Luteolin Pretreatment Ameliorates Myocardial Ischemia/Reperfusion Injury by lncRNA-JPX/miR-146b Axis.
In the present study, we aimed to find out whether luteolin (Lut) pretreatment could ameliorate myocardial ischemia/reperfusion (I/R) injury by regulating the lncRNA just proximal to XIST (JPX)/microRNA-146b (miR-146b) axis. We established the models in vitro (HL-1 cells) and in vivo (C57BL/6J mice) to certify the protection mechanism of Lut pretreatment on myocardial I/R injury. Dual luciferase reporter gene assay was utilized for validating that JPX could bind to miR-146b. JPX and miR-146b expression levels were determined by RT-qPCR. Western blot was utilized to examine apoptosis-related protein expression levels, including cleaved caspase-9, caspase-9, cleaved caspase-3, caspase-3, Bcl-2, Bax, and BAG-1. Apoptosis was analyzed by Annexin V-APC/7-AAD dualstaining, Hoechst 33342 staining, as well as flow cytometry. Animal echocardiography was used to measure cardiac function (ejection fraction (EF) and fractional shortening (FS) indicators). miR-146b was demonstrated to bind and recognize the JPX sequence site by dual luciferase reporter gene assay. The expression level of miR-146b was corroborated to be enhanced by H/R using RT-qPCR (P < 0.001 vs. Con). Moreover, JPX could reduce the expression of miR-146b, whereas inhibiting JPX could reverse the alteration (P < 0.001 vs. H/R, respectively). Western blot analysis demonstrated that Lut pretreatment increased BAG-1 expression level and Bcl-2/Bax ratio, but diminished the ratio of cleaved caspase 9/caspase 9 and cleaved caspase 3/caspase 3 (P < 0.001 vs. H/R, respectively). Moreover, the cell apoptosis change trend, measured by Annexin V-APC/7-AAD dualstaining, Hoechst 33342 staining, along with flow cytometry, was consistent with that of apoptosis-related proteins. Furthermore, pretreatment with Lut improved cardiac function (EF and FS) (P < 0.001 vs. I/R, respectively), as indicated in animal echocardiography. Our results demonstrated that in vitro and in vivo, Lut pretreatment inhibited apoptosis via the JPX/miR-146b axis, ultimately improving myocardial I/R injury.


Competitive dynamics on complex networks.
We consider a dynamical network model in which two competitors have fixed and different states, and each normal agent adjusts its state according to a distributed consensus protocol. The state of each normal agent converges to a steady value which is a convex combination of the competitors' states, and is independent of the initial states of agents. This implies that the competition result is fully determined by the network structure and positions of competitors in the network. We compute an Influence Matrix (IM) in which each element characterizing the influence of an agent on another agent in the network. We use the IM to predict the bias of each normal agent and thus predict which competitor will win. Furthermore, we compare the IM criterion with seven node centrality measures to predict the winner. We find that the competitor with higher Katz Centrality in an undirected network or higher PageRank in a directed network is most likely to be the winner. These findings may shed new light on the role of network structure in competition and to what extent could competitors adjust network structure so as to win the competition.


[Congenital Langerhans-cell histiocytosis presenting as a varicella infection].
We report on a preterm infant (33rd gestational week) with a varicella-like congenital rash, which initially appeared to respond to therapy with acyclovir. At the age of 3 weeks, lesions were in different stages of evolution and still resembled a varicella zoster virus (VZV) infection. However, since proof of VZV infection was lacking and new lesions erupted at the age of 4 weeks, a skin biopsy was performed which revealed a diagnosis of Langerhans cells histiocytosis. Therapy with prednisone resulted in prompt healing of the lesions. Congenital Langerhans cell histiocytosis is rare and symptoms may vary substantially from case to case. Like in our observation it may be confused with congenital varicella. In case of congenital skin lesions of uncertain etiology a skin biopsy should be performed.


The growing price gap between more and less healthy foods: analysis of a novel longitudinal UK dataset.
The UK government has noted the public health importance of food prices and the affordability of a healthy diet. Yet, methods for tracking change over time have not been established. We aimed to investigate the prices of more and less healthy foods over time using existing government data on national food prices and nutrition content. We linked economic data for 94 foods and beverages in the UK Consumer Price Index to food and nutrient data from the UK Department of Health's National Diet and Nutrition Survey, producing a novel dataset across the period 2002-2012. Each item was assigned to a food group and also categorised as either "more healthy" or "less healthy" using a nutrient profiling model developed by the Food Standards Agency. We tested statistical significance using a t-test and repeated measures ANOVA. The mean (standard deviation) 2012 price/1000 kcal was £2.50 (0.29) for less healthy items and £7.49 (1.27) for more healthy items. The ANOVA results confirmed that all prices had risen over the period 2002-2012, but more healthy items rose faster than less healthy ones in absolute terms:£0.17 compared to £0.07/1000 kcal per year on average for more and less healthy items, respectively (p<0.001). Since 2002, more healthy foods and beverages have been consistently more expensive than less healthy ones, with a growing gap between them. This trend is likely to make healthier diets less affordable over time, which may have implications for individual food security and population health, and it may exacerbate social inequalities in health. The novel data linkage employed here could be used as the basis for routine food price monitoring to inform public health policy.


Giardia intestinalis mitosomes undergo synchronized fission but not fusion and are constitutively associated with the endoplasmic reticulum.
Mitochondria of opisthokonts undergo permanent fission and fusion throughout the cell cycle. Here, we investigated the dynamics of the mitosomes, the simplest forms of mitochondria, in the anaerobic protist parasite Giardia intestinalis, a member of the Excavata supergroup of eukaryotes. The mitosomes have abandoned typical mitochondrial traits such as the mitochondrial genome and aerobic respiration and their single role known to date is the formation of iron-sulfur clusters. In live experiments, no fusion events were observed between the mitosomes in G. intestinalis. Moreover, the organelles were highly prone to becoming heterogeneous. This suggests that fusion is either much less frequent or even absent in mitosome dynamics. Unlike in mitochondria, division of the mitosomes was absolutely synchronized and limited to mitosis. The association of the nuclear and the mitosomal division persisted during the encystation of the parasite. During the segregation of the divided mitosomes, the subset of the organelles between two G. intestinalis nuclei had a prominent role. Surprisingly, the sole dynamin-related protein of the parasite seemed not to be involved in mitosomal division. However, throughout the cell cycle, mitosomes associated with the endoplasmic reticulum (ER), although none of the known ER-tethering complexes was present. Instead, the ER-mitosome interface was occupied by the lipid metabolism enzyme long-chain acyl-CoA synthetase 4. This study provides the first report on the dynamics of mitosomes. We show that together with the loss of metabolic complexity of mitochondria, mitosomes of G. intestinalis have uniquely streamlined their dynamics by harmonizing their division with mitosis. We propose that this might be a strategy of G. intestinalis to maintain a stable number of organelles during cell propagation. The lack of mitosomal fusion may also be related to the secondary reduction of the organelles. However, as there are currently no reports on mitochondrial fusion in the whole Excavata supergroup, it is possible that the absence of mitochondrial fusion is an ancestral trait common to all excavates.


