Hz), which selectively reflected the to-be-maintained frequency of the cued tactile vibration. The results expand previous evidence for parametric representations of vibrotactile frequency in the prefrontal cortex and corroborate a central role of dynamic β-band synchronization during active processing of an analog stimulus quantity in human working memory. In particular, our findings suggest that such processing supports not only sustained maintenance but also purposeful modification and updating of the task-relevant working memory contents.


Materials In Paintings (MIP): An interdisciplinary dataset for perception, art history, and computer vision.
In this paper, we capture and explore the painterly depictions of materials to enable the study of depiction and perception of materials through the artists' eye. We annotated a dataset of 19k paintings with 200k+ bounding boxes from which polygon segments were automatically extracted. Each bounding box was assigned a coarse material label (e.g., fabric) and half was also assigned a fine-grained label (e.g., velvety, silky). The dataset in its entirety is available for browsing and downloading at materialsinpaintings.tudelft.nl. We demonstrate the cross-disciplinary utility of our dataset by presenting novel findings across human perception, art history and, computer vision. Our experiments include a demonstration of how painters create convincing depictions using a stylized approach. We further provide an analysis of the spatial and probabilistic distributions of materials depicted in paintings, in which we for example show that strong patterns exists for material presence and location. Furthermore, we demonstrate how paintings could be used to build more robust computer vision classifiers by learning a more perceptually relevant feature representation. Additionally, we demonstrate that training classifiers on paintings could be used to uncover hidden perceptual cues by visualizing the features used by the classifiers. We conclude that our dataset of painterly material depictions is a rich source for gaining insights into the depiction and perception of materials across multiple disciplines and hope that the release of this dataset will drive multidisciplinary research.


The antioxidant action of human extracellular fluids. Effect of human serum and its protein components on the inactivation of alpha 1-antiproteinase by hypochlorous acid and by hydrogen peroxide.
The elastase-inhibitory capacity of purified human alpha 1-antiproteinase is inactivated by low concentrations of the myeloperoxidase-derived oxidant hypochlorous acid, but much higher concentrations are required to inhibit the elastase-inhibitory capacity of serum samples. The protective effect of serum appears to be largely due to albumin. High concentrations of H2O2 also inactivate the elastase-inhibitory capacity of alpha 1-antiproteinase, by a mechanism not involving formation of hydroxyl radicals. Serum offers protection against H2O2 inactivation of alpha 1-antiproteinase. The relevance of these results to the tissue damage produced by activated phagocytes is discussed.


The relationship between the VO2 slow component, muscle metabolites and performance during very-heavy exhaustive exercise.
This study examined the relationship between the V O(2) response, particularly the slow component (SC), muscle metabolite changes and performance during very-heavy exhaustive exercise. Sixteen active females performed a graded exercise test to determine V O(2peak) and the lactate threshold followed 48h later by a constant-load cycle test to exhaustion (ET) at 85% V O(2peak) intensity. Muscle biopsies and capillary blood samples were obtained before and after the ET to determine changes in muscle ATP, pH, lactate and phosphocreatine and also plasma pH and lactate. Breath-by-breath data from the ET were smoothed using 5-s averages and fit to a three-component exponential model. The mean time to exhaustion (t(exh)) during the ET was 16.8 (+/-6.4) min. Results showed no correlation between the SC and t(exh) or any muscle metabolite changes (p>0.05). Significant correlations (p<0.05) were evident between t(exh) and tau; tau(0) (r=-0.54), tau(1) (r=-0.65), change in (Delta) pH(b) (r=-0.60), Delta[La(-)](b) (r=-0.58) and [La(-)](b post) (r=-0.64). Significant correlations (p<0.05) were also evident between tau(1) and [La(-)](b post) (r=0.54). Furthermore, a negative value resulted when the accumulated oxygen deficit was calculated for the entire duration of the ET. Results showed no association between the amplitude of the SC and t(ext) or to changes in muscle/blood metabolites, suggesting that the SC is not a determinant of high-intensity exercise tolerance. Furthermore, it is possible that a reduced perturbation of anaerobic energy sources, as a result of a faster tau(1), may have contributed to a longer t(exh).


Mesenchymal stem cells and their extracellular vesicles in urological cancers: Prostate, bladder, and kidney.
Mesenchymal stem cells (MSCs) are recognized for their remarkable ability to differentiate into multiple cell types. They are also known to possess properties that can fight cancer, leading to attempts to modify MSCs for use in anticancer treatments. However, MSCs have also been found to participate in pathways that promote tumor growth. Many studies have been conducted to explore the potential of MSCs for clinical applications, but the results have been inconclusive, possibly due to the diverse nature of MSC populations. Furthermore, the conflicting roles of MSCs in inhibiting tumors and promoting tumor growth hinder their adaptation to anticancer therapies. Antitumorigenic and protumorigenic properties of MSCs in urological cancers such as bladder, prostate, and renal are not as well established, and data comparing them are still limited. MSCs hold significant promise as a vehicle for delivering anticancer agents and suicide genes to tumors. Presently, numerous studies have concentrated on the products derived from MSCs, such as extracellular vesicles (EVs), as a form of cell-free therapy. This work aimed to review and discuss the current knowledge of MSCs and their EVs in urological cancer therapy.


Regulation of cell proliferation by epidermal growth factor.
Epidermal Growth Factor (EGF) is a 6045 dalton polypeptide which stimulates the proliferation of various cell types in vitro and in vivo. EGF binds to diffusely distributed membrane receptors which rapidly cluster primarily on coated pits areas on the plasma membrane. Subsequently, the EGF-receptor complexes are endocytosed and degraded by lysosomal enzymes. The lateral diffusion coefficient (D) of EGF-receptor complexes on cultured cells increases gradually from D = 2.8 X 10(-10) cm2/sec at 5 degrees C to 8.5 X 10(-10) cm2/sec at 37 degrees C. In the same range of temperature the rotational correlation times change from 25 to 50 microseconds to approximately 350 microseconds. Hence, at 4 degrees C, the occupied EGF receptors translate and rotate rapidly in the plane of the membrane. At 37 degrees C, EGF receptors form microclusters composed of 10 to 50 molecules. Moreover, it is concluded that both at 4 degrees C and 37 degrees C lateral diffusion of the occupied receptors is not the rate determining step for either receptor clustering or internalization. EGF receptor is a 150,000 to 170,000 dalton glycoprotein. The receptor is in close proximity to an EGF-sensitive, cAMP-independent, tyrosine-specific protein kinase which also phosphorylates the receptor molecules itself. The EGF sensitive kinase is similar to the kinase activity which is associated with certain RNA tumor viruses. The fact that the non-mitogenic cyanogen-bromide cleaved EGF is as potent as native EGF in stimulating phosphorylation suggests that EGF-induced, protein phosphorylation is a necessary but insufficient signal for the induction of DNA synthesis by EGF. EGF receptor serves also as the binding site for Transforming Growth Factors (TGF) which compete with EGF and induce anchorage-independent growth of normal cells in soft agar. Tumor promoters such as phorbol ester effect the binding of EGF to its membrane receptors and its ability to stimulate DNA synthesis. EGF itself has also some tumor promoting activity. Hence, the membrane receptor for EGF seems to participate in the regulation of normal and neoplastic growth. Monoclonal antibodies against EGF receptor (IgM) induce various early and delayed effects of EGF, while their monovalent Fab' fragments are devoid of biological activity. These observations support the notions that EGF receptor rather than EGF itself is the active moiety and that the role of the hormone is to perturb the receptor in the appropriate way, probably by inducing the microaggregation of EGF receptors.


Public Health Requirements and Authorities in State Statutory Disaster Recovery Law: A Cross-Sectional Legal Assessment.
State statutory laws serve as a vital tool for public health entities to assist communities with recovery from disasters. However, no systematic assessment has examined the content of state law addressing disaster recovery or explored if and how the public health role is discussed in state law addressing disaster recovery. This study examined public health-related requirements, authorities, and activities in state disaster recovery laws. Nexis Uni, a legal database, was used to identify codified state statutory laws that authorize or require specific state or local public health entity actions, or set conditions where public health entity actions could be authorized/required, related to disaster recovery planning, implementation, or evaluation (ie, health disaster recovery laws). Disaster recovery laws were reviewed and coded to identify health-related requirements, authorities, and activities planned for recovery. Most states (n = 47) have disaster recovery laws, and 17 states were found to have 30 codified statutory health disaster recovery laws. Half (n = 15) of identified laws require a public health liaison to or representation on a recovery committee or other organization/body working on recovery planning or implementation activities. State disaster recovery laws have limited public health requirements, authorities, and activities. Further research is needed to assess the potential public health benefits of components of state law supporting public health involvement in disaster recovery. The development and dissemination of best practices or model laws and tools to provide opportunities for public health actors to inform recovery decision making may enhance the potential for health promotion during disaster recovery.


