Data Preparation for West Nile Virus Agent-Based Modelling: Protocol for Processing Bird Population Estimates and Incorporating ArcMap in AnyLogic.
West Nile Virus (WNV) was first isolated in 1937. Since the 1950s, many outbreaks have occurred in various countries. The first appearance of infected birds in Manitoba, Canada was in 2002. This paper describes the data preparation phase of setting up a geographic information system (GIS) simulation environment for WNV Agent-Based Modelling in Manitoba. The main technology used in this protocol is based on AnyLogic and ArcGIS software. A diverse variety of topics and techniques regarding the data collection phase are presented, as modelling WNV has many disparate attributes, including landscape and weather impacts on mosquito population dynamics and birds' roosting locations, population count, and movement patterns. Different maps were combined to create a grid land cover map of Manitoba, Canada in a shapefile format compatible with AnyLogic, in order to modulate mosquito parameters. A significant amount of data regarding 152 bird species, along with their population estimates and locations in Manitoba, were gathered and assembled. Municipality shapefile maps were converted to built-in AnyLogic GIS regions for better compatibility with census data and initial placement of human agents. Accessing shapefiles and their databases in AnyLogic are also discussed. AnyLogic simulation software in combination with Esri ArcGIS provides a powerful toolbox for developers and modellers to simulate almost any GIS-based environment or process. This research should be useful to others working on a variety of mosquito-borne diseases (eg, Zika, dengue, and chikungunya) by demonstrating the importance of data relating to Manitoba and/or introducing procedures to compile such data.


Reducing Carbapenem Exposure: Extended-Spectrum β-Lactamase Catheter-Associated Urinary Tract Infection Management.
Catheter-associated urinary tract infections are one of the most common sources of infection, accounting for up to 40% of health care-associated infections each year in the United States. Extended-spectrum β-lactamase-producing Enterobacteriaceae are frequent causes of urinary tract infections in health care settings. Prevalent use of carbapenems has led to the emergence of carbapenem-resistant Enterobacteriaceae infections, leaving clinicians with few treatment options. Reducing carbapenem use and investigating alternative options for low-severity extended-spectrum β-lactamase infections is imperative to prevent more cases of carbapenem-resistant Enterobacteriaceae. Although carbapenems are the antibiotics of choice for treating extended-spectrum β-lactamase-producing Enterobacteriaceae catheter-associated urinary tract infections, carbapenem-sparing regimens may be appropriate for treating hemodynamically stable patients with low inoculum levels. Moreover, frontline health care providers can initiate efforts to reduce the development of multidrug-resistant organisms by decresing inappropriate antibiotic use during the treatment of catheter-associated asymptomatic bacteruria, avoiding unnecessary catheterizations, and avoiding culturing urine in asymptomatic patients.


Healthcare Resource Use and Burden Associated with Influenza Transmission Among Household Members with a Primary Infection: Commercial Claims Data Analysis.
To assess the burden of influenza transmission and care-seeking patterns over 3 influenza seasons among commercially insured households with a primary influenza infection. This retrospective cohort study used commercial claims data from the US MarketScan® Commercial and Medicare Supplemental databases for the 2014, 2015, and 2016 influenza seasons. Patients with a billed diagnosis of influenza and with coverage for at least 1 household member under the same health plan policy were included. A secondary diagnosed case was defined as a diagnosis of influenza in a second household member occurring within 14 days of the index case in a household. Among 1,224,808 households with ≥2 members and a primary case of influenza, a secondary case of influenza was reported in 119,883 households (9.8%). A secondary diagnosed case of influenza occurred within 4 days of the primary diagnosis in 93,883 (78.3%) of those households. Both primary and secondary diagnosed influenza cases occurred most often among children (~60%). Household size was positively correlated to both the risk of a second case (6.4% of households with 2 or 3 members versus 12.6% of households with ≥4 members, P < 0.001) and the time to diagnosis of a second case (Spearman rank correlation coefficient = 0.09; P < 0.001). Claims data for 3 influenza seasons (2014, 2015, 2016) showed that intrahousehold transmission of influenza occurs in approximately 10% of households with a primary case and poses a higher burden on larger households. Intrahousehold transmission of influenza represents a large healthcare resource use burden, with an unmet need for interventions that limit transmission.


The role of transport and telecommunications technology in the development of the Scottish Highlands and Islands Medical Service: a historical perspective.
The Highlands and Islands Medical Service (HIMS) was introduced across the Scottish Highlands and Islands region after the publication of the Dewar Report in 1913. It was the first state-funded medical service in the UK and one of the first in the world. The Dewar Committee recommended the establishment of HIMS following research into healthcare provision in the region, concluding that there was insufficient provision. Among Dewar's major findings were the lack of sufficient transport infrastructure, high transport costs and low availability, and the lack of telecommunication services. This historical study with current relevance has addressed the contribution of transport and telecommunication technologies to the overall success of the Highland and Islands Medical Service. We have considered the crucial role of developments in the transport and telecommunications industries in overcoming contemporaneous healthcare problems. Through the study of contemporary letters, newspaper articles and government reports, this study assesses whether the views expressed at the time agree with the central contention that automobiles and telecommunication services were essential to the success of HIMS. This study also assesses the parallels drawn between the problems faced by HIMS in the 1900s and modern-day rural healthcare providers. Automobile use allowed those in the Highlands and Islands to commute with far greater ease, indirectly allowing doctors and members of the healthcare team to travel to see patients further afield and in greater numbers due to reduced travelling time. Additionally, funds provided by other government departments as well as HIMS allowed telecommunication technology to develop in the region, resulting in improved communication between widely dispersed healthcare workers, thereby improving healthcare provision. Prior to the formation of HIMS, the Highlands and Islands region in Scotland struggled to provide sufficient health care to its residents. The formation of HIMS resulted in improved health care in the region while simultaneous developments in the transport and telecommunication industries occurred. Past scholars have established links between the transport and telecommunication industries and healthcare provision in several countries. This study has contributed to existing literature by providing an insight into the relationship between such services in the Highlands and Islands region as well as rural life in the early 1900s. To conclude, the development of the transport and telecommunications industries acted synergistically with HIMS to lead to success in provision of good health care in the region.


Computational Optics Enables Breast Cancer Profiling in Point-of-Care Settings.
The global burden of cancer, severe diagnostic bottlenecks in underserved regions, and underfunded health care systems are fueling the need for inexpensive, rapid, and treatment-informative diagnostics. On the basis of advances in computational optics and deep learning, we have developed a low-cost digital system, termed AIDA (artificial intelligence diffraction analysis), for breast cancer diagnosis of fine needle aspirates. Here, we show high accuracy (>90%) in (i) recognizing cells directly from diffraction patterns and (ii) classifying breast cancer types using deep-learning-based analysis of sample aspirates. The image algorithm is fast, enabling cellular analyses at high throughput (∼3 s per 1000 cells), and the unsupervised processing allows use by lower skill health care workers. AIDA can perform quantitative molecular profiling on individual cells, revealing intratumor molecular heterogeneity, and has the potential to improve cancer diagnosis and treatment. The system could be further developed for other cancers and thus find widespread use in global health.


[Changes in the currents across sodium channels as affected by blood serum on cultured neuroblastoma cells].
Adding of 5% bovine serum to internally perfused voltage-clamped serum deprived neuroblastoma cells rapidly stimulates transient sodium current. This stimulating effect is mainly due to the increase in the peak sodium conductance by almost 24 per cent, on the average. Besides that a modifying effect was observed resulting in the 6 mV shift of the sodium peak conductance curve towards more negative potentials and in the 5 mV shift of steady inactivation curve towards more positive ones. The sign of the latter shift was changed to the opposite under the action of serum thermally pretreated at 100 degrees C. This procedure led also to more than two fold lowering of the stimulating effect. Experiments with serum deprivation demonstrate different degrees of reversibility of the serum effects, the most reversible being the inactivation curve shift. EGF, insulin, dexamethasone, transferrin, ATP, serotonin and their combinations in physiological concentrations failed to give the typical whole serum effects. The serum is supposed to contain at least two active components of unknown nature, one of which being thermoresistant.


Clinical significance of molecular detection of carcinoma cells in lymph nodes and peripheral blood by reverse transcription-polymerase chain reaction in patients with gastrointestinal or breast carcinomas.
This study evaluates the clinical significance of detection of carcinoembryonic antigen (CEA) mRNA in the dissected lymph nodes and peripheral blood samples of patients with gastrointestinal or breast carcinomas. A total of 406 lymph nodes obtained from 65 patients were analyzed by both histologic and molecular examination of CEA-specific reverse transcriptase-polymerase chain reaction (RT-PCR). Peripheral blood samples from another 102 patients were also analyzed by CEA-specific RT-PCR. Patients were followed up prospectively for 24 +/- 12 months. Of 406 lymph nodes, the positive detection rate increased from 20% by histologic examination to 60% by RT-PCR examination. The recurrence rate was 40% in 15 cases showing positive results in both examinations, 14% in 29 cases showing histologically negative but RT-PCR positive results, and none in 21 cases showing negative results in both examinations. The positive detection rate for CEA mRNA in peripheral blood samples increased with advancing stage of disease. With respect to 62 curatively operated cases, CEA mRNA was detected in 12 cases. Four of these 12 cases developed metastatic disease after surgery whereas none of 50 cases negative by RT-PCR developed metastasis. It has been shown that RT-PCR is a powerful tool to detect CEA mRNA in the lymph nodes or the peripheral blood. This is potentially very useful to determine high-risk patients for metastasis. Serial analysis is warranted to assess the long-term significance of this method and its therapeutic and prognostic implications.


Treatment of urinary tract infection in persons with spinal cord injury: guidelines, evidence, and clinical practice. A questionnaire-based survey and review of the literature.
To investigate current clinical practice in the treatment of urinary tract infections (UTIs) in persons with spinal cord injury (SCI) in SCI centers where German is spoken and to compare it with current guidelines and evidence-based standards evaluated by a literature review. A standardized questionnaire was mailed to 16 SCI rehabilitation centers. The results were compared with a literature review Of the 16 centers, 13 responded. Indications for UTI treatment, medications, and treatment duration differed substantially among the individual centers and from the existing guidelines. Antibiotic treatment is regarded as the method of choice. Compared with the existing literature, patients in two center were undertreated, whereas they were overtreated in seven centers. Even in specialized centers, treatment of UTI in patients with SCI is based more on personal experience of the treating physicians than on published evidence. This may at least partly be due to the paucity of evidence-based data. The observed tendency toward overtreatment with antibiotics carries substantial future risks, as this strategy may well lead to the induction of multiresistant bacterial strains. Therefore, developing guidelines would be an important step toward a unification of the different treatment strategies, thus reducing unnecessary antibiotic treatment. Furthermore, evidence-based studies evaluating the success of antibiotic treatment as well as the usefulness of alternative strategies are urgently needed.