Ginsenoside Rg3 Attenuates Lipopolysaccharide-Induced Acute Lung Injury via MerTK-Dependent Activation of the PI3K/AKT/mTOR Pathway.
Acute lung injury (ALI) is a common clinical disease with high morbidity in both humans and animals. Ginsenoside Rg3, a type of traditional Chinese medicine extracted from ginseng, is widely used to cure many inflammation-related diseases. However, the specific molecular mechanism of the effects of ginsenoside Rg3 on inflammation has rarely been reported. Thus, we established a mouse model of lipopolysaccharide (LPS)-induced ALI to investigate the immune protective effects of ginsenoside Rg3 and explore its molecular mechanism. In wild type (WT) mice, we found that ginsenoside Rg3 treatment significantly mitigated pathological damages and reduced myeloperoxidase (MPO) activity as well as the production of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6); furthermore, the production of anti-inflammatory mediators interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), polarization of M2 macrophages and expression levels of the phosphorylation of phosphatidylinositol 3-hydroxy kinase (PI3K), protein kinase B (PKB, also known as AKT), mammalian target of rapamycin (mTOR) and Mer receptor tyrosine kinase (MerTK) were promoted. However, there were no significant differences with regards to the pathological damage, MPO levels, inflammatory cytokine levels, and protein expression levels of the phosphorylation of PI3K, AKT and mTOR between the LPS treatment group and ginsenoside Rg3 group in MerTK-/- mice. Taken together, the present study demonstrated that ginsenoside Rg3 could attenuate LPS-induced ALI by decreasing the levels of pro-inflammatory mediators and increasing the production of anti-inflammatory cytokines. These processes were mediated through MerTK-dependent activation of its downstream the PI3K/AKT/mTOR pathway. These findings identified a new site of the specific anti-inflammatory mechanism of ginsenoside Rg3.


Ratio imaging instrumentation.
Using ratio imaging to obtain quantitative information from microscope images is a powerful tool that has been used successfully in numerous studies. While ratio imaging reduces the effects of many parameters that can interfere with accurate measurements, it is not a panacea. In designing a ratio-imaging experiment all of the potential problems discussed in this chapter must be considered. Undoubtedly, other problems that were not discussed can also interfere with accurate and meaningful measurements. Many of the problems discussed here were observed in the authors' laboratories. In our experience there are no standard routines or methods that can foresee every problem before it has been encountered. Good experimental design can minimize problems, but the investigator must continue to be alert. Progress in instrumentation continues to overcome some of the difficulties encountered in ratio imaging. CCD cameras with 12- to 14-bit pixel depth are being used more frequently, and several confocal microscope manufacturers are now also using 12-bit digitization. The dramatic increase in the use of confocal microscopes over the past decade is now causing microscope manufacturers to more critically evaluate the effect of axial chromatic aberration in objectives, and recent designs to minimize this problem are being implemented. Other developments such as the use of AOTFs to attenuate laser lines extend the applicability of ratio imaging. Ratio imaging is clearly applicable to a wide range of cell biological problems beyond its widespread use for measuring ion concentrations. Imaginative but careful use of this technique should continue to provide novel insights into the properties of cells.


Diabetes susceptibility in the Canadian Oji-Cree population is moderated by abnormal mRNA processing of HNF1A G319S transcripts.
The G319S HNF1A variant is associated with an increased risk of type 2 diabetes in the Canadian Oji-Cree population. We hypothesized that the variant site at the 3' end of exon 4 might influence splicing and characterized mRNA transcripts to investigate the mutational mechanism underlying this susceptibility to diabetes. We established lymphoblastoid cell lines from a G319S homozygote and controls. HNF1A transcripts were characterized in the cell lines and pancreatic tissue by sequence analysis of RT-PCR products and quantification using real-time PCR. Susceptibility to mRNA surveillance was investigated using cycloheximide. Full-length G319S mRNA accounted for 24% of mRNA transcripts in the homozygous G319S cell line. A novel isoform lacking the terminal 12 bases of exon 4 was upregulated (55% of mRNA transcripts) compared with control cell lines (33%) and human pancreatic tissue (17%). Two abnormal transcripts present only in the G319S cell line included premature termination codons as a result of the inclusion of seven nucleotides from intron 4 or the deletion of exon 8. Cycloheximide treatment increased the levels of both transcripts. The G319S variant results in the production of two abnormal transcripts and an alteration in the relative balance of normal splicing products. This is predicted to lead to a reduction in total HNF1A transcript levels, but residual hepatocyte nuclear factor-1alpha protein activity in G319S homozygotes may still reach up to 66% of normal levels. A combination of abnormal splicing and reduced activity of the G319S protein may explain the diabetes susceptibility.


Transitional venous anomalies and DVAs draining brain AVMs: A single-institution case series and review of the literature.
Developmental venous anomalies (DVAs) are typically benign lesions purely venous in nature. However, a subset of DVAs are either 1) associated with brain arteriovenous malformations (AVMs) or 2) demonstrate shunting themselves. The goal of this case series and literature review is to present clinical characteristics, management strategies and outcomes of this patient population. Consecutive patients with arteriovenous shunting DVAs or DVAs draining nidal-AVMs were retrospectively reviewed. Lesions were classified as transitional DVAs or AVM-associated DVAs. Variables studied included clinical presentation, location, size, venous drainage, and malformation architecture. Treatment outcomes were evaluated. We identified 8 patients with transitional or AVM-associated DVAs from our institution. Six patients had unruptured lesions and two presented with hemorrhage. We classified 5 malformations as transitional DVAs and 3 as AVMs draining into DVAs. Three patients were conservatively managed, while 5 patients underwent treatment of the shunt by means of surgery (4) or radiosurgery (1). One patient suffered a right frontal venous infarct resulting in left sided weakness post-operatively. In the literature review we found 44 additional cases (Total = 30 transitional DVAs and 22 AVM-associated DVAs). Patients with transitional DVAs were more symptomatic than patients with AVM-associated DVAs (41.4% vs 22.2%). Permanent neurologic deficit following radiosurgical or microneurosurgical treatment of transitional DVAs was 28.6% compared to 16.7% for AVMs draining into DVAs. Transitional DVAs and AVMs draining into DVAs are rare lesions. Treatment is associated with substantial risk of venous infarct, particularly in situations where the draining vein is occluded.