Deciphering the inhibition effect of thymoquinone on xanthine oxidase activity using differential pulse voltammetry in combination with theoretical studies.
Xanthine oxidase (XO) catalyzes the oxidation of xanthine to uric acid. Over-production of uric acid is a risk factor for hyperuricemia and other diseases. Although allopurinol decreases uric acid levels, it causes severe adverse effects. Therefore, more effort is needed in finding novel XO inhibitors with fewer side effects. In this study, differential pulse voltammetry was used to investigate the inhibitory effect of thymoquinone (TQ) on the XO activity while the major problem was the overlap of the obtained signals. Thus, Parallel Factor Analysis (PARAFAC) was applied to extract the useful information. Also, docking was used to investigate how TQ and the active site of XO fit together. PARAFAC results based on the voltammetry studies revealed that TQ blocks the catalytic centers of XO, which leads to a decrease in the electrochemical signal of Mo center in XO. The results also indicated the dose-dependent inhibition of XO with TQ. Molecular docking studies were shown TQ surrounds the active sites of XO and reduces the oxidation of xanthine to uric acid. Therefore, the electrochemical response of Mo decreases in the presence of TQ. This finding is in good agreement with the results obtained from molecular docking studies.


Ethical and practical challenges to studying patients who opt out of large-scale biorepository research.
Large-scale biorepositories that couple biologic specimens with electronic health records containing documentation of phenotypic expression can accelerate scientific research and discovery. However, differences between those subjects who participate in biorepository-based research and the population from which they are drawn may influence research validity. While an opt-out approach to biorepository-based research enhances inclusiveness, empirical research evaluating voluntariness, risk, and the feasibility of an opt-out approach is sparse, and factors influencing patients' decisions to opt out are understudied. Determining why patients choose to opt out may help to improve voluntariness, however there may be ethical and logistical challenges to studying those who opt out. In this perspective paper, the authors explore what is known about research based on the opt-out model, describe a large-scale biorepository that leverages the opt-out model, and review specific ethical and logistical challenges to bridging the research gaps that remain.


Activation of the neutrophil respiratory burst oxidase.
The neutrophil respiratory burst oxidase is a multicomponent activatable enzyme comprising one of the major phagocyte antimicrobial systems. In the genetic disorder chronic granulomatous disease, absent oxidase function is associated with recurrent, severe, and often life-threatening infections. The components of the oxidase system include both membrane-bound and soluble cytosolic proteins. A primary feature of stimulus-dependent activation is the translocation of a complex of cytosolic factors to the membrane, where they associate with a flavocytochrome enzyme. Interactions among the various oxidase components occur through a number of specific regions, including SH3 domains and proline-rich motifs. The fully assembled complex functions as an electron transport system, moving electrons from cytosolic NADPH to molecular oxygen to form superoxide, which, along with subsequent reactive products, exerts microbicidal and cytotoxic activities.


Development and usage of eXtension's HorseQuest: an online resource.
eXtension (pronounced e-extension) is an online resource transforming how faculty can collaborate and deliver equine education. As the first Community of Practice launched from eXtension, HorseQuest (HQ) offers free, interactive, peer-reviewed, online resources on a variety of equine-related topics at http://www.extension.org. This group has adapted traditional educational content to the online environment to maximize search engine optimization, to be more discoverable and relevant in the online world. This means that HQ resources are consistently being found on the first page of search results. Also, by researching key words searched by Internet users, HQ has guided new content direction and determined potential webcast topics based on relevance and frequency of those searches. In addition to establishing good search engine optimization, HQ has been utilizing the viral networking aspect of YouTube by uploading clips of existing equine educational videos to YouTube. HorseQuest content appears in mainstream media, is passed on by the user, and helps HQ effectively reach their community of interest (horse enthusiasts). HorseQuest partners with My Horse University to produce webcasts that combine concise knowledge exchange via a scripted presentation with viewer chat and incoming questions. HorseQuest has produced and published content including 12 learning modules, 8 webchats, 21 webcasts, and 572 videos segments. After the official public launch, there was a steady increase in average number of visits/mo and average page views/mo over the 26-mo period. These regressions show a statistically significant increase in visits (P < 0.001) of approximately 450 visits per month and a significant increase in page views (P = 0.004) of about 373 page views per month. HorseQuest is a resource for several state 4-H advancement and competition programs and will continue to be incorporated into traditional extension programs, while reaching and affecting global audiences.


Stability and change in etiological factors for alcohol use disorder and major depression.
Alcohol use disorder (AUD) and major depressive disorder (MDD) are often comorbid. It is not understood how genetic risk factors for these disorders relate to each other over time and to what degree they are stable. Age-dependent characteristics of the disorders indicate that different genetic factors could be relevant at different stages of life, and MDD may become increasingly correlated with AUD over time. DSM-IV diagnoses of AUD and MDD were assessed by interviews of 2,801 young adult twins between 1999 and 2004 (T1) and 2,284 of the same twins between 2010 and 2011 (T2). Stability, change, and covariation were investigated in longitudinal biometric models. New genetic factors explained 56.4% of the genetic variance in AUD at T2. For MDD, there was full overlap between genetic influences at T1 and T2. Genetic risk factors for MDD were related to AUD, but their association with AUD did not increase over time. Thus, genetic risk factors for AUD, but not MDD, vary with age, suggesting that AUD has age-dependent heritable etiologies. Molecular genetic studies of AUD may therefore benefit from stratifying by age. The new genetic factors in AUD were not related to MDD. Environmental influences on the 2 disorders were correlated in middle, but not in young adulthood. The environmental components for AUD correlated over time (r = .27), but not for MDD. Environmental influences on AUD can have long-lasting effects, and the effects of preventive efforts may be enduring. Environment influences seem to be largely transient. (PsycINFO Database Record


Proteoglycans in normal and severely osteoarthritic human cartilage.
Proteoglycans from osteoarthritic cartilage were compared with those from normal articular cartilage. Normal proteoglycan aggregates are larger in size and more homogeneous than those in osteoarthritis. Proteoglycan monomers from both sources gave two peaks on controlled pore glass-bead chromatography. Although the retarded material from normal cartilage showed an affinity for hyaluronate, the same material from osteoarthritic cartilage did not. The hyaluronate-binding capacity of the material which is partly in the void volume and partly retarded was similar in both types of cartilage. These results suggest that in osteoarthritic cartilage the proteoglycan aggregates are smaller and more heterogeneous and that the chondroitin sulphate side chains are shorter. They also indicate that there are two populations of proteoglycan, one with its hyaluronate-binding-protein region of core protein intact and the other either possessing an inactive binding region or totally lacking it.


Incidence of cancer and overall risk of mortality in individuals treated with raltegravir-based and non-raltegravir-based combination antiretroviral therapy regimens.
There are currently few data on the long-term risk of cancer and death in individuals taking raltegravir (RAL). The aim of this analysis was to evaluate whether there is evidence for an association. The EuroSIDA cohort was divided into three groups: those starting RAL-based combination antiretroviral therapy (cART) on or after 21 December 2007 (RAL); a historical cohort (HIST) of individuals adding a new antiretroviral (ARV) drug (not RAL) to their cART between 1 January 2005 and 20 December 2007, and a concurrent cohort (CONC) of individuals adding a new ARV drug (not RAL) to their cART on or after 21 December 2007. Baseline characteristics were compared using logistic regression. The incidences of newly diagnosed malignancies and death were compared using Poisson regression. The RAL cohort included 1470 individuals [with 4058 person-years of follow-up (PYFU)] compared with 3787 (4472 PYFU) and 4467 (10 691 PYFU) in the HIST and CONC cohorts, respectively. The prevalence of non-AIDS-related malignancies prior to baseline tended to be higher in the RAL cohort vs. the HIST cohort [adjusted odds ratio (aOR) 1.31; 95% confidence interval (CI) 0.95-1.80] and vs. the CONC cohort (aOR 1.89; 95% CI 1.37-2.61). In intention-to-treat (ITT) analysis (events: RAL, 50; HIST, 45; CONC, 127), the incidence of all new malignancies was 1.11 (95% CI 0.84-1.46) per 100 PYFU in the RAL cohort vs. 1.20 (95% CI 0.90-1.61) and 0.83 (95% CI 0.70-0.99) in the HIST and CONC cohorts, respectively. After adjustment, there was no evidence for a difference in the risk of malignancies [adjusted rate ratio (RR) 0.73; 95% CI 0.47-1.14 for RALvs. HIST; RR 0.95; 95% CI 0.65-1.39 for RALvs. CONC] or mortality (adjusted RR 0.87; 95% CI 0.53-1.43 for RALvs. HIST; RR 1.14; 95% CI 0.76-1.72 for RALvs. CONC). We found no evidence for an oncogenic risk or poorer survival associated with using RAL compared with control groups.