Early administration of intrapleural streptokinase in the treatment of multiloculated pleural effusions and pleural empyemas.
In the treatment of multiloculated pleural effusions and empyemas tube thoracostomy often fails and more aggressive surgical therapy is required. Intrapleural administration of fibrinolytics is a valuable alternative. Between October 1994 and December 1995 28 patients (aged 22 to 62 years) with multiloculated pleural effusions were treated with intrapleural instillations of streptokinase after unsuccessful conventional chest tube drainage. Twenty-three pleural effusions were grossly purulent, others were loculated effusions with low pH. The most common cause of the pleural effusions was pneumonia. Duration of illness before hospitalization was 3 to 105 (mean 21.8) days. Treatment with streptokinase was started most commonly one day after chest tube placement. Once a day after clamping the chest tube streptokinase was administered intrapleurally for 10-15 minutes as a solution of 250,000 units in 100 ml normal saline. The tube remained clamped for 3 hours. Two to 8 (mean 3.7) instillations per patient were needed. Twenty-one cases (72.4%) showed excellent resolution of pleural effusion and needed no more therapy. However, one patient died in hospital due to purulent meningitis and bilateral pneumonia. Eight patients needed further surgical treatment, e.g. decortication, in 5 cases together with wedge lung resection. Eleven patients experienced some adverse effects of streptokinase therapy, most frequently chest pain and elevation of body temperature in one case pleural effusion became hemorrhagic, and one patient had nasal bleeding. We conclude that usage of intrapleural streptokinase in the treatment of multiloculated pleural effusions (including pleural empyemas) reduces the need for major surgical interventions in quite a large group of patients.


Duct endoscopy and endoscopic biopsy in the evaluation of nipple discharge.
Microdochectomy is usually performed on patients with nipple discharge caused by intraductal proliferative lesions, such as intraductal papilloma and carcinoma. But this operation often sacrifices large amounts of normal mammary gland even when the lesion is a benign intraductal papilloma a few millimeters in diameter. We have developed duct endoscopy for the mammary duct system, and have reliably performed biopsies for intraductal proliferative lesions intraductally. From June 1989 to April 1990, we examined 22 cases by duct endoscopy, and performed endoscopic biopsy in 16 cases. The method of endoscopic biopsy is as follows. First, a bougie is inserted, without anesthesia other than Xylocaine jelly, into the orifice of the duct to enlarge it. Second, the outer cylinder and the inner needle are inserted; then the inner needle is removed, and the endoscope is inserted. After examination, the outer cylinder is moved up to the lesion to be biopsied and the endoscope is taken out. Then a sample is taken into the outer cylinder by aspiration. We diagnosed 10 cases of benign lesion and 5 cases of malignant lesion by cytological and/or histological examination. In conclusion, endoscopic biopsy, aided by duct endoscopy, is a useful and harmless diagnostic procedure in the evaluation of nipple discharge.


Culture in chaos: the need for leadership and followership in medicine.
The health care industry is changing at a dizzying pace and most of its players are struggling to maintain some form of the status quo. But resisting change will not prove fruitful--ultimately, it will rob physician executives of the opportunity to be architects in designing a new, more efficient health care system and their role in it. Because health care is a complex adaptive system (CAS)--change occurs rapidly and events are unpredictable--the old command and control style of leadership and a linear way of interpreting events is too rigid and, therefore, an ineffective model for guiding change. Complexity science offers insights about leading for change. In CASs, changes emerge in response to environmental demands for adaptability. Since the nature of these demands is unpredictable, the role of leadership is to manage the relationships and context out of which these changes emerge. A leadership style is called for that leads to purpose, makes positive changes by influencing context and relationships, and takes followers to a better place.


An outer membrane-disorganizing peptide PMBN sensitizes E. coli strains to serum bactericidal action.
The small cationic outer membrane-disorganizing peptide PMBN sensitized four smooth, encapsulated strains of Escherichia coli (serotypes 02:K1, 04:K12, 018:K1, and 018:K5) to the lethal action of serum. The concentrations of PMBN required were low (0.3 to 1.0 microgram/ml). One E. coli strain (IH 11030; 075:K5) remained virtually resistant to serum and also to anti-075 hyperimmune serum plus complement (C) even in the presence of PMBN. This strain was nevertheless sensitive to the outer membrane permeability-increasing action of PMBN. In the bactericidal system, PMBN could be replaced by high concentrations of lysine20 or protamine but not lysine4. The PMBN-dependent bactericidal activity of GPS was abolished by heating or zymosan treatment that inactivate its C but not by lack of the action of the classical pathway of the C in C4-deficient GPS. PMBN formed a bactericidal system also with normal rabbit, rat, and human serum but not with mouse serum. The bactericidal system against E. coli 018:K1 and its derivative EH 817 (018:K1-) was found to require a factor that can be removed from normal sera by absorption with a rough E. coli strain. This factor could be replaced by specific anti-018 antibodies. The bactericidal activity of fetal calf serum plus PMBN against E. coli 018:K1 was enhanced by normal rabbit or anti-E. coli 018 hyperimmune serum. We suggest that PMBN unshields the deep structures and the hydrophobic membrane milieu of the outer membrane and facilitates the insertion of the membrane attack complex of the C into this milieu.


Neolithic and Bronze Age migration to Ireland and establishment of the insular Atlantic genome.
The Neolithic and Bronze Age transitions were profound cultural shifts catalyzed in parts of Europe by migrations, first of early farmers from the Near East and then Bronze Age herders from the Pontic Steppe. However, a decades-long, unresolved controversy is whether population change or cultural adoption occurred at the Atlantic edge, within the British Isles. We address this issue by using the first whole genome data from prehistoric Irish individuals. A Neolithic woman (3343-3020 cal BC) from a megalithic burial (10.3× coverage) possessed a genome of predominantly Near Eastern origin. She had some hunter-gatherer ancestry but belonged to a population of large effective size, suggesting a substantial influx of early farmers to the island. Three Bronze Age individuals from Rathlin Island (2026-1534 cal BC), including one high coverage (10.5×) genome, showed substantial Steppe genetic heritage indicating that the European population upheavals of the third millennium manifested all of the way from southern Siberia to the western ocean. This turnover invites the possibility of accompanying introduction of Indo-European, perhaps early Celtic, language. Irish Bronze Age haplotypic similarity is strongest within modern Irish, Scottish, and Welsh populations, and several important genetic variants that today show maximal or very high frequencies in Ireland appear at this horizon. These include those coding for lactase persistence, blue eye color, Y chromosome R1b haplotypes, and the hemochromatosis C282Y allele; to our knowledge, the first detection of a known Mendelian disease variant in prehistory. These findings together suggest the establishment of central attributes of the Irish genome 4,000 y ago.


Medical anti-shock trousers (pneumatic anti-shock garments) for circulatory support in patients with trauma.
Medical antishock trousers (MAST) have been used to increase venous return to the heart until definitive care could be given. This, combined with compression of blood vessels, is believed to cause the movement of blood from the lower body to the brain, heart and lungs. However, the equipment is expensive, and may have adverse effects. To quantify the effect on mortality and morbidity of the use of medical anti-shock trousers (MAST)/ pneumatic anti-shock garments (PASG) in patients following trauma. Trials were identified by searches of the Cochrane Injuries Group Trials Register, the Cochrane Controlled Trials Register, MEDLINE, EMBASE, BIDS ISI Service and Science Citation Index. References in relevant papers identified were followed up. A citation analysis of references to randomised controlled trials was conducted using the Science Citation Index. Authors of identified trials were contacted and asked about any other trials that may have been conducted, whether published or unpublished. Randomised and quasi-randomised trials of MAST/PASG in patients following trauma (excluding fractures of the extremities in which MAST/PASG may be used as a splint). Data were extracted independently by two reviewers. Data were collected on mortality, duration of hospitalisation and ICU stay, and quality of allocation concealment. Two trials were identified that met the inclusion criteria. These trials included 1202 randomised patients in total; however, data for only 1075 of these were available. The relative risk of death with MAST was 1.13 (95% CI 0.97 to 1.32). Duration of hospitalisation and of intensive care unit stay was longer in the MAST treated group. The weighted mean difference in the length of intensive care unit stay was 1.7 days (95% CI 0.33 to 2.98). There is no evidence to suggest that MAST/PASG application reduces mortality, length of hospitalisation or length of ICU stay in trauma patients and it is possible that it may increase these. These data do not support the continued use of MAST/PASG in the situation described. However, it should be recognised that, due to the poor quality of the trials, conclusions should be drawn with caution.