The State of Remote Sensing Capabilities of Cascading Hazards over High Mountain Asia.
Cascading hazard processes refer to a primary trigger such as heavy rainfall, seismic activity, or snow melt, followed by a chain or web of consequences that can cause subsequent hazards influenced by a complex array of preconditions and vulnerabilities. These interact in multiple ways and can have tremendous impacts on populations proximate to or downstream of these initial triggers. High Mountain Asia (HMA) is extremely vulnerable to cascading hazard processes given the tectonic, geomorphologic, and climatic setting of the region, particularly as it relates to glacial lakes. Given the limitations of in situ surveys in steep and often inaccessible terrain, remote sensing data are a valuable resource for better understanding and quantifying these processes. The present work provides a survey of cascading hazard processes impacting HMA and how these can be characterized using remote sensing sources. We discuss how remote sensing products can be used to address these process chains, citing several examples of cascading hazard scenarios across HMA. This work also provides a perspective on the current gaps and challenges, community needs, and view forward towards improved characterization of evolving hazards and risk across HMA.


Doctors' attitudes to health centres.
In one Inner London health district many doctors seemed reluctant to work in health centres. To investigate the reasons, 44 general practitioners in two matched groups were interviewed. Those working in health centres appreciated the advantages of pleasant premises and the presence of a primary health care team. Other doctors believed health centres were disliked by patients, were bureaucratic in organization, and involved difficult interpersonal relationships. These were confirmed as real problems by health centre doctors. Thus, reluctance to join health centre practices is based on a realistic appraisal of the drawbacks. Recommendations are made.


Controlling the stereospecific bonding motif of Au-thiolate links.
Over the last decades, organosulfur compounds at the interface of noble metals have proved to be extremely versatile systems for both fundamental and applied research. However, the anchoring of thiols to gold remained an object of controversy for a long time. The RS-Au-SR linkage, in particular, is a robust bonding configuration that displays interesting properties. It is generated spontaneously at room temperature and can be used for the production of extended molecular nanostructures. In this work we explore the behavior of 1,4-bis(4-mercaptophenyl)benzene (BMB) on the Au(111) surface, which results in the formation of 2D crystalline metal-organic assemblies stabilized by this type of Au-thiolate bonds. We show how to control the thiolate's stereospecific bonding motif and thereby choose whether to form ordered arrays of Au3BMB3 units with embedded triangular nanopores or linearly stacked metal-organic chains. The former turn out to be thermodynamically favored structures and display confinement of the underneath Au(111) surface state. The electronic properties of single molecules as well as of the 2D crystalline self-assemblies have been characterized both on the metal-organic backbone and inside the associated pores.


Epidemiological of and risk factors for Alzheimer's disease: a review.
Alzheimer's disease (AD) is the most common form of dementia. It is a degenerative, incurable and terminal disease. The increasing prevalence of AD is, among other reasons, due to population aging, which is, to a certain extent, seen worldwide. Continuous advances in health care keep increasing life expectancy. Official statistics are likely to significantly underestimate the actual prevalence of AD. Alzheimer's disease represents an important public health problem. Its aetiology is still unknown and for this reason, it is necessary to study all potential risk factors which may contribute to the development of this disease. We searched original and review articles addressing Alzheimer's disease using key words Alzheimer's disease, epidemiology, risk factors and prevention. We found and used one hundred and four references. Based on epidemiological studies, genetic studies, neuroimaging methods and neuropathology research, three basic etiological hypotheses of the development of AD have been formulated: genetic, vascular and psychosocial. At present, the level of evidence is insufficient for the etiological role of other factors, such as nutrition, occupational exposure to various substances and inflammation. From the point of view of early diagnosis and application of primary or secondary prevention principles, genetic factors are the most important.


Is health status impaired in childhood cancer survivors? A systematic review and meta-analysis.
An increase in survival rates of childhood cancer is associated with long-term health issues in survivors. We conducted a systematic review and meta-analysis comparing health status-related endpoints in childhood cancer survivors (CCS) versus controls. Eighty-six studies (n = 98,480 participants, 62% CCS) were included in the review. Of these, 73 studies (n = 96,550, 63% CCS) could be meta-analyzed. CCS showed a lower left ventricular ejection and fractional shortening (SMD=-0.59 and -0.55, respectively, both p < 0.01 [n=1,824 and 1,880]), a lower HDL-cholesterol concentration (SMD=-0.48, p<0.001, n=1,378) and a higher waist-to-hip ratio (SMD=0.61, p < 0.01, n=229) than their healthy peers. No significant differences were found for the remaining endpoints. CCS is associated with a lower left ventricular function and HDL-cholesterol level, and a higher waist-to-hip ratio than healthy controls. These findings support the need to closely monitor the cardiometabolic health status of CCS and to implement preventive lifestyle interventions for this population.


Vectors and Gene Delivery to the Retina.
One of the great advantages of the retina as a target tissue for gene delivery is the wide array of genetic tools that have been developed in the past decade. This includes a variety of vectors for therapeutic gene delivery to most types of retinal neurons and glia, as well as cell type-specific promoters for restricted gene expression in distinct neuronal subtypes. Within the scope of neuroscience applications and for gene therapy, it is now routine to express reporter genes, replacement genes, neuronal activity indicators, and microbial opsins in specific neuronal types in the mouse retina. However, there are considerable anatomical, physiological, immunological, and behavioral differences between the mouse and the human that limit the usefulness of these tools in humans and nonhuman primates. Several advances are now being made toward the goal of applying viral targeting tools to understand the primate retina. Here, we describe these advances, consider their potential to advance our understanding of the primate retina, and describe what will be needed to move forward.


[Ipsilateral adrenalectomy is not obligatory in nephrectomy for renal cell carcinoma].
To analyse the necessity of obligatory ipsilateral adrenalectomy (IA) for renal cell carcinoma (RCC), we made a study of 329 RCC patients operated from 2002 to 2007. Nephrectomy was conducted in 208 (63.2%) patients, renal resection--in 121 (36.8%), adrenalectomy--in 19 (5.8%) patients. High-contrast multislice computed tomography (HCMCT) was performed in all the patients. Preoperative HCMCT detected adrenal lesions in 62 (18.84%) patients. Adrenal adenoma was suspected in 39 (11.8%) patients: ipsilateral in 19 (48.77%), contralateral in 11 (28.23%), bilateral in 9 (23%) patients. Adrenal hyperplasy was diagnosed in 11 (3.34%) patients. It was ipsilateral in 5 (45.4%), contralateral in 4 (36.4%), bilateral in 2 (18.2%) patients. The tumor invaded the ipsilateral adrenal in 4 (1.2%) patients. A RCC metastasis into the adrenal was suspected in 8 (2.4%) patients. A synchroneous affection was seen in 5 (1.5%) patients: ipsilateral in 4 (80%) and bilateral in 1 (20%) patients. RCC invaded the ipsilateral adrenal in 1.2% patients with RCC, its adrenal metastasis was detected in 1.5% RCC patients. In preservation of the adrenal in adenoma or hyperplasy 5-year follow-up registered no changes. Neither pathological processes were diagnosed for 5 years in preservation of unaffected adrenal. Thus, adrenalectomy is not obligatory in radical nephrectomy.