Video-assisted thoracoscopic surgery for migration of a Kirschner wire in the spinal canal: a case report and literature review.
Orthopedic wires and pins are regularly used for the treatment of dislocations and bone fractures. Migration of these metallic fixation devices into the spinal canal is an uncommon complication. We present a 35-year-old man who underwent thoracic spinal canal migration of a Kirschner wire. The patient had undergone treatment of acromioclavicular joint dislocation with Kirschner wire fixation. Two months after the operation, a chest radiograph showed a Kirschner wire in the thoracic cavity. Chest computed tomography (CT) showed the object extended transversely across the spinal canal. Emergency video-assisted thoracoscopic surgery (VATS) was successfully performed to remove the Kirschner wire without any complication. The patient made an uneventful recovery and was discharged on the seventh day after surgery. In our opinion, it is important to pay attention to the migration of metallic fixation devices. Surgical removal of such migrated devices is necessary for preventing disastrous consequences. VATS is a safe and effective treatment in such cases.


Increasing tumor thickness is associated with recurrence and poorer survival in patients with Merkel cell carcinoma.
Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine tumor usually occurring on sun-exposed skin in elderly patients. Clinical and pathologic factors associated with disease progression and mortality in patients with MCC are poorly defined. Recently, it has been reported that p63 expression in primary MCC is strongly associated with clinical outcome. MCC patients diagnosed between July 1, 1993 and July 31, 2009 were identified from the surgical pathology records of the Sydney South West Area Health Service. Clinical, pathologic, treatment, and survival data were obtained and immunohistochemical analyses for p53, p63, and Ki-67 were performed. The associations of clinical and pathologic features with disease-free and disease-specific survival were analyzed. Ninety-five patients were identified (67 males, 28 females; median age at diagnosis of primary MCC 76 [range, 42-93] years). Increasing primary tumor thickness was significantly associated with poorer disease-free survival (5-year survival 18 % in tumors >10 mm thick compared with 69 % for patients with tumors ≤10 mm thick, p = 0.002) and disease-specific survival (5-year survival 74 % in tumors >10 mm thick compared with 97 % for patients with tumors ≤10 mm thick, p = 0.006). There was a strong positive correlation between the Ki-67 index (proportion of Ki-67-positive tumor nuclei) and tumor thickness (r = 0.39, n = 45, p = 0.008). Positive staining for p63 in MCC was infrequent (9 % of primary MCC) and showed no significant association with disease outcome. Tumor thickness is significantly associated with disease-free survival in MCC. We recommend that primary tumor thickness be routinely recorded in the pathology reports of patients with primary MCC.


Constructive feedforward ART clustering networks. II.
For pt.I see ibid., p.645-61 (2002). Part I of this paper defines the class of constructive unsupervised on-line learning simplified adaptive resonance theory (SART) clustering networks. Proposed instances of class SART are the symmetric fuzzy ART (S-Fuzzy ART) and the Gaussian ART (GART) network. In Part II of our work, a third network belonging to class SART, termed fully self-organizing SART (FOSART), is presented and discussed. FOSART is a constructive, soft-to-hard competitive, topology-preserving, minimum-distance-to-means clustering algorithm capable of: 1) generating processing units and lateral connections on an example-driven basis and 2) removing processing units and lateral connections on a minibatch basis. FOSART is compared with Fuzzy ART, S-Fuzzy ART, GART and other well-known clustering techniques (e.g., neural gas and self-organizing map) in several unsupervised learning tasks, such as vector quantization, perceptual grouping and 3-D surface reconstruction. These experiments prove that when compared with other unsupervised learning networks, FOSART provides an interesting balance between easy user interaction, performance accuracy, efficiency, robustness, and flexibility.


How a fungus shapes biotechnology: 100 years of Aspergillus niger research.
In 1917, a food chemist named James Currie made a promising discovery: any strain of the filamentous mould Aspergillus niger would produce high concentrations of citric acid when grown in sugar medium. This tricarboxylic acid, which we now know is an intermediate of the Krebs cycle, had previously been extracted from citrus fruits for applications in food and beverage production. Two years after Currie's discovery, industrial-level production using A. niger began, the biochemical fermentation industry started to flourish, and industrial biotechnology was born. A century later, citric acid production using this mould is a multi-billion dollar industry, with A. niger additionally producing a diverse range of proteins, enzymes and secondary metabolites. In this review, we assess main developments in the field of A. niger biology over the last 100 years and highlight scientific breakthroughs and discoveries which were influential for both basic and applied fungal research in and outside the A. niger community. We give special focus to two developments of the last decade: systems biology and genome editing. We also summarize the current international A. niger research community, and end by speculating on the future of fundamental research on this fascinating fungus and its exploitation in industrial biotechnology.


The polarity protein Scrib is essential for directed endothelial cell migration.
Polarity proteins are involved in the apico-basal orientation of epithelial cells, but relatively little is known regarding their function in mesenchymal cells. We hypothesized that polarity proteins also contribute to endothelial processes like angiogenesis. Screening of endothelial cells revealed high expression of the polarity protein Scribble (Scrib). On fibronectin-coated carriers Scrib siRNA (siScrib) blocked directed but not random migration of human umbilical vein endothelial cells and led to an increased number and disturbed orientation of cellular lamellipodia. Coimmunoprecipitation/mass spectrometry and glutathione S-transferase (GST) pulldown assays identified integrin α5 as a novel Scrib interacting protein. By total internal reflection fluorescence (TIRF) microscopy, Scrib and integrin α5 colocalize at the basal plasma membrane of endothelial cells. Western blot and fluorescence activated cell sorting (FACS) analysis revealed that silencing of Scrib reduced the protein amount and surface expression of integrin α5 whereas surface expression of integrin αV was unaffected. Moreover, in contrast to fibronectin, the ligand of integrin α5, directional migration on collagen mediated by collagen-binding integrins was unaffected by siScrib. Mechanistically, Scrib supported integrin α5 recycling and protein stability by blocking its interaction with Rab7a, its translocation into lysosomes, and its subsequent degradation by pepstatin-sensitive proteases. In siScrib-treated cells, reinduction of the wild-type protein but not of PSD95, Dlg, ZO-1 (PDZ), or leucine rich repeat domain mutants restored integrin α5 abundance and directional cell migration. The downregulation of Scrib function in Tg(kdrl:EGFP)(s843) transgenic zebrafish embryos delayed the angiogenesis of intersegmental vessels. Scrib is a novel regulator of integrin α5 turnover and sorting, which is required for oriented cell migration and sprouting angiogenesis.


Validation of Davson's equation in patients suffering from idiopathic normal pressure hydrocephalus.
The so-called Davson's equation relates baseline intracranial pressure (ICP) to resistance to cerebrospinal fluid outflow (Rout), formation of cerebrospinal fluid (If) and sagittal sinus pressure (PSS) There is a controversy over whether this fundamental equation is applicable in patients with normal pressure hydrocephalus (NPH). We investigated the relationship between Rout and ICP and also other compensatory, clinical and demographic parameters in NPH patients. We carried out a retrospective study of 229 patients with primary NPH who had undergone constant-rate infusion studies in our hospital. Data was recorded and processed using ICM+ software. Relationships between variables were sought by calculating Pearson product correlation coefficients and p values. We found a significant, albeit weak, relationship between ICP and Rout (R = 0.17, p = 0.0049), Rout and peak-to-peak amplitude of ICP (AMP) (R = 0.27, p = 3.577e-05) and Rout and age (R = 0.16, p = 0.01306). The relationship found between ICP and Rout provides indirect evidence to support disturbed Cerebrospinal fluid circulation as a key factor in disturbed CSF dynamics in NPH. Weak correlation may indicate that other factors-variable PSS and formation of CSF outflow-contribute heavily to linear model expressed by Davson's equation.


Pretraining and posttraining assessment of residents' performance in the fourth accreditation council for graduate medical education competency: patient communication skills.
Structured communication curricula will improve surgical residents' ability to communicate effectively with patients. A prospective study approved by the institutional review board involved 44 University of Connecticut general surgery residents. Residents initially completed a written baseline survey to assess general communication skills awareness. In step 1 of the study, residents were randomized to 1 of 2 simulations using standardized patient instructors to mimic patients receiving a diagnosis of either breast or rectal cancer. The standardized patient instructors scored residents' communication skills using a case-specific content checklist and Master Interview Rating Scale. In step 2 of the study, residents attended a 3-part interactive program that comprised (1) principles of patient communication; (2) experiences of a surgeon (role as physician, patient, and patient's spouse); and (3) role-playing (3-resident groups played patient, physician, and observer roles and rated their own performance). In step 3, residents were retested as in step 1, using a crossover case design. Scores were analyzed using Wilcoxon signed rank test with a Bonferroni correction. Case-specific performance improved significantly, from a pretest content checklist median score of 8.5 (65%) to a posttest median of 11.0 (84%) (P = .005 by Wilcoxon signed rank test for paired ordinal data)(n = 44). Median Master Interview Rating Scale scores changed from 58.0 before testing (P = .10) to 61.5 after testing (P = .94). Difference between overall rectal cancer scores and breast cancer scores also were not significant. Patient communication skills need to be taught as part of residency training. With limited training, case-specific skills (herein, involving patients with cancer) are likely to improve more than general communication skills.