Diet as prophylaxis and treatment for venous thromboembolism?
Both prophylaxis and treatment of venous thromboembolism (VTE: deep venous thrombosis (DVT) and pulmonary emboli (PE)) with anticoagulants are associated with significant risks of major and fatal hemorrhage. Anticoagulation treatment of VTE has been the standard of care in the USA since before 1962 when the U.S. Food and Drug Administration began requiring randomized controlled clinical trials (RCTs) showing efficacy, so efficacy trials were never required for FDA approval. In clinical trials of 'high VTE risk' surgical patients before the 1980s, anticoagulant prophylaxis was clearly beneficial (fatal pulmonary emboli (FPE) without anticoagulants = 0.99%, FPE with anticoagulants = 0.31%). However, observational studies and RCTs of 'high VTE risk' surgical patients from the 1980s until 2010 show that FPE deaths without anticoagulants are about one-fourth the rate that occurs during prophylaxis with anticoagulants (FPE without anticoagulants = 0.023%, FPE while receiving anticoagulant prophylaxis = 0.10%). Additionally, an FPE rate of about 0.012% (35/28,400) in patients receiving prophylactic anticoagulants can be attributed to 'rebound hypercoagulation' in the two months after stopping anticoagulants. Alternatives to anticoagulant prophylaxis should be explored. The literature concerning dietary influences on VTE incidence was reviewed. Hypotheses concerning the etiology of VTE were critiqued in relationship to the rationale for dietary versus anticoagulant approaches to prophylaxis and treatment.Epidemiological evidence suggests that a diet with ample fruits and vegetables and little meat may substantially reduce the risk of VTE; vegetarian, vegan, or Mediterranean diets favorably affect serum markers of hemostasis and inflammation. The valve cusp hypoxia hypothesis of DVT/VTE etiology is consistent with the development of VTE being affected directly or indirectly by diet. However, it is less consistent with the rationale of using anticoagulants as VTE prophylaxis. For both prophylaxis and treatment of VTE, we propose RCTs comparing standard anticoagulation with low VTE risk diets, and we discuss the statistical considerations for an example of such a trial. Because of (a) the risks of biochemical anticoagulation as anti-VTE prophylaxis or treatment, (b) the lack of placebo-controlled efficacy data supporting anticoagulant treatment of VTE, (c) dramatically reduced hospital-acquired FPE incidence in surgical patients without anticoagulant prophylaxis from 1980 - 2010 relative to the 1960s and 1970s, and (d) evidence that VTE incidence and outcomes may be influenced by diet, randomized controlled non-inferiority clinical trials are proposed to compare standard anticoagulant treatment with potentially low VTE risk diets. We call upon the U. S. National Institutes of Health and the U.K. National Institute for Health and Clinical Excellence to design and fund those trials.


Proteomic analysis of colorectal cancer reveals alterations in metabolic pathways: mechanism of tumorigenesis.
Colorectal cancer is the second leading killer cancer worldwide and presently the most common cancer among males in Singapore. The study aimed to detect changes of protein profiles associated with the process of colorectal tumorigenesis to identify specific protein markers for early colorectal cancer detection and diagnosis or as potential therapeutic targets. Seven pairs of colorectal cancer tissues and adjacent normal mucosa were examined by two-dimensional gel electrophoresis at basic pH range (pH 7-10). Intensity changes of 34 spots were detected with statistical significance. 16 of the 34 spots were identified by MALDI-TOF/TOF tandem mass spectrometry. Changes in protein expression levels revealed a significantly enhanced glycolytic pathway (Warburg effect), a decreased gluconeogenesis, a suppressed glucuronic acid pathway, and an impaired tricarboxylic acid cycle. Observed changes in protein abundance were verified by two-dimensional DIGE. These changes reveal an underlying mechanism of colorectal tumorigenesis in which the roles of impaired tricarboxylic acid cycle and the Warburg effect may be critical.


Inter- and intraindividual variation of endotoxin- and beta(1 --> 3)-glucan-induced cytokine responses in a whole blood assay.
Inflammatory airway responses to bioaerosols and to their active compounds, such as endotoxin and beta(1 --> 3)-glucan, vary between individuals. These differences may be explained by variation in cytokine responsiveness, which can be assessed by in vitro stimulation tests with isolated blood leukocytes or lung macrophages. In large-scale population studies, ex vivo induced cytokine production may also be tested with a more simple 'whole blood assay' (WBA). However, applicability of a WBA to characterize a subject's responsiveness depends largely on its reproducibility. This study was conducted to: 1) assess the within- and between-subject variability in cytokine production in a WBA after stimulation with endotoxin or beta(1 --> 3)-glucan; and 2) to determine under which conditions this test is most discriminating between subjects and most reproducible within subjects. Blood was collected from 14 healthy volunteers, of whom 10 also participated on a second occasion. Each blood sample was used in two WBA tests; the first WBA was initiated two hours and the second 26 hours after venapuncture. The WBA test itself comprised overnight incubation with serial dilutions of endotoxin [lipopolysaccharide (LPS)] and curdlan (a beta(1 --> 3)-glucan), after which blood cell supernatant was collected. Interleukin(IL)-1beta, IL6, IL8 and tumor necrosis factor alpha (TNFalpha) were determined in the supernatant. In all individuals, a dose-dependent production of cytokines was observed for both LPS and curdlan. For all cytokines, variation between subjects was higher than within subjects, and this was most pronounced for IL1beta and IL6. There was moderate-to-high correlation in the induced release of all four cytokines, and between cytokine release induced by LPS or curdlan. Optimal stimulation concentrations were 6.25 and 12.5 ng/mL for endotoxin and 12500 and 25000 ng/mL for curdlan. Cytokine production in WBA initiated 26 hours after venapuncture showed lower between-subject and larger within-subject variance, thus favoring an early initiation of the assay. In conclusion, measuring endotoxin- or glucan-induced cytokine production in a WBA initiated within two hours after venapuncture appears to be an effective method to determine a person's cytokine responsiveness, at least in healthy naive subjects.


CAXII Is a sero-diagnostic marker for lung cancer.
To develop sero-diagnostic markers for lung cancer, we generated monoclonal antibodies using pulmonary adenocarcinoma (AD)-derived A549 cells as antigens by employing the random immunization method. Hybridoma supernatants were immunohistochemically screened for antibodies with AMeX-fixed and paraffin-embedded A549 cell preparations. Positive clones were monocloned twice through limiting dilutions. From the obtained monoclonal antibodies, we selected an antibody designated as KU-Lu-5 which showed intense membrane staining of A549 cells. Based on immunoprecipitation and MADLI TOF/TOF-MS analysis, this antibody was recognized as carbonic anhydrase XII (CAXII). To evaluate the utility of this antibody as a sero-diagnostic marker for lung cancer, we performed dot blot analysis with a training set consisting of sera from 70 lung cancer patients and 30 healthy controls. The CAXII expression levels were significantly higher in lung cancer patients than in healthy controls in the training set (P<0.0001), and the area under the curve of ROC was 0.794, with 70.0% specificity and 82.9% sensitivity. In lung cancers, expression levels of CAXII were significantly higher in patients with squamous cell carcinoma (SCC) than with AD (P = 0.035). Furthermore, CAXII was significantly higher in well- and moderately differentiated SCCs than in poorly differentiated ones (P = 0.027). To further confirm the utility of serum CAXII levels as a sero-diagnostic marker, an additional set consisting of sera from 26 lung cancer patients and 30 healthy controls was also investigated by dot blot analysis as a validation study. Serum CAXII levels were also significantly higher in lung cancer patients than in healthy controls in the validation set (P = 0.030). Thus, the serum CAXII levels should be applicable markers discriminating lung cancer patients from healthy controls. To our knowledge, this is the first report providing evidence that CAXII may be a novel sero-diagnostic marker for lung cancer.


Evaluation of misting controls to reduce respirable silica exposure for brick cutting.
It is estimated that more than 1.7 million workers in the United States are potentially exposed to respirable crystalline silica, with a large percentage having been exposed to silica concentrations higher than the limits set by current standards and regulations. The purpose of this study is to characterize the use of water-misting engineering controls to reduce exposure to respirable crystalline silica for construction workers engaged in the task of brick cutting. Since data concerning the efficacy of engineering controls collected at worksites is often confounded by factors such as wind, worker skill level, the experiments were conducted in a laboratory environment. A completely enclosed testing chamber housed the brick-cutting saw. Respirable dust concentrations were measured using the Model 3321 Aerodynamic Particle Sizer. Specifically, the laboratory experiment was designed to compare dust suppression through water misting using conventional freely flowing water techniques. Brass atomizing nozzles with three flow rates were used for making this comparison: low (5.0 ml s(-1) or 4.8 gal h(-1)), medium (9.0 ml s(-1) or 8.6 gal h(-1)) and high (18 ml s(-1) or 17.3 gal h(-1)). The flow rate for freely flowing water, using manufacturer-supplied equipment, was 50 ml s(-1) (48 gal h(-1)). The experiment consisted of five replications of five samples each (low-misting, medium-misting, high-misting, freely flowing water and no control). The order of sampling within each replicate was randomized. Estimates of dust reduction showed that low-misting nozzles reduced the respirable mass fraction of dust by about 63%, medium-misting nozzles by about 67%, high-misting nozzles by about 79% and freely flowing water by about 93%. Based on these results, it may be feasible to use misting to control respirable silica dust instead of freely flowing water. This strategy is of practical interest to the construction industry which must frequently limit the amount of water used on construction sites.


Sympathetic Overactivation in Patients With Essential Hypertension and Hepatic Iron Overload.
Iron overload has been recently shown to be associated with a hyperadrenergic state in genetic hemochromatosis. Whether this is also the case in essential hypertension, characterized by sympathetic activation and frequently by body iron overload, is unknown. In 17 healthy normotensive controls (age 52.3±3.2 years, mean±SE), in 21 age-matched patients with hypertension with iron overload (HT+), defined by serum ferritin levels, and in 28 hypertensives without this condition, we measured efferent postganglionic muscle sympathetic nerve traffic (microneurography), heart rate and blood pressure variability (power spectral analysis), serum ferritin, and metabolic variables. Muscle sympathetic nerve traffic was significantly (P<0.02 at least) greater in HT+ than in patients with hypertension without iron overload and normotensive subjects both when expressed as bursts incidence over time (41.8±1.4 versus 31.5±1.4 and 23.6±0.9 bursts/min) and as bursts corrected for heart rate (55.3±1.8 versus 42.3±1.2 and 31.7±1.2 bursts/100 heartbeats). In HT+, low-frequency systolic blood pressure variability was significantly reduced. In HT+, but not in the other 2 groups, muscle sympathetic nerve traffic was significantly related to serum ferritin (r=0.51, P<0.03), transferrin saturation (r=0.47, P<0.03), and hepatic iron load (r=0.76, P<0.0001, magnetic resonance imaging), as well as to homeostatic model assessment index values (r=0.46, P<0.05). These data provide the first evidence that in HT+ elevated serum ferritin is associated with a hyperadrenergic state of greater magnitude than the one seen in patients with hypertension without iron overload. They also show that the potentiation of the sympathetic activation detected in HT+ is related to elevated serum ferritin and to the associated metabolic alterations, possibly participating in the increased cardiovascular risk characterizing iron overload.