Thyroid disorders and breast cancer risk in Asian population: a nationwide population-based case-control study in Taiwan.
To evaluate whether hyperthyroidism or hypothyroidism increases the risk of subsequent breast cancer in an Asian population. Nationwide population-based case-control study. All healthcare facilities in Taiwan. A total of 103 466 women (mean age 53.3 years) were enrolled. 51 733 adult women with newly diagnosed primary breast cancer without a previous cancer history between 2006 and 2011 were identified and included in our study. 51 733 women with no cancer diagnosis prior to the index date were age matched as controls. Diagnosis of hyperthyroidism or hypothyroidism prior to the diagnosis of breast cancer or the same index date was identified, age, histories of thyroid disease treatment, oestrogen use and radioactive iodine treatment were adjusted. To identify risk differences in developing breast cancer among patients with a medical history of hyperthyroidism or hypothyroidism. There was a significantly increased risk of breast cancer in women with hyperthyroidism under the age of 55 years (age <45: OR 1.16, P=0.049; age 45-55: OR 1.15, P=0.019). Patients with hypothyroidism also showed an increased risk of breast cancer (OR 1.19, P=0.029) without statistical significance after stratification by age group (age <45, 45-55, >55 years). Treatment for thyroid disorders did not alter the association in subgroup analyses (P=0.857; 0.262, respectively). Asian women under 55 years of age with history of hyperthyroidism have a significantly increased risk of breast cancer regardless of treatment. Women with history of hypothyroidism may also have an increased risk.


[Methodology of epidemiologic studies of endogenous psychoses].
The author suggests that a chronoepidemiological approach and the method of phasic-spatial analysis should be used a sa main orientation and tool of the study into the causes and conditions of a mass character of endogenic psychoses. This method involves a wide range of temporal, spatial, quantitative, qualitative, empirical and theoretical epidemiological parameters of the disease. The method makes it possible to elucidate different forms of cause-and-effect relationships of synchronous and diachronous nature. The efficacy of the method was assessed in a retrospective study of schizophrenic patients in the city of Andizhan. This study revealed an action of an unknown factor in the early ontogenesis of patients. On the basis of phasograms of the distribution of schizophrenia a conclusion is drawn that the unknown factor has a physical nature and cyclically varying force characteristics with a period of about 10 years.


A Bayesian approach to an integrated multimodal noninvasive diagnosis of definitive nonalcoholic steatohepatitis in the spectrum of nonalcoholic fatty liver disease.
The distinction between definitive nonalcoholic steatohepatitis (NASH) and other histological patterns of nonalcoholic fatty liver disease (NAFLD) continues to rely on liver biopsy, which has risks and limitations. We explored the usefulness of a Bayesian approach to establish the likelihood ratios (LRs) of different noninvasive diagnostic modalities (circulating cytokeratin-18 fragment levels, hydrogen breath test, transient elastography) for distinguishing definitive NASH from other forms of NAFLD. From a series of 235 consecutive patients with biopsy-proven NAFLD enrolled at a tertiary referral hepatology clinic, we identified 135 patients with definitive NASH and 100 with other forms of NAFLD. Bayesian probabilities in the form of LRs were estimated for predicting definitive NASH. In conditional logistic regression models, the probability of having definitive NASH was associated with diabetes mellitus [odds ratio (OR) 2.89; 95% confidence interval (CI) 1.71-4.85], positive transient elastography results (OR 2.11; 95% CI 1.08-4.09), and apoptosis marker M30 (OR 2.57; 95% CI 1.78-3.93). We then estimated the LRs for variables independently related to definitive NASH, which were as follows: diabetes(+) LR=2.42; M30(+) LR=2.12; and transient elastography(+) LR=1.77. On the basis of the LR form of Bayes' theorem, the prediction model that took into account diabetes, M30 measurements, and the results of transient elastography at a tertiary hospital determined an 81% probability of distinguishing definitive NASH from other forms of NAFLD. A Bayesian approach combining clinical, laboratory, and imaging data may be useful for identifying patients with the highest probability of having definitive NASH.


Early detection of pemetrexed-induced inhibition of thymidylate synthase in non-small cell lung cancer with FLT-PET imaging.
Inhibition of thymidylate synthase (TS) results in a transient "flare" in DNA thymidine salvage pathway activity measurable with FLT ([18F]thymidine)-positron emission tomography (PET). Here we characterize this imaging strategy for potential clinical translation in non-small cell lung cancer (NSCLC). Since pemetrexed acts by inhibiting TS, we defined the kinetics of increases in thymidine salvage pathway mediated by TS inhibition following treatment with pemetrexed in vitro. Next, using a mouse model of NSCLC, we validated the kinetics of the pemetrexed-mediated "flare" in thymidine salvage pathway activity in vivo using FLT-PET imaging. Finally, we translated our findings into a proof-of-principle clinical trial of FLT-PET in a human NSCLC patient. In NSCLC cells in vitro, we identified a burst in pemetrexed-mediated thymidine salvage pathway activity, assessed by 3H-thymidine assays, thymidine kinase 1 (TK1) expression, and equilibrative nucleoside transporter 1 (ENT1) mobilization to the cell membrane, that peaked at 2hrs. This 2hr time-point was also optimal for FLT-PET imaging of pemetrexed-mediated TS inhibition in murine xenograft tumors and was demonstrated to be feasible in a NSCLC patient. FLT-PET imaging of pemetrexed-induced TS inhibition is optimal at 2hrs from therapy start; this timing is feasible in human clinical trials.


Changes in women's physical health during the first postpartum year.
To examine changes in women's physical health during the first postpartum year. Participants completed surveys at 1, 3, 6, 9, and 12 months post partum. Four hundred thirty-six first-time mothers who gave birth at one of two St Paul, Minn, hospitals during a 12-month period and who met the criteria for the study. Physical symptoms and number of illness days experienced within the previous 2 weeks. Physical problems seen at a higher prevalence at 1 month post partum included breast symptoms, vaginal discomfort, fatigue, hemorrhoids, poor appetite, constipation, increased sweating, acne, hand numbness or tingling, dizziness, hot flashes, and illness days. Several of these disorders--hemorrhoids, dizziness, fatigue, and constipation--persisted beyond 1 month and were joined by other "late" problems, including respiratory symptoms, sexual concerns, and hair loss. Women who returned to the work force noted more symptoms of respiratory infections, and women with vaginal deliveries had a higher prevalence of hemorrhoids, vaginal discomfort, pain with intercourse, difficulty reaching orgasm, sinus problems, and acne. Recovery from childbirth often requires more than the 6 weeks traditionally allotted, and postpartum health appears to be affected by delivery type and work status.