Parent-child attachment and internalizing symptoms in childhood and adolescence: a review of empirical findings and future directions.
The purpose of this paper is to evaluate the theory and evidence for the links of parent-child attachment with internalizing problems in childhood and adolescence. We address three key questions: (a) how consistent is the evidence that attachment security or insecurity is linked to internalizing symptoms, anxiety, and depression? (b) How consistent is the evidence that specific forms of insecurity are more strongly related to internalizing symptoms, anxiety, and depression than are other forms of insecurity? (c) Are associations with internalizing symptoms, anxiety, and depression consistent for mother-child and father-child attachment? The current findings are consistent with the hypothesis that insecure attachment is associated with the development of internalizing problems. The links between specific insecure attachment patterns and internalizing problems are difficult to evaluate. Father-child and mother-child attachments have a comparable impact, although there are relatively few studies of father-child attachment. No moderators consistently affect these relations. We also propose two models of how attachment insecurity may combine with other factors to lead to anxiety or depression.


Safety of percutaneous endoscopic gastrostomy in high-risk patients.
Percutaneous endoscopic gastrostomy (PEG) is a minimally invasive procedure. However, failure to transilluminate the anterior wall of the stomach or visualize the indentation of the physician's finger represents the most frequent obstacles encountered by the endoscopist in safely completing PEG tube placement. We described several methods to safely assess PEG placement in high-risk patients. An abdominal plain film after gastric insufflated with 500 mL of air is obtained before PEG in patients. The body of the stomach near the angularis, equidistant from the greater and lesser curves, was defined as the optimal gastric puncture point. The location of the puncture points varied greatly, being situated over the right upper quadrant in 31% of patients, left upper in 59%, left lower in 5%, and right lower quadrant in 5% of patients. If there is any question of safe puncture site selection, safe track technique can be used to provide the information of depth and angle of the puncture tract. Computed tomography can provide detailed anatomy and orientation along the PEG tube and show detailed anatomical images along the PEG tract. Computed tomography-guided PEG tube placement is used when there is difficulty either insufflating the stomach, or the patients had previous surgery, or anatomical problems. Full assessment of the position of the stomach and adjacent organs prior to gastric puncture may help minimize the risk for potential complications and provide safety for the high-risk patients.


Compensatory lung growth after bilobectomy in emphysematous rats.
Lung volume reduction surgery (LVRS) is an option for emphysematous patients who are awaiting lung transplantation. LVRS reduces nonfunctional portions of lung tissues and favors the compensatory lung growth (CLG) of the remaining lobes. This phenomenon diminishes dyspnea and improves both the respiratory mechanics and quality of life for the patients. An animal model of elastase-induced pulmonary emphysema was used to investigate the structural and functional lung response after LVRS. Bilobectomy was performed six weeks after elastase instillation. Two weeks after bilobectomy, CLG effects were evaluated by lung mechanics and histomorphometric analysis. After bilobectomy, the emphysematous animals presented decreased mean linear intercepts, increased elastic fiber proportion, and increased alveolar surface density, total volumes of airspace, tissue and respiratory region and absolute surface area. We conclude that bilobectomy promoted CLG in emphysematous animals, resulting in alveolar architecture repair.


Stimulus-Induced Relief of Intentionally Incorporated Frustration Drives Refolding of a Water-Soluble Biomimetic Foldamer.
Frustrated, or nonoptimal, interactions have been proposed to be essential to a protein's ability to display responsive behavior such as allostery, conformational signaling, and signal transduction. However, the intentional incorporation of frustrated noncovalent interactions has not been explored as a design element in the field of dynamic foldamers. Here, we report the design, synthesis, characterization, and molecular dynamics simulations of the first dynamic water-soluble foldamer that, in response to a stimulus, exploits relief of frustration in its noncovalent network to structurally rearrange from a pleated to an intercalated columnar structure. Thus, relief of frustration provides the energetic driving force for structural rearrangement. This work represents a previously unexplored design element for the development of stimulus-responsive systems that has potential application to materials chemistry, synthetic biology, and molecular machines.


Gut mucosal cells transfer α-synuclein to the vagus nerve.
Epidemiological and histopathological findings have raised the possibility that misfolded α-synuclein protein might spread from the gut to the brain and increase the risk of Parkinson's disease (PD). While past experimental studies in mouse models have relied on gut injections of exogenous recombinant α-synuclein fibrils to study gut to brain α-synuclein transfer, the possible origins of misfolded α-synuclein within the gut have remained elusive. We recently demonstrated that sensory cells of the gut mucosa express α-synuclein. In this study, we employed mouse intestinal organoids expressing human α-synuclein to observe the transfer of α-synuclein protein from gut epithelial cells in organoids co-cultured with vagal nodose neurons that are otherwise devoid of α-synuclein expression. In intact mice that express pathological human α-synuclein, but no mouse α-synuclein, α-synuclein fibril templating activity emerges in α-synuclein seeded fibril aggregation assays in tissues from the gut, vagus nerve, and dorsal motor nucleus. In newly engineered transgenic mice that restrict pathological human α-synuclein expression to intestinal epithelial cells, α-synuclein fibril-templating activity transfers to the vagus nerve and to the dorsal motor nucleus. Subdiaphragmatic vagotomy prior to the induction of α-synuclein expression in the gut epithelial cells effectively protects the hindbrain from the emergence of α-synuclein fibril templating activity. Overall, these findings highlight a novel potential non-neuronal source of fibrillar α-synuclein protein that might arise in gut mucosal cells.


The number of parents who are patients attending adult psychiatric services.
Having a parent with a mental illness is a major risk to children's wellbeing. The first step in developing policies and procedures that could assist these children is to determine the numbers of parents attending adult psychiatric services. This is the first systematic examination of the literature regarding the prevalence and family circumstances of parents attending adult psychiatric services. Nine peer reviewed publications showed parent prevalence in adult services ranging from 12.2 to 45.0%. Prevalence variability is associated with the type of adult service (e.g. inpatient and outpatient), sampling (e.g. single service versus whole of state) and parent characteristics (e.g. sex, diagnosis, relationship status, family information). A large minority of adult psychiatric service patients are parents. Given the prevention and early intervention benefits for parents and their families, adult psychiatric services need to be responsive to their needs. Future research should distinguish the type of service being audited, parent sex and diagnosis and the family circumstances that imbue greater risks to families, as well as opportunities to support children.


Impact of a disruption of a pathway delivering copper to mitochondria on Podospora anserina metabolism and life span.
A global depletion of cellular copper as the result of a deficiency in high-affinity copper uptake was previously shown to affect the phenotype and life span of the filamentous fungus Podospora anserina. We report here the construction of a strain in which the delivery of copper to complex IV of the mitochondrial respiratory chain is affected. This strain, PaCox17::ble, is a PaCox17-null mutant that does not synthesize the molecular chaperone targeting copper to cytochrome c oxidase subunit II. PaCox17::ble is characterized by a decreased growth rate, a reduction in aerial hyphae formation, reduced female fertility, and a dramatic increase in life span. The mutant respires via a cyanide-resistant alternative pathway, displays superoxide dismutase (SOD) activity profiles significantly differing from those of the wild-type strain and is characterized by a stabilization of the mitochondrial DNA. Collectively, the presented data define individual components of a molecular network effective in life span modulation and copper as an element with a dual effect. As a cofactor of complex IV of the respiratory chain, it is indirectly involved in the generation of reactive oxygen species (ROS) and thereby plays a life span-limiting role. In contrast, Cu/Zn SOD as a ROS-scavenging enzyme lowers molecular damage and thus positively affects life span. Such considerations explain the reported differences in life span of independent mutants and spread more light on the delicate tuning of the molecular network influencing biological ageing.


Effective use of the research consultant.
A principal investigator (PI) often includes a consultant in a proposal for a research project either at the request of the funding agency or because a consultant may add expertise to the research team. The most effective use of the consultant may vary according to the needs and gaps in areas of expertise of the team. Lippitt and Lippitt (1978) developed a model for guiding consultation that has been adapted in this article to guide not only the consultant but also the researcher in how to effectively use a consultant. The model is adaptable whether the principal investigator is new to designing and implementing research projects and needs a consultant expert in the research process or the PI has much research experience and needs a clinically expert consultant. The six phases of this model from contact and entry through contract completion is a step-by-step guide that is adaptable to the needs of the PI and research team.