Selective denervation of the heart.
Total denervation of the canine heart consisted of intrapericardial neural dissection of the left atrium, left superior pulmonary vein, and main pulmonary artery and cutting of the ventrolateral cardiac nerve (stage I). The fat pad and all nerves were removed from between the pulmonary artery and aorta (stage II). Dissection proceeded from the pericardial reflection along the superior vena cava to the azygos vein, which was cleared, double tied, and cut. The right pulmonary artery was cleaned, and the superior right atrium was dissected to its intersection with the left atrium (stage III). Denervation was tested by electrical stimulation of both vagi and stellate ganglia, while recording inotropic, chronotropic, and dromotropic events, before and after each stage. Stage I deleted most left autonomic input to the heart without interrupting right sympathetics. Stage II completed left autonomic denervation but preserved much of the right sympathetic input. Large nerves along the dorsal surface of the pulmonary artery carried inputs from both left and right sympathetics. Stage III completed the denervation of atrioventricular and sinoatrial nodal structures and removed all remaining ventricular inotropic influences. Selective denervation of atrioventricular and sinoatrial nodal regions appears feasible for preparation of chronic canine models.


Step-by-step Guide to Create Competency-Based Assignments as an Alternative for Traditional Summative Assessment.
This article was migrated. The article was marked as recommended. The sudden, prolonged COVID-19 lockdown has offered a great challenge to the medical school. This was not only at the level of learning and curricular design but also the level of assessment. The traditional summative assessment tools have collapsed during this Pandemic. Herein, we provide a five-step guide for designing competency-based E-assignments for summative assessment. Innovative assignments designs are crucially required for fair summative assessment of the medical students, mainly in the pre-clerkship phase. These need to be innovative, engaging, competency-based, well-designed, with defined rubrics, integrated, and interdisciplinary whenever possible. These should also enforce the concepts of self-assessment and student peer assessment. Including the students in the formulation and design enhances their self-motivation where there is no face-to-face education. Designing an assignment with a quality product as an outcome increases the students' enthusiasm and self-confidence. A brief case-study is included as an example. Teaching after the pandemic era will greatly change with inevitable changes in the dogmatic concepts. Formative and summative assessments are probably changing seats which might be sustained for some time post-COVID-19.


[Toxicity of venoms from snakes of medical importance in México].
The characterization of the toxic activities of snake venoms is necessary to understand the physiopathology of the envenomation and to test the potency of the antivenoms used to treat this pathology. Because of the lack of data on the toxic activities of venoms from Mexican snakes of medical importance, we studied the venoms from Bothrops asper, Athropoides nummifrr, Agkistrodon billineatus, Crotalus durissus durissus, Crotalus basiliscus, Crotalus scutulatus, Crotalus atrox and Micrurus nigrocinctus. The studies performed were: SDS-PAOE, determination of lethal potency, hemorrhagic, necrotizing, coagulation on plasma and fibrinogen, phospholipasic and fibri(noge)nolytic activities. In addition we studied the neutralizing capacity of the toxic activities of an antivenom currently used for the treatment of snakebites in Mexico. The venom from viperids showed important hemorrhagic, necrotizing, coagulative on plasma, prothrombinic, fibrinogenolytic and phospholipase activities. The venoms with the highest lethal potency were those of Micrurus nigrocinctus and Crotalus scutulatus; however, the viperine venom that globally displayed the most potent toxic activities was from Bothrops asper. All the venoms showed toxic activities of similar range to those described for other American venomous snakes. The activity on plasma or fibrinogen varied widely among the different venoms but all displayed capacity to act on the coagulation system. The antivenom tested not only neutralized the lethality B. asper venom but also its other toxic activities.


[Malignant vascular tumors of the lung (cytologic and histologic parallels)].
Analysis of 78 observations (including 6 of the author's own) of primary malignant vascular tumours of the lung, showed that these tumours had no characteristic clinicoroentgenological features; in this connection the question of their preoperative cytological diagnosis is of importance. The retrospective collations of cytological and histological data in 8 patients made it possible to establish criteria of cytological diagnosis of similar tumours. For the first time in the Soviet literature a suggestion was put forward that basing on the data of cytological investigations it is possible in a number of cases to give a detailed verification of tumours of the lung with presumable indication to hemangioendothelioma, angiosarcoma, or hemangiopericytoma. Metastases of malignant vascular tumours of other localizations in the lung are of analogous cytological pattern. correct diagnosis of primary of metastatic tumour can be made only if all the complex of clinico-roentgenological and cytological data are taken into account.


Establishment of a novel classification system for alveolar morphology in infants with unilateral complete cleft lip and palate.
Unilateral complete cleft lip and palate (UCCLP) is one of the most severe clinical subtypes among cleft lip and palate (CLP), making repair surgery and subsequent orthodontic treatment particularly challenging. Presurgical nasoalveolar molding (PNAM) has shown conflicting and heterogeneous results in the treatment of UCCLP patients, raising questions about whether the diversity in alveolar anatomical morphology among these patients plays a role in the effectiveness of PNAM treatment. We collected 90 digital maxillary models of infants with UCCLP and performed mathematical clustering analysis, including principal component analysis (PCA), decision tree modeling, and area under the ROC Curve (AUC) analysis, to classify alveolar morphology and identify key measurements. We also conducted clinical evaluations to assess the association between the alveolar morphology and CLP treatment outcomes. Using mathematical clustering analysis, we classified the alveolar morphology into three distinct types: average form, horizontal form, and longitudinal form. The decision tree model, AUC analysis, and comparison analysis revealed that four measurements (Trans ACG-ACL, ML length, MG length and Inc length) were essential for clustering the alveolar morphology of infants with UCCLP. Furthermore, the blinded clinical evaluation indicated that UCCLP patients with alveolar segments of horizontal form had the lowest treatment outcomes. Overall, our findings establish a novel quantitative classification system for the morphology of alveolar bone in infants with UCCLP and suggest that this classification may be associated with the outcomes of CLP treatment. The multidisciplinary CLP team should thoroughly evaluate and classify the specific alveolar morphology when administering PNAM to infants with UCCLP.


Retroviral transfer of CPP32beta gene into malignant gliomas in vitro and in vivo.
Malignant gliomas are highly aggressive neoplasms that are very resistant to current therapeutic approaches, including irradiation, chemotherapy, and immunotherapy. To improve the prognosis, it is absolutely essential to explore novel modalities of treatment. Recently, we have demonstrated that interleukin 1beta-converting enzyme (ICE), a mammalian homologue of the Caenorhabditis elegans cell death gene ced-3, induces apoptotic cell death in malignant glioma cells. To date, ICE and ICE-like proteases (the ICE family), such as Ich-1L, CPP32beta, Mch2alpha, and Mch3alpha, have been shown to mediate apoptosis in some cells. The purpose of this study is to determine whether the ICE gene family functions as a useful tool for the treatment of malignant glioma cells through induction of apoptosis. The transient transfection assays showed that CPP32beta and Mch2alpha genes induced apoptotic cell death in malignant glioma cells more effectively than did the ICE, Ich-1L, and Mch3alpha genes. To improve the efficiency of gene transfer into malignant glioma cells, we constructed the retroviral vectors containing the ICE gene family. The retroviral transfer of CPP32beta or Mch2alpha gene effectively induced apoptosis in malignant glioma cells in vitro. Furthermore, treatment of tumors grown in mice with retrovirus containing CPP32beta significantly inhibited growth of the tumors through induction of apoptosis. The retroviral transfer of CPP32beta or Mch2alpha, therefore, may be a novel and promising approach for the treatment of malignant glioma, an invariably fatal tumor.


Function of metabolic and organelle networks in crowded and organized media.
(Macro)molecular crowding and the ability of the ubiquitous cytoskeleton to dynamically polymerize-depolymerize are prevalent cytoplasmic conditions in prokaryotic and eukaryotic cells. Protein interactions, enzymatic or signaling reactions - single, sequential or in complexes - whole metabolic pathways and organelles can be affected by crowding, the type and polymeric status of cytoskeletal proteins (e.g., tubulin, actin), and their imparted organization. The self-organizing capability of the cytoskeleton can orchestrate metabolic fluxes through entire pathways while its fractal organization can frame the scaling of activities in several levels of organization. The intracellular environment dynamics (e.g., biochemical reactions) is dominated by the orderly cytoskeleton and the intrinsic randomness of molecular crowding. Existing evidence underscores the inherent capacity of intracellular organization to generate emergent global behavior. Yet unknown is the relative impact on cell function provided by organelle or functional compartmentation based on transient proteins association driven by weak interactions (quinary structures) under specific environmental challenges or functional conditions (e.g., hypoxia, division, differentiation). We propose a qualitative, integrated structural-functional model of cytoplasmic organization based on a modified version of the Sierspinsky-Menger-Mandelbrot sponge, a 3D representation of a percolation cluster, and examine its capacity to accommodate established experimental facts.


A real world data of dabigatran etexilate: multicenter registry of oral anticoagulants in nonvalvular atrial fibrillation.
Atrial fibrillation (AF) is a common cardiac arrhythmia. Dabigatran etixalate (DE) is one of the new oral anticoagulant drugs being used in nonvalvular AF (NVAF). There is no adequate real world data in different populations about DE. The aim of this registry was to evaluate the efficacy and safety of DE Consecutive NVAF patients treated with warfarin or both DE doses were enrolled during 18 months study period. The patients were re-evaluated at regular 6-month intervals during the follow-up period. During the follow-up period outcomes were documented according to RELY methodology A total of 555 patients were analyzed. There was no significant difference in ischemic stroke rates (p = 0.73), death rates (p = 0.15) and MI rates (p = 0.56) between groups. The rate of major bleeding was significantly higher in warfarin and dabigatran 150 mg group than dabigatran 110 mg (p < 0.001). Intracranial bleeding rate and relative risk were significantly lower in dabigatran 110 mg group than warfarin group (p = 0.004). Dyspepsia was significantly higher in both DE doses than warfarin (p = 0.004) Both DE doses are as effective as warfarin in reducing stroke rates in NVAF patients, without increasing MI rates. Intracranial bleeding rates are significantly lower in warfarin than both doses of DE and gastrointestinal bleeding risk increases with increased DE doses.