Automation of slide staining for large tissue sections.
Staining is a critical step in tissue analysis as it enhances the visibility and contrast of tissue structures for microscopic examination. Large tissue sections such as the human brain, heart, and liver are becoming increasingly important in studying complex tissue structures, providing critical information about the tissue's normal or abnormal development, function, and disease processes. Manual staining methods are still widely used and are prone to inconsistencies and inaccuracies, leading to unreliable results. Commercially available automated staining systems offer a more efficient alternative, but currently, these systems are only available for smaller 1" x 3" slides which are ill-suited for examining larger tissue sections. To address this challenge, we present a custom-designed Large format Automated Slide Stainer that can handle various glass slides, from the standard 1" x 3" slides to the custom-sized 2" x 3", 5" x 7", and 6" x 8" glass slides. The system uses a Cartesian robotic arm to stain the slides and has a user-friendly and intuitive interface for creating and modifying custom staining protocols. Safety features include chemical isolation, a ventilation system, an emergency shutdown, and a protective shield to minimize hazards from handling chemicals and biological materials. The automated stainer showed little variability in positioning with a mean offset error of 1.65 ± 0.65 mm and 1.73 ± 0.76 mm in the X and Y axes, respectively. In addition, the automated staining process showed better uniformity than manual staining. A pairwise distance was used to evaluate how well image histograms matched within a batch. The automated staining had a mean pairwise distance of 0.0070 ± 0.0017 (Nissl) and 0.0060 ± 0.0003 (Hematoxylin and Eosin(H&E)), which were far superior to the manual staining distances (Nissl: 0.0173 ± 0.0107 and H&E: 0.0185 ± 0.0067). This system represents a substantial advancement in tissue staining and has the potential to improve the reliability of tissue analysis significantly.Clinical relevance - Automated system for providing accurate, reproducible, and high-throughput staining of large tissue sections for use in histopathology and research.


Cosolute paramagnetic relaxation enhancements detect transient conformations of human uracil DNA glycosylase (hUNG).
The human DNA repair enzyme uracil DNA glycosylase (hUNG) locates and excises rare uracil bases that arise in DNA from cytosine deamination or through dUTP incorporation by DNA polymerases. Previous NMR studies of hUNG have revealed millisecond time scale dynamic transitions in the enzyme-nonspecific DNA complex, but not the free enzyme, that were ascribed to a reversible clamping motion of the enzyme as it scans along short regions of duplex DNA in its search for uracil. Here we further probe the properties of the nonspecific DNA binding surface of {(2)H(12)C}{(15)N}-labeled hUNG using a neutral chelate of a paramagnetic Gd(3+) cosolute (Gd(HP-DO3A)). Overall, the measured paramagnetic relaxation enhancements (PREs) on R(2) of the backbone amide protons for free hUNG and its DNA complex were in good agreement with those calculated based on their relative exposure observed in the crystal structures of both enzyme forms. However, the calculated PREs systematically underestimated the experimental PREs by large amounts in discrete regions implicated in DNA recognition and catalysis: active site loops involved in DNA recognition (268-274, 246-250), the uracil binding pocket (143-148, 169-170), a transient extrahelical base binding site (214-216), and a remote hinge region (129-132) implicated in dynamic clamping. These reactive hot spots were not correlated with structural, hydrophobic, or solvent exchange properties that might be common to these regions, leaving the possibility that the effects arise from dynamic sampling of exposed conformations that are distinct from the static structures. Consistent with this suggestion, the above regions have been previously shown to be flexible based on relaxation dispersion measurements and course-grained normal-mode analysis. A model is suggested where the intrinsic dynamic properties of these regions allows sampling of transient conformations where the backbone amide groups have greater average exposure to the cosolute as compared to the static structures. We conclude that PREs derived from the paramagnetic cosolute reveal dynamic hot spots in hUNG and that these regions are highly correlated with substrate binding and recognition.


APOE epsilon4 is associated with obstructive sleep apnea/hypopnea: the Sleep Heart Health Study.
Obstructive sleep apnea/hypopnea (OSAH) has a strong heritable component, although its genetic basis remains largely unknown. One epidemiologic study found a significant association between the APOE epsilon4 allele and OSAH in middle-aged adults, a finding that was not replicated in a cohort of elderly adults. The objective of this study was to further examine the association of the APOE epsilon4 allele with OSAH in a community-dwelling cohort, exploring age dependency of the association. A genetic association study was performed, nested within a prospective cohort study of the cardiovascular consequences of OSAH. Unattended, in-home nocturnal polysomnography was used to measure apnea-hypopnea index (AHI) in 1,775 participants age 40 to 100 years. OSAH was defined as an AHI > or = 15. The relation of APOE genotype to prevalent OSAH was analyzed using generalized estimating equations to account for non-independent observations of individuals from the same sibship. At least one APOE epsilon4 allele was present in 25% of subjects, with 1.3% epsilon4/epsilon4 homozygotes. The prevalence of OSAH was 19%. After adjustment for age, sex, and BMI, the presence of any APOE epsilon4 allele was associated with increased odds of OSAH (OR 1.41, 95% CI 1.06 to 1.87, p = 0.02). The effect was approximately twice as great in subjects <75 (OR 1.61, CI 1.02 to 2.54) as in those > or =75 years old (OR 1.32, CI 0.91 to 1.90). Exploratory analyses revealed that the strongest effect of APOE epsilon4 was in subjects age <65 (OR 3.08, CI 1.43 to 6.64), and was stronger in those with hypertension or cardiovascular disease than in those without. The APOE epsilon4 allele is associated with increased risk of OSAH, particularly in individuals under age 65. The mechanisms underlying this association are uncertain. Age-dependency of the APOE-OSAH association may explain previous conflicting results.


Descriptive and injunctive norms of waterpipe smoking among college students.
Smoking tobacco via a waterpipe (WP) is on the rise, particularly among college students. One reason for this may be normative perceptions of WP tobacco smoking (WTS) among this population. The current study examined the perceived and actual descriptive and injunctive norms of WTS among a college student sample. Participants were 894 college students enrolled at a large, Midwestern university. Participants completed measures of WTS frequency and quantity and perceived/actual descriptive and injunctive norms of WTS. Over one-third of the sample reported ever trying WTS, while only 2% reported current (past month) use. When comparing ever and never WP smokers, ever smokers reported greater perceived peer approval of WTS. Both males and females overestimated WTS frequency of same-sex students at their university. The current study is one of the first to investigate descriptive and injunctive norms of WTS among college students. Students who report WTS are more likely to overestimate descriptive norms of WTS among their peers, suggesting corrective normative feedback regarding actual use by peers may be an important target for WTS intervention among college students. Future research should investigate the temporal association between normative perceptions and WTS behaviors among college students.