The Effect of a Six-Month Dancing Program on Motor-Cognitive Dual-Task Performance in Older Adults.
Dancing is a complex sensorimotor activity involving physical and mental elements which have positive effects on cognitive functions and motor control. The present randomized controlled trial aims to analyze the effects of a dancing program on the performance on a motor-cognitive dual task. Data of 35 older adults, who were assigned to a dancing group or a health-related exercise group, are presented in the study. In pretest and posttest, we assessed cognitive performance and variability of minimum foot clearance, stride time, and stride length while walking. Regarding the cognitive performance and the stride-to-stride variability of minimum foot clearance, interaction effects have been found, indicating that dancing lowers gait variability to a higher extent than conventional health-related exercise. The data show that dancing improves minimum foot clearance variability and cognitive performance in a dual-task situation. Multi-task exercises (like dancing) might be a powerful tool to improve motor-cognitive dual-task performance.


Effect of early oxygen therapy and antiviral treatment on disease progression in patients with COVID-19: A retrospective study of medical charts in China.
Until now, no antiviral treatment has been proven to be effective for the coronavirus disease 2019 (COVID-19). The timing of oxygen therapy was considered to have a great influence on the symptomatic relief of hypoxemia and seeking medical intervention, especially in situations with insufficient medical resources, but the evidence on the timing of oxygen therapy is limited. Medical charts review was carried out to collect the data of hospitalized patients with COVID-19 infection confirmed in Tongji hospital, Wuhan from 30th December 2019 to 8th March 2020. In this study, the appropriate timing of oxygen therapy and risk factors associated with severe and fatal illness were identified and the effectiveness of antivirus on disease progression was assessed. Among 1362 patients, the prevalence of hypoxia symptoms was significantly higher in those patients with severe and fatal illness than in those with less severe disease. The onset of hypoxia symptoms was most common in the second to third week after symptom onset, and patients with critical and fatal illness experienced these symptoms earlier than those with mild and severe illness. In multivariable analyses, the risk of death increased significantly when oxygen therapy was started more than 2 days after hypoxia symptoms onset among critical patients (OR, 1.92; 95%CI, 1.20 to 3.10). Compared to the critically ill patients without IFN-a, the patients who were treated with IFN-a had a lower mortality (OR, 0.60; 95%CI, 0.39 to 0.91). Early initiation of oxygen therapy was associated with lower mortality among critical patients. This study highlighted the importance of early oxygen therapy after the onset of hypoxia symptoms. Our results also lend support to potentially beneficial effects of IFNα on critical illness.


Irrigation management of sigmoid colostomy.
Questionnaires were sent to 270 patients who had undergone abdominoperineal resection and sigmoid colostomy at the Mayo Clinic, Rochester, Minn, during the ten years from 1972 to 1982; 223 patients returned their questionnaires with evaluable data. Sixty percent of the patients were continent with irrigation, and 22% were incontinent with irrigation. Eighteen percent had discontinued irrigation for various reasons. The proportion continent was higher in women, younger patients, and previously constipated patients. A poorly constructed colostomy may cause acute angle, parastoma hernia, stomal prolapse, or stenosis and thus be the cause of failure of irrigation.


Spectrum constructing with nonuniform samples using least-squares approximation by cosine polynomials.
The least-squares approximation of cosine polynomials is used to construct the spectrum from the simulated nonuniform samples of the interferogram given by a step-mirror-based static Fourier transform spectrometer. Numerical and experimental results show the stability of the algorithm and a spectrum-constructing error of 0.03%.


Amino acid changes in the spike protein of feline coronavirus correlate with systemic spread of virus from the intestine and not with feline infectious peritonitis.
Recent evidence suggests that a mutation in the spike protein gene of feline coronavirus (FCoV), which results in an amino acid change from methionine to leucine at position 1058, may be associated with feline infectious peritonitis (FIP). Tissue and faecal samples collected post mortem from cats diagnosed with or without FIP were subjected to RNA extraction and quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) to detect FCoV RNA. In cats with FIP, 95% of tissue, and 81% of faecal samples were PCR-positive, as opposed to 22% of tissue, and 60% of faecal samples in cats without FIP. Relative FCoV copy numbers were significantly higher in the cats with FIP, both in tissues (P < 0.001) and faeces (P = 0.02). PCR-positive samples underwent pyrosequencing encompassing position 1058 of the FCoV spike protein. This identified a methionine codon at position 1058, consistent with the shedding of an enteric form of FCoV, in 77% of the faecal samples from cats with FIP, and in 100% of the samples from cats without FIP. In contrast, 91% of the tissue samples from cats with FIP and 89% from cats without FIP had a leucine codon at position 1058, consistent with a systemic form of FCoV. These results suggest that the methionine to leucine substitution at position 1058 in the FCoV spike protein is indicative of systemic spread of FCoV from the intestine, rather than a virus with the potential to cause FIP.


Fighting an old disease with modern tools: characteristics and molecular detection methods of drug-resistant Mycobacterium tuberculosis.
Tuberculosis (TB) is an ancient disease, but not a disease of the past. The increasing prevalence of drug-resistant strains of Mycobacterium tuberculosis, the causative agent of TB, demands new measures to combat the situation. Rapid and accurate detection of the pathogen, and its drug susceptibility pattern, is essential for timely initiation of treatment, and ultimately, control of the disease. Molecular-based methods offer a great chance to improve detection of drug-resistant TB; however, their development and usage should be accompanied with a profound understanding of drug resistance mechanisms and circulating M. tuberculosis strains in specific settings, as otherwise, the usefulness of such tests may be limited. This review gives an overview of the history of TB treatment and drug resistance, drug resistance mechanisms for the most commonly used drugs and molecular methods designed to detect drug-resistant strains.


Radiation track, DNA damage and response-a review.
The purpose of this paper has been to review the current status and progress of the field of radiation biophysics, and draw attention to the fact that physics, in general, and radiation physics in particular, with the aid of mathematical modeling, can help elucidate biological mechanisms and cancer therapies. We hypothesize that concepts of condensed-matter physics along with the new genomic knowledge and technologies and mechanistic mathematical modeling in conjunction with advances in experimental DNA (Deoxyrinonucleic acid molecule) repair and cell signaling have now provided us with unprecedented opportunities in radiation biophysics to address problems in targeted cancer therapy, and genetic risk estimation in humans. Obviously, one is not dealing with 'low-hanging fruit', but it will be a major scientific achievement if it becomes possible to state, in another decade or so, that we can link mechanistically the stages between the initial radiation-induced DNA damage; in particular, at doses of radiation less than 2 Gy and with structural changes in genomic DNA as a precursor to cell inactivation and/or mutations leading to genetic diseases. The paper presents recent development in the physics of radiation track structure contained in the computer code system KURBUC, in particular for low-energy electrons in the condensed phase of water for which we provide a comprehensive discussion of the dielectric response function approach. The state-of-the-art in the simulation of proton and carbon ion tracks in the Bragg peak region is also presented. The paper presents a critical discussion of the models used for elastic scattering, and the validity of the trajectory approach in low-electron transport. Brief discussions of mechanistic and quantitative aspects of microdosimetry, DNA damage and DNA repair are also included as developed by the authors' work.


The choice between two distinct T cell determinants within a 23-amino acid region of lysozyme depends on their structural context.
The specificity of C57BL/6 T cells reactive to peptide aa 74-96 of hen egg-white lysozyme (HEL) was analyzed by using a panel of synthetic peptides of varying lengths from this region. It was found that peptide 74-96-reactive T cells induced by native HEL (aa 1-129) or its denatured fragment L2 (aa 13-105) recognized two distinct but overlapping determinants contained within aa 74-90 or aa 81-96, respectively. Peptide 74-96 itself induced both peptide 74-90-and peptide 81-96-specific T cells. Thus, a choice was made between these two potential T cell determinants on peptide 74-96, depending on which immunogen was used. Interestingly, the ability of both peptide determinants aa 74-90 and aa 81-96 to stimulate peptide 74-96-reactive T cells was partly dependent on the presence of residues within the overlap region (aa 81-90), suggesting that this region may play an important role in Iab-restricted T cell activation. This was further supported by the poor immunogenicity of shorter peptides 74-86 or 85-96, lacking residues from the overlap region in B6 mice. These two short peptides were nevertheless capable of eliciting T cell responses in B10.A mice, suggesting that the importance of this overlap region in obtaining a response to peptide 74-96 is related to the MHC haplotype.


Looking back on the discovery of alpha-bungarotoxin.
This review is a personal narration by a retiring pharmacologist from Taiwan who looks back at his discovery of alpha-bungarotoxin from the historical perspective of Taiwan during the last 50 years, with accounts of his experiences and his efforts to overcome hardship. How the alpha-toxin was isolated and characterized as an irreversible specific nicotinic acetylcholine (ACh) receptor antagonist, and how it subsequently became a useful experimental probe are presented here. The dilemma of differentiating the actions of tubocurarine and alpha-bungarotoxin is analyzed. The author also outlines findings based on work done in his laboratory using alpha-bungarotoxin as a tool on particular aspects of synaptic transmission. These include presynaptic receptor for positive feedback of transmitter release, explosive release of ACh, up- and downregulation of ACh receptors after chronic drug treatment, autodesensitization of junctional ACh receptors, differences in action between natural transmitter and exogenous agonists and that between junctional and extrajunctional ACh receptors. Some experimental pitfalls, in which biomedical scientists are frequently trapped, are raised. Finally, some anecdotes are appended from which the reader may further understand scientific life in the 20th century, including its joys and regrets.