Comparison of Flavonoids and Centella asiatica for the treatment of chronic anal fissure. A randomized clinical trial.
We aim to test and compare the effects of Flavonoids (Fs) and Centella asiatica (Ca), and the traditional treatment to find out which best deals with healing time, bleeding and pain in the treatment of chronic Anal Fissure (AF). Materials of Study: 98 outpatients were divided randomly into treated (either Fs or Ca) and control group. The control group (Group C, n=32) received the traditional treatment along with the other two subgroups which were treated, additionally, with Fs (Group A, n=30) or Ca (Group B, n=36). Patients were observed once weekly over 8 consecutive weeks. The median time to stop bleeding in the group A was 1 week, in the Group B was 3 weeks and in the group C was 4 weeks. There were significant differences between Groups in terms of time to end bleeding (A vs B: p-value= 0.022; A vs C: p-value<0.001; B vs C: p-value=0.070). As for pain score from baseline to the 2nd week were statistically different between Groups A and B on the one hand and Group C on the other hand (A vs C: p-value=0.004; B vs C: p-value 0.035). All patients healed within 8th week. Either patients treated with Fs or Ca experienced early pain disappearance. Fs and Ca did not show side effects CONCLUSIONS: The treatment with Fs is the most effective for bleeding. Patients additionally treated with either Fs or Ca experienced an earlier healing and disappearance of pain in comparison with patients underwent to the traditional treatment. Anal bleeding, Anal fissure, Defecation pain.


[Cardiovascular prevention in the over-80 age group is not beneficial].
The high prevalence and incidence of cardiovascular disease in the oldest old justify consideration of both primary and secondary prevention measures in this age group. However, evidence for the effectiveness of any preventive intervention is lacking. Regarding primary prevention, it is also unknown which elderly are actually at risk of developing new cardiovascular disease.


Type I procollagen propeptide in patients on CAPD: its relationships with bone histology, osteocalcin, and parathyroid hormone.
Serum procollagen type I carboxyterminal propeptide (PICP) has been shown to be a useful marker of bone formation in patients undergoing haemodialysis. However, PICP levels has not been evaluated in depth in patients maintained on continuous ambulatory peritoneal dialysis (CAPD). Therefore serum and dialysate levels of PICP, its peritoneal clearance (Clp), mass transfer (MTp), and its possible relationship with osteocalcin, parathyroid hormone (PTH), and bone histomorphometry were studied in a group of CAPD patients. Serum PICP was just above the normal range with significant amounts detected in the dialysate but no correlations were found between levels of serum PICP, dialysate PICP, and Clp-PICP. One patient with systemic lupus and osteitis fibrosa had extraordinarily high serum and dialysate levels of PICP. The patient later developed sclerosing peritonitis. No associations were seen between serum PICP and Clp-PICP and any of the 18 bone histomorphometric parameters evaluated. Dialysate level of PICP correlated negatively with mineral appositional rate (r = -0.62, P < 0.01) and mineralization lag time (r = 0.64, P < 0.01). MTp-PICP correlated positively with mineral appositional rate (r = 0.65, P < 0.01). Serum osteocalcin and serum PTH levels did not correlate to serum, dialysate, Clp or MTp measurements of PICP. These results suggest that measurements of PICP in CAPD patients do not give substantial information as an non-invasive marker of bone histology.


Serological evidence of exposure to tick fever organisms in young cattle on Queensland dairy farms.
To compare the features of farms on which the exposure of young cattle to tick fever organisms is sufficient to ensure that immunity is high and the risk of clinical disease is low (endemic stability) with those of farms on which exposure is insufficient to induce widespread immunity (hence without endemic stability); to examine the relationships between the management of ticks and tick fever, and endemic stability to Babesia bovis, B. bigemina and Anaplasma marginale. Cross-sectional study of 874 cattle between the ages of 6 and 15 months on 64 dairy farms, from three centres in south-eastern Queensland (Mutdapilly, Dayboro and Kenilworth) and one centre in far-north Queensland (Malanda). Blood samples collected from between 5 and 20 calves from each farm were submitted for serological assay to determine exposure to B. bovis, B. bigemina and A. marginale. A questionnaire about the farm characteristics and the management of ticks and tick fever was completed with each farmer. On 73% of farms, confirmed clinical cases of tick fever were recalled by the farmer, indicating that tick fever was a threat on most farms. The majority of herds in the study (54 of 64) did not have sufficient numbers of seropositive animals aged between 6 and 15 months to have a low risk of tick fever. Region had an effect on the likelihood of endemic stability for all tick fever organisms. Cattle near Malanda in Far-north Queensland were more likely to be seropositive to B. bovis and B. bigemina. The method, strategy and intensity of tick control were not related to the likelihood of endemic stability when the effect of region was considered. The decision to leave a few ticks on cattle in an effort to induce endemic stability did increase the likelihood of endemic stability to A. marginale. However, in practical terms, it was ineffective, because only 26% of these farms had endemic stability against all three organisms. Given the low proportion of farms that have endemic stability to the tick fever organisms and the high likelihood of clinical disease, vaccination is recommended to protect dairy cattle from tick fever throughout the tick infested area of Queensland. However, further work is required to determine the economic value of vaccination, taking into account the costs of vaccination, of outbreaks and the protective value of vaccination.


Preeclampsia Associates with Asthma, Allergy, and Eczema in Childhood.
Preeclampsia reflects an unusual increase in systemic inflammation during pregnancy. We studied associations between preeclampsia and asthma, allergy, and eczema in Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) and in national registries. COPSAC2000 is a high-risk birth cohort of 411 Danish children. Asthma, allergy, and eczema were diagnosed prospectively, and lung function measured at age 1 month and 7 years. Sensitization was evaluated at age 6 months, 18 months, 4 years, and 6 years by skin prick tests and IgE measurements. The register-based cohort included 1.7 million children from Danish national registries in the 35-year period 1977-2012. Children born to mothers with preeclampsia were analyzed regarding risk of asthma, allergy, and eczema. In the COPSAC2000 cohort, 5.6% (n = 23) were diagnosed with preeclampsia. Preeclampsia was associated with increased risk of treatment with inhaled corticosteroids at age 7 years (adjusted odds ratio, 4.01 [95% confidence interval (CI), 1.11-14.43]; P = 0.0337), increased bronchial responsiveness to methacholine (adjusted β-coefficient log-μmol, -0.80 [95% CI, -1.55 to -0.06]; P = 0.0348), and allergic rhinitis (adjusted odds ratio, 4.83 [95% CI, 1.58-14.78]; P = 0.0057) in the 7-year-old children. Furthermore, the children had an increased risk of sensitization to both aeroallergens and food allergens, and increased amount of total IgE during childhood. In the registry-based cohort, 3.7% (n = 62,728) were born to mothers with preeclampsia. Preeclampsia was associated with increased risk of asthma, eczema, and aeroallergen and food allergy, especially pronounced after a duration of preeclampsia of 14 days or more. Maternal asthma increased the risk of preeclampsia. Preeclampsia is a shared prenatal risk factor for asthma, eczema, and allergy in childhood pointing toward in utero immune programming of the child.


Partial characterization of the phosphotransferase system of human central-nervous-system myelin.
The phosphotransferase system of human central-nervous-system myelin was investigated. Evidence obtained indicated the presence of at least two different phosphotransferase systems (cyclic nucleotide-dependent and -independent) in myelin, which were found to be firmly associated with the membrane. The cyclic AMP-dependent kinase of myelin and white-matter cytosol preferentially phosphorylated certain histone fractions and displayed only modest activity with basic protein as substrate. On the other hand, the cyclic nucleotide-independent system showed specificity toward basic protein. Its activity was not only dependent on Mg2+ but it was greatly enhanced by this bivalent cation. Whereas the cyclic nucleotide-dependent kinase could be extracted with buffers containing Triton X-100, the bivalent cation-regulated kinase resisted solubilization from myelin under these conditions.


Selective control of membrane ruffling and actin plaque assembly by the Rho GTPases Rac1 and CDC42 in FcepsilonRI-activated rat basophilic leukemia (RBL-2H3) cells.
Engagement of the high affinity IgE receptor (FcepsilonRI) in mast cells elicits a series of intracellular signalling events including cytoskeletal reorganization and granule exocytosis. To analyze the coupling of receptor activation to specific cytoskeletal responses, we expressed dominant negative mutant forms of the Rho GTPases CDC42 and Rac1 in rat RBL-2H3 tumor mast cells. We show here that dominant inhibition of CDC42 function decreases cell adhesion, interferes with Fc(epsilon)RI-induced actin plaque assembly and reduced the recruitment of vinculin at the cell-substratum interface, while the inhibitory Rac1 mutant abolishes Fc(epsilon)RI-mediated membrane ruffling. The expression of trans-dominant inhibitory forms of either CDC42 or Rac1 significantly inhibited antigen-induced degranulation. Altogether, our results demonstrate that CDC42 and Rac1 control distinct pathways downstream of FcepsilonRI engagement leading either to the induction of actin plaques, or to the production of membrane ruffles. These two pathways are critically involved during the degranulation response induced by Fc(epsilon)RI aggregation.


Recovery of DNA synthesis from inhibition by ultraviolet light in mammalian cells.
In general mammalian cells recover from DNA synthesis inhibition by ultraviolet light (u.v.) before most of the pyrimidine dimers have been removed from the genome. This is a complex phenomenon whose biological significance has not been fully assessed. In Chinese hamster V79 cells this recovery seems to be directly coupled to an enhanced rate of double-stranded DNA elongation. The presence of the DNA polymerase alpha inhibitor, aphidicolin, after u.v. irradiation produces two different responses. At low concentration, sufficient to inhibit 95% of DNA replication but having no effect on excision repair, the drug has no effect on the recovery. This shows that ongoing replicative DNA synthesis is not required for recovery. At higher concentrations of aphidicolin, sufficient to block excision repair, the recovery phenomenon was prevented. The recovery was also prevented by actinomycin D at a concentration that inhibits 60% of RNA synthesis. In quantitative autoradiography experiments in which previously irradiated cells were fused with unirradiated cells the nuclei of the latter exhibited a higher resistance to inhibition by u.v. than nuclei from non-fused cells. These results indicate that: (1) even the low repair rate exhibited by V79 cells (relative to human cells) is important for recovery; although most of the dimers remain in the V79 genome after recovery of DNA synthesis, either the removal of lesions from some important region of chromatin or the activity of the repair process itself is important for the recovery; (2) the recovery mechanism is induced and depends on RNA synthesis and the production of specific factors. Finally, we have observed that cells previously treated with fluorodeoxyuridine become more resistant to inhibition by u.v. After irradiation these cells replicate DNA faster than untreated cells. Since it has been shown that this drug activates unused origins of replication in Chinese hamster cells, reducing the average replicon size, we assume that the acquired resistance has to do with the operation of a larger number of smaller replicons. This may also be the mechanism whereby recovery from inhibition occurs after u.v. irradiation.