The Psychology of Replication and Replication in Psychology.
Like other scientists, psychologists believe experimental replication to be the final arbiter for determining the validity of an empirical finding. Reports in psychology journals often attempt to prove the validity of a hypothesis or theory with multiple experiments that replicate a finding. Unfortunately, these efforts are sometimes misguided because in a field like experimental psychology, ever more successful replication does not necessarily ensure the validity of an empirical finding. When psychological experiments are analyzed with statistics, the rules of probability dictate that random samples should sometimes be selected that do not reject the null hypothesis, even if an effect is real. As a result, it is possible for a set of experiments to have too many successful replications. When there are too many successful replications for a given set of experiments, a skeptical scientist should be suspicious that null or negative findings have been suppressed, the experiments were run improperly, or the experiments were analyzed improperly. This article describes the implications of this observation and demonstrates how to test for too much successful replication by using a set of experiments from a recent research paper.


Gastric cancer in coal miners: a case-control study in a coal mining area.
In collaboration with three pathology departments a case-control study was conducted in the southern part of the Netherlands to investigate the risk of gastric cancer in coal miners. Between 1 January 1973 and 31 December 1983, 323 male patients were diagnosed as having a malignant neoplasm of the stomach. For each case a control was selected from the same pathology department, matched on year of birth and regardless of diagnosis. The archives of the Central Coal Miners Pension Fund were searched to obtain information about whether or not a patient had ever worked for a coal mining company in the Netherlands. Twenty two per cent of the patients had been registered as an underground coal miner, compared with 20% of the control group (odds ratio of 1.14, 95% confidence interval: 0.33-1.73). Those with gastric cancer who had ever worked underground in a coal mine did so for an average period of 16.9 years compared with an average of 19.7 years in the control group. The study gives no indication that the underground workers of the Dutch coal mines had a raised risk of developing a malignant neoplasm of the stomach.


A journey to produce platelets in vitro.
Allogeneic platelet transfusions protect patients from bleeding episodes and also make aggressive medical procedures such as those involving marrow transplants requiring chemotherapy and/or radiotherapy possible. These patients are dependent upon an unfailing supply of platelets that can sometimes be in short supply due to high demands coupled with an extremely short expiration date for platelet products of only 5 days. One approach that is under investigation to overcome platelet shortages is to harness the extraordinary capabilities of stem cells to proliferate and differentiate into various cell types and to use this ability to specifically produce clinical scale quantities of functional platelets in bioreactors. To accomplish such an enormous and complex task requires an appreciation of the regulatory mechanisms that occur during the development of megakaryocytes (MKs) and the subsequent biogenesis of functional platelets from mature MKs. This means understanding the complex network of intracellular and extracellular regulatory mechanisms that act at each phase of a developmental process that ushers stem cells along the MK lineage to produce billions of platelets per day in a healthy individual.


Immune and metabolic responses in early and late sepsis during mild dietary zinc restriction.
Mild dietary zinc (Zn) deficiency is widespread in human populations, but its influence on recovery after acute illness is poorly understood. In a mouse model of abdominal sepsis (cecal ligation puncture), systemic immune responses and liver metabolism were monitored in early (24 h) and late (5 d) phases, under control conditions and during mild dietary Zn restriction. Mice were fed diets adequate or marginally deficient (ZM) in Zn (30 versus 10 mg zinc/kg diet) for 4 wk, before undergoing laparotomy alone (nonseptic control) or cecal ligation puncture (septic). Among nonseptic mice, the ZM state was not associated with differences in inflammation or metabolic responses. Among septic mice, mortality did not differ between the zinc adequate and ZM groups. In the early phase, the ZM state amplified increases in plasma interleukin (IL) 6, tumor necrosis factor alpha, and IL-10, while dampening the interferon gamma response. In the late phase, subtle but significant ZM-associated increases were observed in plasma IL-5 and interferon gamma levels and hepatic protein synthesis, the latter of which appeared to be mammalian target of rapamycin independent and was associated with increased hepatic tumor necrosis factor alpha messenger RNA content. Without increasing mortality, the ZM state is associated with a more disordered acute systemic inflammatory response and persistence or enhancement of acute phase responses within the liver parenchyma.


The impact of genetic variation in DRD2 and SLC6A3 on smoking cessation in a cohort of participants 1 year after enrollment in a lung cancer screening study.
Smoking cessation strategies continue to have disappointing results. By determining the interindividual genetic differences that influence smoking behaviors, we may be able to develop tailored strategies that increase the likelihood of successful cessation. This study attempts to determine genetic influences on the relationship between the dopamine pathway and smoking cessation by examining associations with a variable number tandem repeat variation in SLC6A3 and the DRD2 variants TaqIA (A2 vs. A1), TaqIB (B2 vs. B1), C957T (C vs. T), and -141C Ins/Del (C vs. Del). Baseline smokers in the Pittsburgh Lung Screening Study who provided information on smoking status 1 year later were evaluated. We frequency-matched those who were not abstinent at 1 year to those who were abstinent at 1 year by gender, decade of age, and time of enrollment (3-month intervals) in a 3:1 ratio (N = 881). Logistic regression was used to identify the effect of genotype on abstinence at 1 year. In a model containing the matching variables and other genotypes, DRD2 TaqIA was significantly associated with being abstinent at 1 year (P = 0.01). Compared to participants who were homozygous for the TaqIA major allele (A2A2), participants who carried at least one minor allele (A1) were less likely to quit (Odds Ratio: 0.47, 95% CI: 0.24-0.94). The other dopamine receptor genotypes and the SLC6A3 genotype were not associated with smoking status at 1 year. The association between DRD2 TaqIA and smoking cessation supports the hypothesis that genetic variation in the dopamine pathway influences smoking cessation.


Conditioning insulin effects.
It has previously been demonstrated that after a number of insulin injections in rats, an injection of a placebo leads to an elevation in blood sugar. It has been suggested that this apparent conditioned compensatory response is an artifact resulting from stressing the subject (when large doses of insulin are used) or represents a nonassociative phenomenon (when small doses of insulin are used). These two suggestions were rejected on the basis of the results of Experiments 1 and 2, respectively. Experiments 3 and 4 demonstrated that although the behavioral effects of insulin can be conditioned to the injection procedure, such conditioned insulinlike behaviors (contrary to suggestions of many investigators) are not mediated by a pypoglycemic state.


Fructose intake increases hyperlipidemia and modifies apolipoprotein expression in apolipoprotein AI-CIII-AIV transgenic mice.
Fructose intake has increased steadily during the past two decades. The objective of this study was to determine the effect of fructose intake on lipid metabolism in apolipoprotein (apo) AI-CIII-AIV transgenic (Tg) mice that have severe hypertriglyceridemia and moderate hypercholesterolemia. Tg and control mice were fed for 9 mo a commercial nonpurified diet and had free access to water or 250 g/L fructose solution. In Tg mice, fructose intake increased triglycerides and cholesterol but did not induce insulin resistance. There were no differences in human hepatic apo AI and apo CIII mRNA levels in fructose-fed mice compared with untreated mice, but apo AIV mRNA was greater, indicating a differential expression of the apo AI and apo AIV genes in response to dietary perturbations. Interestingly, the plasma concentration of the three human apolipoproteins was enhanced in fructose-fed Tg mice compared with untreated Tg mice. Our data suggest that long-term fructose consumption had strong adverse effects in this hyperlipidemic mouse model.