Genetic Analysis for Cooking and Eating Quality of Super Rice and Fine Mapping of a Novel Locus qGC10 for Gel Consistency.
Rice (Oryza sativa L.) is an important cereal that provides food for more than half of the world's population. Besides grain yield, improving grain quality is also essential to rice breeders. Amylose content (AC), gelatinization temperature (GT) and gel consistency (GC) are considered to be three indicators for cooking and eating quality in rice. Using a genetic map of RILs derived from the super rice Liang-You-Pei-Jiu with high-density SNPs, we detected 3 QTLs for AC, 3 QTLs for GT, and 8 QTLs for GC on chromosomes 3, 4, 5, 6, 10, and 12. Wx locus, an important determinator for AC and GC, resided in one QTL cluster for AC and GC, qAC6 and qGC6 here. And a novel major QTL qGC10 on chromosome 10 was identified in both Lingshui and Hangzhou. With the BC4F2 population derived from a CSSL harboring the segment for qGC10 from 93-11 in PA64s background, it was fine mapped between two molecular markers within 181 kb region with 27 annotated genes. Quantitative real-time PCR results showed that eight genes were differentially expressed in endosperm of two parents. After DNA sequencing, only LOC_Os10g04900, which encodes a F-box domain containing protein, has 2 bp deletion in the exon of PA64s, resulting in a premature stop codon. Therefore, LOC_Os10g04900 is considered to be the most likely candidate gene for qGC10 associated with gel consistency. Identification of qGC10 provides a new genetic resource for improvement of rice quality.


Diadenosine 5',5'''-p1,p4-tetraphosphate deficiency in blood platelets of the Chédiak-Higashi syndrome.
Diadenosine tetraphosphate (AP4A) is an unusual nucleotide found in a variety of cells, including platelets. It has been suggested that platelet AP4A is stored in the dense granules and is metabolically inactive. We have studied the AP4A content of blood platelets in two patients and three cattle with Chédiak-Higashi syndrome (CHS), a hereditary platelet defect with dense granule deficiency. Acid-soluble extractions of whole blood and platelets were neutralized. The adenosine triphosphate (ATP) level was measured by luminescence technique. To measure the AP4A content, the neutralized extract was treated with phosphomonoesterase for removal of ATP. The AP4A content was then measured by coupling the phosphodiesterase and luciferase reaction. The AP4A content was 0.43 nmol/mg protein for normal human platelets and 0.004 nmol/mg protein for CHS platelets. The ATP/AP4A ratio was 67 for normal and 3,023 for CHS platelets. The whole blood AP4A was reduced by 89% in CHS patients who had only a slight decrease in ATP level (26% reduction). Similarly, bovine platelets with CHS showed a marked decrease of AP4A content and a moderate reduction of the ATP level. The platelet ATP/AP4A ratio was 351 and 3,133 for normal and CHS cattle, respectively. Results demonstrate a marked reduction of AP4A in CHS platelets and suggest that AP4A may be a useful marker for the measurement of dense granule content in platelets.


Activation of p27Kip1 Expression by E2F1. A negative feedback mechanism.
The E2F1 transcription factor is a critical regulator of cell cycle due to its ability to promote S phase entry. However, E2F1 overexpression also sensitizes cells to apoptosis and E2F1-null mice are predisposed to tumor development, suggesting that it also has properties of a growth suppressor. E2F1 transcription function is regulated by interaction with hypophosphorylated pRb. Cdk inhibitors such as p16INK4a and p27Kip1 inhibit pRb phosphorylation by the cyclin D/Cdk4 and cyclin E/Cdk2 complexes, thus keeping E2F1 in an inactive state. We found that E2F1 binds to the p27 promoter in vivo and activates p27 mRNA and protein expression. Depletion of endogenous E2F1 by siRNA causes a reduction in basal p27 expression level. Inhibition of endogenous p27 expression by siRNA increases E2F1 transcriptional activity and permits accelerated cell cycle progression by exogenous E2F1. These observations suggest that induction of p27 acts as a negative feedback mechanism for E2F1 and may also contribute to other functions of E2F1.


A practical guide to promote informatics-driven efficient biotopographic material development.
Micro/nano topographic structures have shown great utility in many biomedical areas including cell therapies, tissue engineering, and implantable devices. Computer-assisted informatics methods hold great promise for the design of topographic structures with targeted properties for a specific medical application. To benefit from these methods, researchers and engineers require a highly reusable "one structural parameter - one set of cell responses" database. However, existing confounding factors in topographic cell culture devices seriously impede the acquisition of this kind of data. Through carefully dissecting the confounding factors and their possible reasons for emergence, we developed corresponding guideline requirements for topographic cell culture device development to remove or control the influence of such factors. Based on these requirements, we then suggested potential strategies to meet them. In this work, we also experimentally demonstrated a topographic cell culture device with controlled confounding factors based on these guideline requirements and corresponding strategies. A "guideline for the development of topographic cell culture devices" was summarized to instruct researchers to develop topographic cell culture devices with the confounding factors removed or well controlled. This guideline aims to promote the establishment of a highly reusable "one structural parameter - one set of cell responses" database that could facilitate the application of informatics methods, such as artificial intelligence, in the rational design of future biotopographic structures with high efficacy.


Internet Addiction, Psychological Distress, and Coping Responses Among Adolescents and Adults.
As Internet use grows, so do the benefits and also the risks. Thus, it is important to identify when individuals' Internet use is problematic. In the present study, 449 participants aged from 16 to 71 years of age were sourced from a wide range of English-speaking Internet forums, including social media and self-help groups. Of these, 68.9% were classified as nonproblematic users, 24.4% as problematic users, and 6.7% as addictive Internet users. High use of discussion forums, high rumination levels, and low levels of self-care were the main contributing factors to Internet addiction (IA) among adolescents. For adults IA was mainly predicted through engagement in online video gaming and sexual activity, low email use, as well as high anxiety and high avoidant coping. Problematic Internet users scored higher on emotion and avoidance coping responses in adults and higher on rumination and lower on self-care in adolescents. Avoidance coping responses mediated the relationship between psychological distress and IA. These findings may assist clinicians with designing interventions to target different factors associated with IA.


History of shoulder instability and subsequent injury during four years of follow-up: a survival analysis.
Little is known about the risk factors for glenohumeral joint instability. We hypothesized that a prior history of instability would be a significant risk factor for subsequent injury. We conducted a prospective cohort study over a four-year period within a high-risk group of young athletes to address the research hypothesis. Subjects were freshmen entering the U.S. Military Academy in June of 2006. Part of the baseline assessment included documenting a prior history of glenohumeral instability on entry into the study. All subjects were followed for subsequent glenohumeral joint instability events until graduation in May of 2010. The primary outcome of interest in this study was time to glenohumeral instability event during the follow-up period. We examined injury outcomes, looking for any instability, anterior instability, and posterior instability events. Cox proportional-hazards regression models were used to analyze the data. Among the 714 subjects, eight shoulders were excluded from the analyses due to prior surgical stabilization, leaving 1420 shoulders, of which 126 had a self-reported prior history of instability. There were forty-six (thirty-nine anterior and seven posterior) acute instability events documented in the cohort during the follow-up period. Subjects with a prior history of instability were over five times (p < 0.001) more likely to sustain an acute (anterior or posterior) instability event during the follow-up period. Subjects with a history of instability were also 5.6 times (p < 0.001) more likely to experience a subsequent anterior instability event and 4.6 times (p = 0.068) more likely to experience a posterior instability event during follow-up. Similar results were observed in multivariable models after controlling for the influence of demographic and baseline physical examination findings. Despite meeting the rigorous physical induction standards for military service, subjects with a prior history of glenohumeral joint instability were approximately five times more likely to experience a subsequent instability event, regardless of direction, within this high-risk athletic population.


Regulating the level of intracellular hydrogen peroxide: the role of peroxiredoxin IV.
Hydrogen peroxide (H2O2) can act as a signalling molecule affecting the cell cycle as well as contributing towards the oxidative stress response. The primary target of this molecule is oxidation-sensitive cysteine residues in proteins such as protein tyrosine phosphatases. The cell has robust mechanisms to remove H2O2 that need to be regulated for H2O2 to react with and modify protein thiols. In particular, the family of peroxiredoxins are capable of the rapid removal of even trace amounts of this molecule. It has been suggested that the inactivation of peroxiredoxins by hyperoxidation may allow H2O2 levels to increase in cells and thereby modify critical thiol groups in proteins. We have been studying how the H2O2 produced during disulfide formation in the ER (endoplasmic reticulum) is metabolized and have shown that ER-resident peroxiredoxin IV not only can remove H2O2, but also contributes to de novo disulfide formation. In the present article, we review recent data on the structure and function of this enzyme as well as its sensitivity to hyperoxidation.