Ligand-based peptide design and combinatorial peptide libraries to target G protein-coupled receptors.
G protein-coupled receptors (GPCRs) are considered to represent the most promising drug targets; it has been repeatedly said that a large fraction of the currently marketed drugs elicit their actions by binding to GPCRs (with cited numbers varying from 30-50%). Closer scrutiny, however, shows that only a modest fraction of (≈60) GPCRs are, in fact, exploited as drug targets, only ≈20 of which are peptide-binding receptors. The vast majority of receptors in the humane genome have not yet been explored as sites of action for drugs. Given the drugability of this receptor class, it appears that opportunities for drug discovery abound. In addition, GPCRs provide for binding sites other than the ligand binding sites (referred to as the "orthosteric site"). These additional sites include (i) binding sites for ligands (referred to as "allosteric ligands") that modulate the affinity and efficacy of orthosteric ligands, (ii) the interaction surface that recruits G proteins and arrestins, (iii) the interaction sites of additional proteins (GIPs, GPCR interacting proteins that regulate G protein signaling or give rise to G protein-independent signals). These sites can also be targeted by peptides. Combinatorial and natural peptide libraries are therefore likely to play a major role in identifying new GPCR ligands at each of these sites. In particular the diverse natural peptide libraries such as the venom peptides from marine cone-snails and plant cyclotides have been established as a rich source of drug leads. High-throughput screening and combinatorial chemistry approaches allow for progressing from these starting points to potential drug candidates. This will be illustrated by focusing on the ligand-based drug design of oxytocin (OT) and vasopressin (AVP) receptor ligands using natural peptide leads as starting points.


Preliminary evaluation of low-grade toxicity with conformal radiation therapy for prostate cancer on RTOG 9406 dose levels I and II.
To evaluate the rates of low-grade late effects in patients treated for prostate cancer on Radiation Therapy Oncology Group (RTOG) 9406. Between August 1994 and September 1999, 424 patients were entered on this dose escalation trial of three-dimensional conformal radiation therapy (3D-CRT) for localized adenocarcinoma of the prostate at doses of 68.4 Gy (level I) and 73.8 Gy (level II). We have previously reported Grade 3 or greater late toxicity of patients treated on the first two dose levels of this trial. This analysis examines the distribution of all late toxicities in these patients. All radiation prescriptions were a minimum dose to a planning target volume (PTV). Patients were stratified according to clinical stage and risk of seminal vesicle invasion (SVI) based upon Gleason score and presenting prostate-specific antigen. Group 1 includes patients with T1,2 disease with SVI risk < 15%, and Group 2 includes patients with T1,2 disease with SVI risk > 15%. Group 3 patients had T3 disease. Average months at risk after completion of therapy ranged from 21.4 to 40.1 months for patients treated at dose level I and 10.0 to 34.2 months for patients at dose level II. The frequency of all grades of late effects was compared with a similar group of patients treated in RTOG studies 7506 and 7706 with adjustments made for the interval from completion of therapy. The RTOG toxicity scoring scales for late effects were used for grading. The rate of Grade 3 or greater late toxicity continues to be low compared with RTOG historical controls. No Grade 4 or 5 late sequelae were reported in any of the 393 evaluable patients during the period of observation. The frequency of patients free of any complications was lower in RTOG 9406 than in historical controls. In the 73 Group 1 patients treated on dose level 1, there were 24 patients without sequelae compared with an expected rate of 39.7 (p = 0.013), and in 80 Group 3 patients at dose level II there were 24 patients without sequelae when 56.2 were expected (p < 0.0001). Other groups treated at these dose levels demonstrated a nonsignificant reduction in the rate of patients free of any side effects. These data suggest that the reduction in high-grade morbidity may be related to a shift of complications to lower grades. Morbidity of 3D-CRT in the treatment of prostate cancer is low. It is important to continue to closely examine late effects in patients treated in RTOG 9406. The primary objective of dose escalation without an increase rate of >/= Grade 3 sequelae has been achieved. However, the reduction in Grade 3 complications may have resulted in a higher incidence of Grade 1 or 2 late effects. Because Grade 2 late effects may have a significant impact on a patient's quality of life, it is important to reduce these complications as much as possible. Clinical trials should use quality-of-life measures to determine that trade-offs between severity and rates of toxicity are acceptable to patients.


Heterogeneous 18F-FDG uptake in recurrent respiratory papillomatosis.
Recurrent respiratory papillomatosis (RRP) describes an infection of the upper aerodigestive tract by the human papilloma virus most commonly affecting the larynx with rare lung involvement in 1%-2% of affected patients. We describe an unusual case of a 28-year-old male patient with a longstanding history of RRP where a whole-body PET/CT obtained for disease staging revealed multiple cavitary pulmonary nodules in addition to the more typical tracheobronchial papillomas. In the case described herein, we report heterogeneous uptake of 18F-FDG among these RRP lesions, suggesting significant unexpected variability in the underlying metabolic behavior of these lesions.


Development of Zinc-Specific iCEST MRI as an Imaging Biomarker for Prostate Cancer.
The healthy prostate contains the highest concentration of mobile zinc in the body. As this level decreases dramatically during the initial development of prostate cancer, in vivo detection of prostate zinc content may be applied for diagnosis of prostate cancer. Using 19 F ion chemical exchange saturation transfer magnetic resonance imaging (iCEST MRI) and TF-BAPTA as a fluorinated Zn-binding probe with micromolar sensitivity, we show that iCEST MRI is able to differentiate between normal and malignant prostate cells with a 10-fold difference in contrast following glucose-stimulated zinc secretion in vitro. The iCEST signal decreased in normal prostate cells upon downregulation of the ZIP1 zinc transporter. In vivo, using an orthotopic prostate cancer mouse model and a transgenic adenocarcinoma of the mouse prostate (TRAMP) model, a gradual decrease of >300 % in iCEST contrast following the transition of normal prostate epithelial cells to cancer cells was detected.


LC-MS/MS Quantitation of HILIC-Enriched N-glycopeptides Derived from Low-Abundance Serum Glycoproteins in Patients with Narcolepsy Type 1.
Glycoproteomic analysis is always challenging because of low abundance and complex site-specific heterogeneity. Glycoproteins are involved in various biological processes such as cell signaling, adhesion, and cell-cell communication and may serve as potential biomarkers when analyzing different diseases. Here, we investigate glycoproteins in narcolepsy type 1 (NT1) disease, a form of narcolepsy characterized by cataplexy-the sudden onset of muscle paralysis that is typically triggered by intense emotions. In this study, 27 human blood serum samples were analyzed, 16 from NT1 patients and 11 from healthy individuals serving as controls. We quantified hydrophilic interaction liquid chromatography (HILIC)-enriched glycopeptides from low-abundance serum samples of controls and NT1 patients via LC-MS/MS. Twenty-eight unique N-glycopeptides showed significant changes between the two studied groups. The sialylated N-glycopeptide structures LPTQNITFQTESSVAEQEAEFQSPK HexNAc6, Hex3, Neu5Ac2 (derived from the ITIH4 protein) and the structure IVLDPSGSMNIYLVLDGSDSIGASNFTGAK HexNAc5, Hex4, Fuc1 (derived from the CFB protein), with p values of 0.008 and 0.01, respectively, were elevated in NT1 samples compared with controls. In addition, the N-glycopeptide protein sources Ceruloplasmin, Complement factor B, and ITH4 were observed to play an important role in the complement activation and acute-phase response signaling pathways. This may explain the possible association between the biomarkers and pathophysiological effects.


Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants.
Holt-Oram syndrome (HOS) is an autosomal dominant condition characterised by the association of congenital heart defect (CHD), with or without rhythm disturbances and radial defects, due to TBX5 variants. The diagnosis is challenged by the variability of expression and the large phenotypic overlap with other conditions, like Okihiro syndrome, TAR syndrome or Fanconi disease. We retrospectively reviewed 212 patients referred for suspicion of HOS between 2002 and 2014, who underwent TBX5 screening. A TBX5 variant has been identified in 78 patients, representing the largest molecular series ever described. In the cohort, 61 met the previously described diagnostic criteria and 17 have been considered with an uncertain HOS diagnosis. A CHD was present in 91% of the patients with a TBX5 variant, atrial septal defects being the most common (61.5%). The genotype-phenotype study highlights the importance of some critical features in HOS: the septal characteristic of the CHD, the bilateral and asymmetric characteristics of the radial defect and the presence of shoulder or elbow mobility defect. Besides, 21 patients presented with an overlapping condition. Among them, 13 had a typical HOS presentation. We discuss the strategies that could be adopted to improve the molecular delineation of the remaining typical patients.


New results on recurrent network training: unifying the algorithms and accelerating convergence.
How to efficiently train recurrent networks remains a challenging and active research topic. Most of the proposed training approaches are based on computational ways to efficiently obtain the gradient of the error function, and can be generally grouped into five major groups. In this study we present a derivation that unifies these approaches. We demonstrate that the approaches are only five different ways of solving a particular matrix equation. The second goal of this paper is develop a new algorithm based on the insights gained from the novel formulation. The new algorithm, which is based on approximating the error gradient, has lower computational complexity in computing the weight update than the competing techniques for most typical problems. In addition, it reaches the error minimum in a much smaller number of iterations. A desirable characteristic of recurrent network training algorithms is to be able to update the weights in an on-line fashion. We have also developed an on-line version of the proposed algorithm, that is based on updating the error gradient approximation in a recursive manner.