The value of anticarcinoembryonic antigen, human milk factor globulin, and antikeratin antibodies in differentiating mesothelioma from lung carcinoma.
Monoclonal anticarcinoembryonic antigen (antiCEA), human milk factor globulin (HMFG2), and antikeratin antibodies were assessed for their value in the differential diagnosis of pleural mesothelioma (53 cases) and carcinoma of the lung (60 cases) in material from necropsies. In 40 of the cases pleural biopsies were also studied in the same manner. AntiCEA was found to be the best discriminating antibody for most types of mesothelioma; HMFG2 was slightly less valuable but a useful additional tool. Antikeratin was the least useful. For both antiCEA and HMFG2 antibodies, however, the proportion of carcinomas staining was smaller than in previous studies and this, combined with the positive staining of some mesotheliomas, reduces the value of the reactions in the individual case. Medical panels adjudicating compensation claims should not use these reactions as the sole criteria in deciding the origin of the tumours in these cases.


Phenolic profile and anti-inflammatory activity of four Moroccan date (Phoenix dactylifera L.) seed varieties.
Date (Phoenix dactylifera L.) seeds are seen as good drug to cure rheumatoid arthritis and asthma in Moroccan traditional medicine. The present research aimed to study the anti-inflammatory effect, of methanol extract of different date seed varieties using membrane stabilizing effect, nitric oxide radical scavenging activity, inhibition of protein denaturation, carrageenan-induced paw edema and croton oil induced ear edema. The polyphenolic profile was examined using HPLC-DAD. Rutin, quercetin, p-coumaric and caffeic acids were the main among the analysed phenolic compounds. Concerning the anti-inflammatory activity, the analysed date seed were significantly effective in scavenging nitric oxide free radical, in stabilisation of erythrocyte membrane and possessed a high anti denaturation effect. In agreement with this finding, date seed exhibited a profound ability to reduce paw and ear swelling induced by carrageenan and croton oil respectively. The biochemical parameters showed that date seed are able to reduce the erythrocyte sedimentation rate (ERS) and C-reactive protein (CRP) concentration in rats used in Carrageenan-induced paw edema model. The predominant phenolic compounds are the potential candidates that drive these activities and the differences observed among varieties are related to their chemical composition. These data suggest that date seeds can be explored as a therapeutic agent for the treatment of inflammatory diseases.


Prediction of depression and anxiety 1 year after moderate-severe traumatic brain injury.
This study examined three scales of the Personality Assessment Inventory (PAI; Anxiety, Anxiety-Related Disorders, and Depression) in 88 participants 1 year after they suffered a moderate-severe traumatic brain injury (TBI). Participants were all enrolled in the federally funded Traumatic Brain Injury Model System project at Carolinas Rehabilitation. The following variables were assessed at the time of injury: age, sex, employment and marital status, and length of loss of consciousness. Disability status, using the Disability Rating Scale (DRS), was assessed at the time of discharge from the rehabilitation hospital. A series of three linear regression analyses found that these variables significantly predicted scores on the Anxiety and Anxiety-Related Disorders scales, which accounted for 14% and 17.7% of the variance, respectively. The variables did not significantly predict scores on the Depression scale. Within each regression analysis, DRS was consistently and negatively related to each PAI scale, such that greater disability was associated with better psychological functioning. Such seemingly paradoxical findings are discussed in terms of anosognosia or poor awareness of psychological functioning among those with greater disability 1 year after TBI.


Involvement of MAF1 homolog, negative regulator of RNA polymerase III in colorectal cancer progression.
Polymerase (Pol) III‑dependent transcription controls the abundance of transfer RNAs, 5S ribosomal RNA and small non‑coding RNAs within cells, and is known to serve an essential role in the maintenance of intracellular homeostasis. However, its contribution to cancer progression has not been extensively explored. The present study demonstrated that the evolutionarily conserved MAF1 homolog, negative regulator of RNA Pol III (MAF1) may be closely associated with malignant potential and poor prognosis in colorectal cancer (CRC). Notably, immunohistochemical analysis of 146 CRC surgical specimens revealed that high expression levels of MAF1 were associated with advanced tumor depth, lymph node metastasis, distant metastasis and poor prognosis. In vitro loss‑of‑function assays revealed that MAF1 knockdown suppressed chemoresistance and migration of CRC cancer cells. Furthermore, detailed analysis of an independent CRC dataset (n=615) demonstrated that the prognostic impact of MAF1 gene expression was particularly marked in microsatellite instability (MSI)‑positive patients, who benefit from immune checkpoint blockade. High expression levels of MAF1 were revealed to be an independent prognostic indicator in MSI‑positive CRC. These findings suggested that MAF1 may have an essential role in CRC progression, particularly in MSI‑positive cases.


Selection of test methods to assess ecological effects of mixed aerosols.
Components of the mixed aerosols generated during military training are known to be of toxicological and/or ecological significance. There are few studies, however, quantifying mixed aerosol effects on ecosystems. Prompted by our finding that one or more of the compounds in the mixed aerosols commonly encountered in military training areas showed mutagenic effects in several species, a multiyear effort is evaluating the use of ecotoxicity testing methods to assess mixed aerosol ecological impacts. Selection of test methods for ecoepidemiology begins with the identification of the data required to meet defined environmental quality objectives. The data requirements are then matched with appropriate test methods, and testing results are related to important ecological effects resulting from aerosol exposure. The critical element of test system selection is to ensure that toxicity testing results relate to important ecological effects. The procedures developed for identifying test methods to assess mixed aerosols are also applicable to a range of environmental contaminants regulated by air, water, and solid waste regulations.


Lymphocyte polarity, the immunological synapse and the scope of biological analogy.
Lymphocytes such as T cells, B cells and natural killer (NK) cells form specialized contacts, called immunological synapses, with other cells in order to engage in specific intercellular communication and killing. Synapse formation is associated with the polarization of the microtubule-organizing center (MTOC) toward the contact site, which enables the directional secretion of cytokines and lytic factors. Although MTOC reorientation to the synapse is crucial for lymphocyte function, it has been difficult to study because of technical constraints. We have developed a photoactivation and imaging strategy that enables high-resolution analysis of cytoskeletal dynamics in individual T cells. Using this approach, we have demonstrated that the lipid second messenger diacylglycerol plays a crucial role in promoting MTOC reorientation by recruiting three members of the protein kinase C family to the synapse. Here, I will discuss these results along with studies from other labs, which have explored the role of polarity-inducing protein complexes after synapse formation. I will also propose a two-step model for MTOC reorientation in lymphocytes that reflects what we now know about the subject. Finally, I will consider the extent to which lymphocyte polarity resembles analogous cell polarity systems in other cell types.