Insulin-like growth factor-1 promoter polymorphisms and colorectal cancer: a functional genomics approach.
Insulin-like growth factor-1 (IGF1) has been proposed to mediate the obesity-related carcinogenic effects of "Western lifestyle". While genetic factors explain at least half of inter-individual IGF1 variation, the IGF1 polymorphisms hypothesised to underlie the variation in cancer incidence rates remain ill-defined. We used a comparative genomics approach to identify putative regulatory polymorphisms in the IGF1 promoter region within a rapidly westernising population, the Singapore Chinese. Association of IGF1 genotype with colorectal cancer risk was assessed among 298 colorectal cancer cases and 1142 controls nested within the Singapore Chinese Health Study. We identified a common (minor allele frequency = 0.36) single-nucleotide polymorphism (SNP), IGF1-2995 C/A, within a consensus domain for an octamer binding factor (Oct1/Oct2) transcription factor binding site. Possession of one or two copies of the minor allele (genotypes AA and CA) conferred an approximate 40% decrease in risk in comparison to genotype CC (odds ratio, 0.59; 95% confidence interval, 0.45 to 0.77). This association was stronger for colon cancer than for rectal cancer (p(heterogeneity)<0.001) and for those who were physically active versus inactive (p(interaction) = 0.05). Models including other previously identified promoter polymorphisms did not provide a better prediction of colorectal cancer risk. Our results support the hypotheses that IGF1 plays a role in colonic carcinogenesis and that genetically inherited variation in IGF1 expression influences risk of colorectal cancer.


Intraoperative seizure outcome of levetiracetam combined with perampanel therapy in patients with glioma undergoing awake brain surgery.
This study aimed to evaluate the efficacy of levetiracetam (LEV) combined with perampanel (PER) therapy for intraoperative seizure treatment to determine whether a combination of LEV and PER can aid in the prevention of intraoperative intractable seizures during awake surgery. The authors performed a retrospective cohort study in 78 consecutive patients with glioma who underwent awake surgery using intraoperative direct electrical stimulation mapping. To prevent intraoperative seizures, 50 patients were treated with the antiepileptic drug LEV only (LEV group) from January 2017 to January 2019, while the remaining 28 patients were treated with LEV plus PER (LEV + PER group) between March 2019 and January 2020. LEV (1000-3000 mg) and/or PER (2-4 mg) were administered before the surgery. Preoperative seizures with International League Against Epilepsy (ILAE) class II-VI occurred in 44% of the patients in the LEV group and in 35.7% of patients in the LEV + PER group, with no significant difference between groups (p = 0.319). Total intraoperative seizures occurred in 18 patients (36.0%) in the LEV therapy group and in 2 patients (7.1%) in the LEV + PER group (p = 0.009). Of these, there were no patients (0%) with intractable seizures in the LEV + PER group. Regarding factors that influence intraoperative seizures in glioma patients during awake brain surgery, multivariate logistic regression models revealed that the occurrence of intraoperative seizures was significantly related to the involvement of motor-related regions (positive vs negative, HR 6.98, 95% CI 1.71-28.56, p = 0.007), preoperative seizure (ILAE class II-VI vs ILAE class I, HR 4.44, 95% CI 1.22-16.11, p = 0.024), and LEV + PER group (positive vs negative, HR 0.07, 95% CI 0.01-0.44, p = 0.005). Treatment-related adverse effects were rare and mild, including sleepiness, tiredness, and dizziness in both treatment groups. This study demonstrates that LEV + PER therapy is significantly associated with a lower risk of intraoperative seizures compared with LEV therapy alone in patients with glioma during awake brain mapping. These findings will help neurosurgeons conduct safe and reliable awake surgeries and reduce the rate of intraoperative intractable seizures during such procedures.


[Cerebral toxoplasmosis in the pattern of secondary CNS involvements in HIV-infected patients in the Russian federation: clinical and diagnostic features].
The incidence of cerebral toxoplasmosis (CT) among all brain involvements was determined in patients with Stage 4B HIV infection (AIDS) in 2003-2009. Clinical and laboratory parameters were estimated in 156 patients to reveal diagnostic criteria. As a result, CT was shown to be a leading cause of neurologic diseases in patients with late-stage HIV infection (34.7% of cases of brain involvement). In 11.5%, it took place as a generalized process. CT concurrent with cytomegalovirus infection, tuberculosis, or other secondary lesions was frequently diagnosed. Of importance in the diagnosis of CT are magnetic resonance imaging results in addition to basic, clinical data that can assume this diagnosis. The high and moderate serum concentrations of T.gondii IgG are of diagnostic value, which may be used as an auxiliary method to verify the diagnosis.


The impact of fish oil and/or probiotics on serum fatty acids and the interaction with low-grade inflammation in pregnant women with overweight and obesity: secondary analysis of a randomised controlled trial.
N-3 long-chain PUFA (LC-PUFA) and probiotics are generally considered to induce health benefits. The objective was to investigate (1) the impact of fish oil and/or probiotics on serum fatty acids (sFA), (2) the interaction of sFA with low-grade inflammation and (3) the relation of sFA to the onset of gestational diabetes mellitus (GDM). Pregnant women with overweight/obesity were allocated into intervention groups with fish oil + placebo, probiotics + placebo, fish oil + probiotics or placebo + placebo in early pregnancy (fish oil: 1·9 g DHA and 0·22 g EPA, probiotics: Lacticaseibacillus rhamnosus HN001 and Bifidobacterium animalis ssp. lactis 420, 1010 CFU, each daily). Blood samples were collected in early (n 431) and late pregnancy (n 361) for analysis of fatty acids in serum phosphatidylcholine (PC), cholesteryl esters (CE), TAG and NEFA with GC and high-sensitivity C-reactive protein and GlycA by immunoassay and NMR spectroscopy, respectively. GDM was diagnosed according to 2 h 75 g oral glucose tolerance test. EPA in PC, CE and TAG and DHA in PC, CE, TAG and NEFA were higher in fish oil and fish oil + probiotics groups compared with placebo. EPA in serum NEFA was lower in women receiving probiotics compared with women not receiving. Low-grade inflammation was inversely associated with n-3 LC-PUFA, which were related to an increased risk of GDM. Fish oil and fish oil + probiotics consumption increase serum n-3 LC-PUFA in pregnant women with overweight/obesity. Although these fatty acids were inversely related to inflammatory markers, n-3 LC-PUFA were linked with an increased risk for GDM.


Burn-associated delayed dilated cardiomyopathy evaluated by cardiac PET and SPECT: Report of a case.
Dilated cardiomyopathy is a delayed-onset and rarely reported cardiac complication of burn injury although the mechanism remains unclear. We thus report a case of dilated cardiomyopathy following severe burn injury, in which technetium 99m sestamibi single-photon emission computed tomography (SPECT), iodine-123 beta-methyl-iodophenylpentadecanoic acid SPECT and 18F-fluorodeoxyglucose positron emission tomography (PET) were performed to evaluate the pathophysiologic condition in combination with cardiac catheterization and myocardial biopsy. The cardiac PET and SPECT images showed reduced myocardial blood flow, decreased fatty acid metabolism, and increased glucose utilization in the left ventricular lateral wall in spite of normal coronary angiography, no significant cardiac fibrosis, and inflammatory cell infiltration, which suggests that myocardial ischemia due to microcirculatory disturbance in hypermetabolic state associated with burn injury might be a causative mechanism of dilated cardiomyopathy in this case. A beta blocker, bisoprolol, was successfully introduced in this patient in combination with oral inotropic agents, pimobendan and digitalis after the prolonged use of intravenous dobutamine infusion, which might have been beneficial for this patient with burn-associated dilated cardiomyopathy not only to reduce regional myocardial ischemia but also to attenuate hypermetabolic state after severe burn injury. <Learning objective: Dilated cardiomyopathy complicated with burn injury has been reported to cause a sudden attack of dyspnea and death. This case report suggests that burn-associated dilated cardiomyopathy may be caused by relative myocardial ischemia due to microvascular disturbance in hypermetabolic state associated with burn injuries and can be treated effectively with beta blockers with or without oral inotropic agents.>.


Sex chromosome evolution: platypus gene mapping suggests that part of the human X chromosome was originally autosomal.
To investigate the evolution of the mammalian sex chromosomes, we have compared the gene content of the X chromosomes in the mammalian groups most distantly related to man (marsupials and monotremes). Previous work established that genes on the long arm of the human X chromosome are conserved on the X chromosomes in all mammals, revealing that this region was part of an ancient mammalian X chromosome. However, we now report that several genes located on the short arm of the human X chromosome are absent from the platypus X chromosome, as well as from the marsupial X chromosome. Because monotremes and marsupials diverged independently from eutherian mammals, this finding implies that the whole human X short arm region is a relatively recent addition to the X chromosome in eutherian mammals.