Understanding the Implications of the Meniscal Ossicle: Patient Presentation, Treatment, and Outcomes.
The meniscal ossicle is observed in clinical practice, yet there currently is limited information on its potential clinical significance. The purpose of this study was to assess the clinical presentation, imaging findings, and clinical treatment and outcomes of a series of patients identified as having a meniscal ossicle. An institutional database was reviewed to identify knees with a meniscal ossicle. Clinical presentation, magnetic resonance imaging (MRI), treatment, and outcomes were analyzed. Radiographs were graded using Kellgren-Lawrence (KL) scores. MRIs were reviewed for the presence and location of meniscal ossicles and additional knee pathology. Knee arthroplasty rates were recorded with the remaining patients contacted to obtain final International Knee Documentation Committee (IKDC) and Tegner's scores. Failure was defined as conversion to arthroplasty or failing IKDC score (< 75.4). Forty-five meniscal ossicles in 45 patients (26 males and 19 females) with a mean age of 51 years (standard deviation [SD] = 19.0) were included. Pain was the most common presenting symptom (89%). Forty-two patients (93%) had an associated meniscus root tear on MRI. Eighteen percent of patients that did not have an ossicle on initial imaging subsequently developed an ossicle. Mean KL grades progressed significantly from baseline of 1.84 (SD = 1.0) to 2.55 (SD = 0.93 p < 0.01) on final follow-up. Thirty-nine percent of baseline radiographs showed KL grades of less than 2 compared with only 15% of follow-up radiographs (p = 0.04). Mean IKDC score obtained for patients ≤ 60 at an average follow-up of 3.1 years (SD = 3.2) was 65.2 (SD = 19.0). Eight out of 45 patients (18%) had progressed to total knee arthroplasty (TKA) by latest available follow-up. Sixty-two percent of patients met failure criteria at latest available follow-up. The meniscal ossicle is most commonly found in the posterior horn or root of the medial meniscus and is highly suggestive to be sequelae of a posterior root tear. Therefore, the presence of a meniscal ossicle should alert the orthopaedic surgeon to the high likelihood of the patient having a meniscus root tear. These patients have shown to have poor clinical outcomes and worsening arthritis.


Knowledge, attitudes, and practices of antiretroviral therapy among HIV-infected adults attending private and public clinics in India.
India has approximately 5.2 million persons infected with HIV. Although antiretroviral therapy (ART) is being widely introduced in public clinics, many HIV-infected persons still seek care via the private sector. A cross-sectional survey was conducted in 2004 at six public and private sites to characterize the knowledge, attitudes, and practices (KAP) of ART among patients with HIV receiving care in India. Of 1667 persons surveyed, 609 (36%) had heard of ART and 19% of these persons reported that ART could cure HIV. Twenty-four percent reported that they were currently taking ART, with 18% of these patients not actually on ART according to their provider. Major barriers to taking ART were cost (33%), lack of knowledge of ART (41%), and deferral by physician (30%). More than half of all public and private patients had not heard of CD4 (57%) or viral load testing (80%), and even fewer had received these tests (32% and 11%, respectively). Private clinic attendees were almost 4 times more likely to be on ART (35% versus 9%, p < 0.0001), more likely to be male, have a higher education, be partnered, have a higher income, and have had a CD4 or viral load (p < 0.0001). Overall, low levels of ART knowledge and access were observed among HIV infected patients, with access to ART being particularly low among patients attending public clinics. In order to make widespread dissemination of ART effective in India, further educational and programmatic efforts are likely needed to optimize access, treatment awareness, and compliance among patients with HIV.


Interactions of nucleolin and ribosomal protein L26 (RPL26) in translational control of human p53 mRNA.
Ribosomal protein RPL26 enhances p53 translation after DNA damage, and this regulation depends upon interactions between the 5'- and 3'-UTRs of human p53 mRNA (Takagi, M., Absalon, M. J., McLure, K. G., and Kastan, M. B. (2005) Cell 123, 49-63; Chen, J., and Kastan, M. B. (2010) Genes Dev. 24, 2146-2156). In contrast, nucleolin (NCL) suppresses the translation of p53 mRNA and its induction after DNA damage. We confirmed reports that RPL26 and NCL interact with each other and then explored the potential role of this interaction in the translational control of p53 after stress. NCL repression of p53 translation utilizes both the 5'- and 3'-UTRs of p53 mRNA, and NCL binds to the same 5'-3'-UTR interaction region that is critical for the recruitment of RPL26 to p53 mRNA after DNA damage. We also found that NCL is able to oligomerize, consistent with a model in which NCL stabilizes this double-stranded RNA structure. We found that the RNA-binding domain of NCL participates in binding to p53 mRNA, is required for both NCL dimerization and NCL-mediated translational repression, and is the domain of NCL that interacts with RPL26. Excessive RPL26 disrupts NCL dimerization, and point mutations in the NCL-interacting region of RPL26 reduce NCL-RPL26 interactions and attenuate both RPL26 binding to human p53 mRNA and p53 induction by RPL26. These observations suggest a model in which the base pairings in the p53 UTR interaction regions are critical for both translational repression and stress induction of p53 by NCL and RPL26, respectively, and that disruption of a NCL-NCL homodimer by RPL26 may be the switch between translational repression and activation after stress.


Reduced visual contrast suppression during major depressive episodes.
Previous studies have suggested that processing of visual contrast information could be altered in major depressive disorder. To clarify the changes at different levels of the visual hierarchy, we behaviourally measured contrast perception in 2 centre-surround conditions, assessing retinal and cortical processing. As part of a prospective cohort study, our sample consisted of controls (n = 29; 21 female) and patients with unipolar depression, bipolar disorder and borderline personality disorder who had baseline major depressive episodes (n = 111; 74 female). In a brightness induction test that assessed retinal processing, participants compared the perceived luminance of uniform patches (presented on a computer screen) as the luminance of the backgrounds was varied. In a contrast suppression test that assessed cortical processing, participants compared the perceived contrast of gratings, which were presented with collinearly or orthogonally oriented backgrounds. Brightness induction was similar for patients with major depressive episodes and controls (p = 0.60, d = 0.115, Bayes factor = 3.9), but contrast suppression was significantly lower for patients than for controls (p < 0.006, d = 0.663, Bayes factor = 35.2). We observed no statistically significant associations between contrast suppression and age, sex, or medication or diagnostic subgroup. At follow-up (n = 74), we observed some normalization of contrast perception. We assessed contrast perception using behavioural tests instead of electrophysiology. The reduced contrast suppression we observed may have been caused by decreased retinal feedforward or cortical feedback signals. Because we observed intact brightness induction, our results suggest normal retinal but altered cortical processing of visual contrast during a major depressive episode. This alteration is likely to be present in multiple types of depression and to partially normalize upon remission.


Content of exercise programmes targeting older people with sarcopenia or frailty - findings from a UK survey.
To establish whether existing exercise programmes offered to people with sarcopenia or frailty adhere to the current evidence base. We conducted a national survey of practitioners delivering exercise programmes to older people with sarcopenia or frailty in the UK. The link to the online survey was distributed through email lists of professional societies, practice networks and social media. Questions covered target population and programme aims, type, duration and frequency of exercise, progress assessment and outcome measures. One hundred and thirty-six responses were received. 94% of respondents reported prescribing or delivering exercise programmes to people with sarcopenia or frailty. Most programmes (81/135 [60%]) were primarily designed to prevent or reduce falls. Resistance training was the main focus in only 11/123 (9%), balance training in 61/123 (50%) and functional exercise in 28/123 (23%). Exercise was offered once a week or less by 81/124 (65%) of respondents. Outcome measures suitable for assessing the effect of resistance training programmes were reported by fewer than half of respondents (hand grip: 13/119 [11%]; chair stands: 55/119 [46%]). Current UK exercise programmes offered to older people with sarcopenia or frailty lack the specificity, frequency or duration of exercise likely to improve outcomes for this patient group.


Observations on the Global Spread of Physician Assistant Education.
The physician assistant concept was developed in the 1960s as a response to the shortage and uneven distribution of generalist doctors. The goal was to increase the public's access to health care. After a half century of development and implementation, the PA model has become a global strategy to augment medical service delivery. In many instances the introduction of the PA was successful. Elsewhere it is in the early stages of development. The name may be modified depending on the country: "physician associate," "clinical assistant," "associate physician" are alternatives. While not all PA start-ups have been successful, where the PA model is thriving and growing, the concept provides rich examples of adaptation and evolution. The notion of including a PA is based on the concept of a medical team model and modified depending on the needs of the nation's health structure, regulation, and policy. Along the way, the education process undergoes modification, depending on the needs of the nation, but what emerges is a strategy for augmenting a stretched physician cadre. The reasons for success and failure are multifactorial, and the early implementation of a PA program can be a daunting task. This article examines the PA education experience in 15 countries. Successful use of PAs suggests that flexible adaptation to health care demand, generalist education, physician acceptance, and cost-effectiveness analysis may be keys that influence policy and their retention. In the end, success, adaptation, and failures are the lessons learned.


Soft and hard tissue response to zirconium dioxide dental implants--a clinical study in man.
Titanium dental implants have been used successfully in implantology for more than 40 years. Recent research, however, suggests that titanium might have more side effects than previously believed. Zirconia ceramics have been employed in orthopaedic surgery for approximately 30 years and were recently introduced into dentistry as a metal replacement for crown and bridge work as well as implant abutments. Zirconium dioxide has been shown in both in vitro and in vivo studies to have desirable osseointegrative properties. This clinical study shows that dental implants made from zirconia are a feasible alternative to titanium dental implants. In addition to excellent cosmetic results, zirconia implants allow a degree of osseointegration and soft tissue response that is superior to titanium dental implants.


Rethinking Mass-Gathering Domains for Understanding Patient Presentations: A Discussion Paper.
The aim of this paper is to further develop an existing data model for mass-gathering health outcomes. Mass-gathering events (MGEs) occur frequently throughout the world. Having an understanding of the complexities of MGEs is important to determine required health resources. Environmental, psychosocial, and biomedical domains may be a logical starting point to determine how data are being collected and reported in the literature; however, it may be that other factors influencing health resources are not identified within these domains. Based on an exhaustive literature synthesis, this paper is the final paper in a series that explores the collection of variables that impact biomedical presentations associated with attendance/participation in MGEs. The authors propose further evolution of the Arbon model to include the addition of several domains, including: event environment; command, control, and communication (C3); public health; health promotion; and legacy when reporting the health outcomes of an event. Including a variety of domains that contribute to an MGE allows for formal evaluation of the event, which in turn informs future knowledge and skill development for both the event management group and the wider community.


A pulsed tangential-flow ultrafiltration technique for studying protein-drug binding.
We describe a pulsed tangential-flow ultrafiltration technique for rapid analysis of protein-drug binding. A protein-drug pulse was injected into a tangential-flow membrane device and made to flow parallel to the surface of a protein-retaining ultrafiltration membrane. The protein and protein-drug complexes were flushed out of the device in the retentate stream, whereas the free drug present in the permeate stream was quantified using on-line UV detector. The height of the permeate drug peak and its area under the curve were both found to be proportional to the free drug concentration in the injected sample. The fraction of bound drug was determined by comparison with peak obtained with protein-free drug sample. The characteristics of the permeate drug peak such as residence time, peak width, and peak height depended on both feed and permeate flow rates. The proposed technique in addition to being fast was "self-priming" in nature because the injected samples were flushed out of the module along with the retentate and permeate. This feature makes this technique particularly suitable for automated sample analysis. The technique was validated using three-model protein-drug combinations: bovine serum albumin (BSA)-antipyrine, BSA-tryptophan, and BSA-aspirin.


Provoked models of asthma: what have we learnt?
Asthma is a chronic inflammatory disease of the airways characterized by physiological abnormalities of variable airflow obstruction and airway hyperresponsiveness (AHR) to a wide variety of physical and inhaled chemical stimuli and the presence of symptoms. AHR is measured by challenging the airways with a variety of agonists and naturally occurring stimuli, which results in constriction of the airway smooth muscle, leading to airway narrowing and airflow limitation. There are two distinct mechanisms by which the airways can narrow to a constrictor stimulus and these are defined by the pathways they take to induce AHR. Direct stimuli are pharmacological agents administered exogenously (such as histamine or methacholine) that act 'directly' on specific receptors on the bronchial smooth muscle to cause constriction. The other mechanism by which the airway can narrow is via the inhalation of indirect stimuli, which include natural stimuli, such as allergen or exercise, and pharmacological agents such as adenosine monophosphate and hyper-osmotic agents (e.g. hypertonic saline or dry powder mannitol). These stimuli induce airway narrowing 'indirectly' by causing the endogenous release of mediators of bronchoconstriction from airway inflammatory cells. Provoked models of asthma have been extremely valuable in understanding the pathobiology of asthma, in aiding diagnosis, in helping to clarify the mechanisms of actions of effective drugs and in the development of new entities to treat asthma. Some provoked models are valuable clinically, particularly those that measure direct AHR, while others, particularly allergen challenge, have been used in animal models and in humans to study the mechanisms of allergen-induced airway inflammation and the associated physiological changes, as well in the development of new drugs for asthma. An emerging role for measurements of AHR is in the evaluation of the optimal treatment for patients with asthma.


LncRNA MAGI2-AS3 inhibites tumor progression by up-regulating STAM via interacting with miR-142-3p in clear cell renal cell carcinoma.
Revealing the role of non-coding RNAs (ncRNAs) in inducing dysregulated pathological responses to external signals may identify therapeutic targets for inhibiting the progression of clear cell renal cell carcinoma (ccRCC). Non-coding RNAs belong to a class of RNA molecules that do not encode proteins but possess diverse biological functions, playing essential roles in the occurrence and development of metastatic and proliferative tumors. To investigate the impact of the upstream interaction between miR-142-3p and lncRNA MAGI2-AS3 on the tumor-suppressive activity of the STAM gene, we firstly conducted bioinformatics analysis to predict the upstream miRNAs of STAM and the upstream lncRNAs of the miRNAs through online databases (miRanda, miRDB, TargetScan, LncBase v2), which were further validated by the starBasev2.0 database. Subsequently, multiple experimental techniques were employed to validate these findings, including RT-qPCR, Western blotting, measurement of cellular functional activity, and luciferase reporter assays. Through these experimental methods, we provided compelling evidence regarding the role of miR-142-3p and MAGI2-AS3 in regulating STAM gene expression and functionality, revealing their potential significance in tumor suppression. Our research demonstrates the importance of the MAGI2-AS3/miR-142-3p/STAM signaling pathway axis in ccRCC. MAGI2-AS3 competes for binding with miR-142-3p, resulting in upregulated STAM gene expression. This upregulation inhibits tumor proliferation and metastasis in ccRCC cells. Conversely, overexpression of miR-142-3p or silencing of MAGI2-AS3 promotes tumor behavior, while downregulation of miR-142-3p inhibits the development of ccRCC. Targeting the MAGI2-AS3/miR-142-3p/STAM axis holds promise as a therapeutic strategy for ccRCC treatment.


A Process-Oriented Model of Decision-Making toward Landscape-Scale Prescribed Fire Implementation in the Southern Great Plains, USA.
In this investigation, we developed a model of the psychological drivers of landowners' decisions to implement prescribed fire on their properties. The Southern Great Plains in the USA evolved with fire and prescribed fire is an important management tool aimed at maintaining and enhancing ecological and economic resilience in the region. The conceptualized model is reflective of a decision-making paradigm that considers decision making to be a process inclusive of a variety of factors and their inter-relationships to arrive at judgments on whether or not to utilize prescribed fire. The approach considered a spectrum of inputs, obstacles, and their associations to capture the complexity of decision making that is often lost when modeling single factors in dynamic social-ecological settings. Further, we considered the decision to use prescribed fire as a multifactor process that incorporates not only individual barriers to fire implementation but inter-barrier associations and other inputs (e.g., sociodemographic variables). Path analysis revealed five statistically significant relationships within the hypothesized model. For prescribed fire decision making, women tended to be more analytical whereas men were more inclined to rely on heuristics. Additionally, those who indicated owning their property for non-consumptive recreation-related reasons were also more inclined to rely upon heuristics. Texans reported more experience with prescribed fire as did respondents who indicated owning property for livestock product. Alternately, those owning their property for an investment and non-consumptive recreation opportunities reported less experience with prescribed fire. Last, ownership for crop and livestock production was positively associated with past wildfire experience. Findings have implications for three issue areas: (1) the provision of an evolved conceptualization through which prescribed fire implementation decisions can be examined, (2) enhancing the approach of prescribed fire outreach to a changing landowner population, and (3) improving the content and delivery of prescribed fire education efforts.


Central sympatholytics prolong survival in experimental sepsis.
One of the main causes of death in European and US intensive care units is sepsis. It involves a network of pro-inflammatory cytokines such as TNF-alpha, IL-1beta and IL-6. Furthermore, there is an up regulation of transcription factors such as nuclear factor (NF) kappaB. It has previously been shown that clonidine is able to significantly reduce pro-inflammatory cytokines in surgical patients. We therefore hypothesise that the clinically used central alpha-2 agonist clonidine has the ability to improve survival in experimental sepsis by inhibiting the sympathetic tone and consequently inhibiting the pro-inflammatory cytokine release. To investigate this therapeutic potential of clonidine in a prospective randomised laboratory investigation we used a murine model of caecal ligation and puncture (CLP) induced sepsis. Animals receiving pre-emptive injections were treated with either clonidine (5 microg/kg) or dexmedetomidine (40 microg/kg) 12 and 1 hours before the operation, as well as 1, 6 and 12 hours afterwards. Another group of animals only received clonidine (5 microg/kg) 1, 6 and 12 hours after the operation, while the pre-emptive injections were normal saline. The control groups received solvent injections at the respective time points. Pre-emptive administration of a central sympatholytic significantly reduced mortality (clonidine: p = 0.015; dexmedetomidine: p = 0.029), although postoperative administration of clonidine failed to significantly prolong survival. Furthermore pre-emptive administration of clonidine significantly attenuated the cytokine response after CLP-induced sepsis (mIL-1beta: p = 0.017; mIL-6: p < 0.0001; mTNF-alpha: p < 0.0001), preserved blood pressure control (p = 0.024) and down-regulated the binding activity of NF-kappaB. There were no changes in the pro-inflammatory cytokine response when peripheral blood was incubated with lipopolysaccharide alone compared with incubation with clonidine (10-4 M) plus LPS (p > 0.05). Our results demonstrate that the pre-emptive administration of either clonidine or dexmedetomidine have the ability to successfully improve survival in experimental sepsis. Furthermore, there seems to be a connection between the central muscarinic network and the vagal cholinergic response. By down-regulating pro-inflammatory mediators sympatholytics may be a useful adjunct sedative in patients with a high risk for developing sepsis.


Asymptomatic inflammatory bowel disease with special reference to ulcerative colitis in apparently healthy persons.
We examined cases of asymptomatic inflammatory bowel diseases, particularly asymptomatic ulcerative colitis, which were found in apparently healthy Japanese persons who underwent general health screening. Patients with positive immunological fecal occult blood test (IFOBT) among approximately 236,000 persons participating in the health screening program at the Aichi Prefectural Center for Health Care for the past 9 yr underwent total colonoscopy. In patients with ulcerative colitis, we investigated the sex and age distributions, extent of lesion, endoscopic activity, incidence rate, and clinical course. In all, 35 cases of inflammatory bowel disease were detected, and 274 cases of colorectal cancer (not discussed here) were detected in the same population. The 35 cases of inflammatory bowel disease consisted of 19 cases of ulcerative colitis (12 of asymptomatic and minimally symptomatic ulcerative colitis, and seven of symptomatic or with past history of ulcerative colitis); five of intestinal tuberculosis; two of Crohn's disease; two of amebic colitis; and seven of endoscopic colitis. The 12 patients with asymptomatic and minimally symptomatic ulcerative colitis consisted of 11 men and one woman aged 36-63 yr (mean 46.2 yr). We classified these cases into three grades of severity according to endoscopic findings: four cases were mild, eight moderate, and none severe. Of these 12 cases, three were found endoscopically because of positive IFOBT, although barium enema was normal. Anatomic types of colitis cases included three of total colitis, three left-sided colitis, two proctitis, and four right-sided or segmental colitis. In one case, the disease extended proximally during the course of observation. We found 35 cases of inflammatory bowel disease because of positive IFOBT performed as part of a general health screening. Of these, 19 cases were ulcerative colitis. These included many asymptomatic and minimally symptomatic cases, which could be very important in helping to elucidate the natural history of ulcerative colitis; thus, long-term follow up is necessary.