Recognition of auditory sequences by aphasic, right-hemisphere-damages and non-brain-damaged subjects.
Non-brain-damaged, nonaphasic right-hemisphere-damaged and aphasic left-hemisphere-damaged subjects performed in a task in which they reported whether pairs of sequences of one, two or four pure tones were the "same" or "different" in pitch. Brain-damaged subjects performed less well than non-brain-damaged subjects. Subjects with right hemisphere damage performed progressively less well as the number of tones within tone sequences increased, but non-brain-damaged and aphasic subjects more accurately reported four-tone than two-tone sequences. The results suggested that the deficits in temporal sequencing by aphasic subjects previously reported in the literature do not result from output disorders, and that subjects with hemisphere lesions exhibit deficits that are consistent with deficits in the ability to process melodic materials.


Long-term maintenance of the anabolic effects of GH on the skeleton in successfully treated patients with acromegaly.
The anabolic actions of growth hormone (GH) are well documented. In acromegaly, the skeletal effects of chronic GH excess have been mainly addressed by evaluating bone mineral density (BMD). Most data were obtained in patients with active acromegaly, and apparently high or normal BMD was observed in the absence of hypogonadism. Data on BMD are not available after successful treatment of acromegaly. Whether the positive effect of GH excess on bone mass is maintained in the long term after clinical and biochemical cure of acromegaly remains to be established. In a cross-sectional study design, lumbar spine and femoral neck BMD was measured in 79 acromegalic patients cured or well controlled on octreotide treatment (45 male and 34 female patients; mean age 57+/-1 years). Successful treatment (by surgery, radiotherapy and/or use of octreotide) was defined as normal age-adjusted IGF-I. Mean time after biochemical remission was 10.2+/-7 years. Normal or increased BMD was observed at the femoral neck and lumbar spine in both men and women in remission after treatment for acromegaly. Similar results were obtained in patients in remission for 5 years or longer. Osteoporosis was present in 15% of the patients, with similar prevalence in men and women. There was no relationship between BMD and duration or severity of GH excess before treatment, gonadal status and presence of pituitary hormone deficiencies. Pituitary irradiation was a strong negative predictor of bone mass at the femoral neck. Long-term bone loss was observed only at the femoral neck. Our data suggest that the anabolic effect of GH on trabecular and cortical bone remains demonstrable after remission of acromegaly, although it may not be maintained at cortical sites in the long term. In the present study, the lack of effect of gonadal status on BMD may be explained by the presence of only mild hypogonadism and by our policy of prompt hormonal replacement therapy for severe hypogonadism. The negative effect of pituitary irradiation on femoral neck BMD remains intriguing, although it is probably related to some degree of the diminished GH secretion frequently observed after this form of treatment.


Expression of autophagy related gene 5 and cyclin E in coronary heart disease and its clinical significance.
To explore the expression of autophagy related genes 5 (ATG5) and cyclin E in coronary heart disease (CHD) and its clinical significance. From April 2018 to August 2018, 80 patients diagnosed with CHD in the Second Xiangya Hospital, Central South University were selected as an observation group, and another 80 healthy subjects were selected as a control group. The expression of ATG5 and cyclin E mRNA in nucleate cells and the plasma protein in the 2 groups were detected and analyzed. The model of macrophage-derived foam cells induced by oxidized low density lipoprotein (ox-LDL) was used to simulate atherosclerosis. The proliferation of macrophage- derived foam cells and the protein levels of ATG5 and cyclin E induced by ox-LDL at different concentrations were examined. Compared with the control group, the levels of ATG5 mRNA and protein in the blood in the observation group were decreased, and the cyclin E mRNA and protein levels were increased, there were statistically difference (both P<0.05). Receiver operating characteristic (ROC) curve showed that the area under curve (AUC) of ATG5 mRNA, cyclin E mRNA, ATG5 protein and cyclin E protein were 0.739, 0.780, 0.671 and 0.807, respectively. Pearson analysis showed that the ATG5 mRNA was negatively correlated with the cyclin E mRNA (r=-0.734, P<0.05),while the plasma ATG5 protein was negatively correlated with the plasma cyclin E protein (r=-0.746, P<0.05). Macrophage-derived foam cell model induced by ox-LDL showed that the proliferation of foam cells and the expression levels of cyclin E protein were increased in a concentration and time-dependent manner, and the expression levels of ATG5 protein were decreased in a concentration-dependent manner. The levels of ATG5 mRNA and protein are lowly expressed while the levels of cyclin E mRNA and protein are highly expressed in the patients with CHD.The ATG5 protein levels are lowly expressed in ox-LDL-treated macrophage-derived foam cells while the cyclin E protein levels are highly expressed in ox-LDL-treated macrophage-derived foam cells. Based on these observations, we conclude that ATG5 inhibits the degradation of the cyclin E and promotes the proliferation of macrophages, involving in the occurrence and development of CHD.


Impact of the Immunogen Nature on the Immune Response against the Major HBV Antigens in an HBsAg and HLA-humanized Transgenic Mouse Model.
Hepatitis B chronic carriage remains as a major public health problem. Protein and DNA vaccines are now widely used in therapeutic vaccine candidates. Although, the hepatitis B surface antigen (HBsAg) based vaccines have been largely studied, candidates comprising both HBsAg and core (HBcAg) either protein- or DNA-based approaches deserve further immunological characterization. In the present study, a repeated dose administration schedule for protein or DNA immunogens was conducted in order to characterize the resulting immune response in a humanized and HBsAg-tolerized setting. A novel transgenic (Tg) mice that express the HBsAg, human MHC class I (HLA-A*0201) and MHC class II (HLA-DRB1*01) molecules and devoid of endogenous murine class I and II molecules was used as a model of HBV chronic carrier. Mice were immunized by subcutaneous (protein) or intramuscular (DNA) routes and the humoral and cellular responses were evaluated. Protein or DNA immunization induced humoral immune responses against both HBsAg and HBcAg. The systematic analysis of epitopes that activate CD4+ and CD8+ T lymphocytes confirmed the accuracy of the model. Cellular immune responses were detected differing in their nature. CD8 T-cell responses were induced mostly after DNA immunization while CD4 T-cell responses were predominant in protein based immunizations. In addition, the intensity of HLA-A2-restricted CD8+ T cell responses was reduced in Tg mice expressing HBsAg when compared to control Tg mice. In conclusion, our results indicate that cellular immune responses necessary for the development of protective immunity can be achieved by DNA or protein immunization. However, important differences in their nature arise when immunogens are administered several times. How to cite this article: Mancini-Bourgine M, Guillen G, Michel ML, Aguilar JC. Impact of the Immunogen Nature on the Immune Response against the Major HBV Antigens in an HBsAg and HLA-humanized Transgenic Mouse Model. Euroasian J Hepato-Gastroenterol 2014;4(1):36-44.


Mechanical defence in seeds to avoid predation by a granivorous ant.
Harvester ants have traditionally been considered as seed predators that negatively affect plants. In some cases, however, they can also act as positive seed dispersers. During field observations, we noted that a portion of Psoralea bituminosa seeds that were collected and carried to the nest by the granivorous harvester ant Messor barbarus were discarded intact in refuse piles outside the nest. We analyzed and compared the physical characteristics of size, mass and toughness in P. bituminosa seeds from two different origins: intact seeds found in the ant's refuse piles and seeds collected directly from the plants. Seeds from refuse piles were similar in width but lighter and tougher than seeds from the plant. Our results point to a mechanical defence based on seed toughness to avoid predation by M. barbarus and suggest that an elevated proportion (approximately 69%) of the seeds produced by P. bituminosa could be too tough to be consumed by this ant. These transported but uneaten seeds could benefit by being moved far from the mother plant and this could act as a selective evolutionary pressure towards tough seeds.


Complete redirectional acetabular osteotomies for neurogenic and syndromic hip dysplasia.
Neurogenic conditions and syndromes are often associated with clinically significant acetabular dysplasia and/or instability of the hip. Options for surgical treatment include reshaping, salvage, or redirectional pelvic osteotomies. "Complete" redirectional osteotomies, including the triple innominate osteotomy and the periacetabular osteotomy, completely free the acetabulum from the rest of the pelvis thereby allowing the surgeon to obtain large corrections and to control the position of the acetabulum in multiple planes. As a result, these procedures can be extremely useful in the treatment of certain neuromuscular conditions. In particular, complete redirectional osteotomies offer several specific advantages in the neurogenic and syndromic patient population: the procedures can be performed after skeletal maturity, they offer the surgeon the ability to correct acetabular version and the hypoplastic acetabulum, they allow hypercoverage when necessary and they may theoretically better preserve marginal ambulatory ability.