Gut microbial RNA and DNA analysis predicts hospitalizations in cirrhosis.
Cirrhosis is associated with gut microbial changes, but current 16S rDNA techniques sequence both dead and live bacteria. We aimed to determine the rRNA content compared with DNA from the same stool sample to evaluate cirrhosis progression and predict hospitalizations. Cirrhotics and controls provided stool for RNA and DNA analysis. Comparisons were made between cirrhotics/controls and within cirrhosis (compensated/decompensated, infected/uninfected, renal dysfunction/not, rifaximin use/not) with respect to DNA and RNA bacterial content using linear discriminant analysis. A separate group was treated with omeprazole for 14 days with longitudinal microbiota evaluation. Patients were followed for 90 days for hospitalizations. Multivariable models for hospitalizations with clinical data with and without DNA and RNA microbial data were created. Twenty-six controls and 154 cirrhotics (54 infected, 62 decompensated, 20 renal dysfunction, 18 rifaximin) were included. RNA and DNA analysis showed differing potentially pathogenic taxa but similar autochthonous taxa composition. Thirty subjects underwent the omeprazole study, which demonstrated differences between RNA and DNA changes. Thirty-six patients were hospitalized within 90 days. In the RNA model, MELD score and Enterococcus were independently predictive of hospitalizations, while in the DNA model MELD was predictive and Roseburia protective. In both models, adding microbiota significantly added to the MELD score in predicting hospitalizations. DNA and RNA analysis of the same stool sample demonstrated differing microbiota composition, which independently predicts the hospitalization risk in cirrhosis. RNA and DNA content of gut microbiota in cirrhosis are modulated differentially with disease severity, infections, and omeprazole use. NCT01458990. VA Merit I0CX001076.


Transfemoral aortic valve implantation new criteria to predict vascular complications.
This study sought to evaluate the incidence, impact, and predictors of vascular complications in transcatheter aortic valve implantation (TAVI). Vascular complications increase morbidity and mortality in transfemoral TAVI; however, there remains a paucity of data describing these serious events. We performed a prospective cohort study of 130 consecutive transfemoral TAVI recipients. Vascular complications were defined by the Valve Academic Research Consortium (VARC) criteria. The ratio of the sheath outer diameter (in millimeters) to the minimal femoral artery diameter (in millimeters) defined the sheath to femoral artery ratio (SFAR). In our cohort of elderly patients (83.3 ± 5.9 years), the logistic EuroScore was 25.8% ± 11.9%. The Edwards valve was used in 102 cases (18- to 24-F) and the CoreValve in 27 (18-F). The minimal femoral artery diameter was 8.17 ± 1.14 mm, and the calcification (0 to 3) and tortuosity scores (0 to 3) were 0.58 ± 0.72 and 0.28 ± 0.53, respectively. The mean sheath diameter was 8.10 ± 0.82 mm, and the mean SFAR was 0.99 ± 0.16. Vascular complications occurred in 27.6% (VARC major: 17.3%, minor: 10.2%), and major vascular complications predicted 30-day mortality (22.7% vs. 7.6%, p = 0.049). The SFAR (hazard ratio [HR]: 186.20, 95% confidence interval [CI]: 4.41 to 7,855.11), center experience (HR: 3.66, 95% CI: 1.17 to 11.49), and femoral calcification (HR: 3.44, 95% CI: 1.16 to 10.17) predicted major complications by multivariate analysis. An SFAR threshold of 1.05 (area under the curve = 0.727) predicted a higher rate of VARC major complications (30.9% vs. 6.9%, p = 0.001) and 30-day mortality (18.2% vs. 4.2%, p = 0.016). Vascular complications in transfemoral TAVI are relatively frequent. VARC major vascular complications increase 30-day mortality and are predicted by experience, femoral calcification, and SFAR. Routine application of SFAR will improve patient selection for transfemoral TAVI and may improve outcome.


Fiber-optic intrinsic distributed acoustic emission sensor for large structure health monitoring.
A fiber-optic intrinsic distributed acoustic emission (AE) sensor is proposed. By measuring the time delay of two signals from two Mach-Zehnder interferometers, the location of AE can be deduced, and the corresponding sensor is experimentally verified to be feasible with a 206 m average location error in a 20 km sensing range, which shows that this proposed sensor is applicable for distributed AE sensing for large structure health monitoring, with the unique advantages of low cost, simple configuration, and long sensing range. The limitations of the proposed sensor are also discussed, and the future work is presented.


[Rapid methods in culturing nonsporulating anaerobes and determining their antibiotic sensitivity by using disks].
A review of methods for determination of sensitivity of nonsporulating anaerobic bacteria to antibacterial drugs with paper disks is presented and the prospects for using the method of cultivation in solid media in Petri dishes under a polymer film are discussed. It is shown that cultivation at a temperature of 42 degrees C for obtaining earlier results instead of the temperature of 37 degrees C usually used for cultivation has no advantages. With an account of the result variability depending on the inoculation dose and other factors it is necessary to determine the boundary values of the growth inhibition zones for resistant, moderate sensitive and sensitive strains with respect to every antibiotic.


ATP-sensitive K+ channels are altered in hypertrophied ventricular myocytes.
Unitary K+ currents in single cells isolated from normal and hypertrophied feline left ventricles were studied with regard to ATP sensitivity using patch-clamp single-channel recording. Data were obtained from excised inside-out membrane patches with symmetrical transmembrane K+ concentration [K+] (140 mM) at 22 +/- 1 degree C and in the absence of divalent cations. In the absence of ATP at the intracellular membrane surface, K+ channel activity was observed during depolarizing and hyperpolarizing pulses ranging from 10 to 120 mV from the K+ equilibrium potential. The current voltage (I-V) curve displayed some inward rectification, with slope conductances becoming nonlinear at strong depolarizations. Rectification was particularly pronounced in cells from hypertrophied left ventricles relative to normal. Single-channel conductance determined from the linear portion of the I-V curve was 77 pS in both groups. The channels were blocked by intracellular Ca2+ (1 mM), extracellular tetraethylammonium (TEA; less than or equal to 2 mM) or 4-aminopyridine (0.5 mM); 2 mM ATP produced a total but reversible inhibition. The effect of ATP was to reduce channel openings; conductance was unaffected. The ATP concentration [( ATP]) that induced half-maximal inhibition of channel activity was 75 microM in normal myocytes but was 250 microM in cells from hypertrophied hearts. Rapid channel activation at diminished [ATP] may provide a protective function by maintaining resting potential or promoting vasodilation in hypertrophied myocardium.


Human sterol regulatory element-binding protein 1a contributes significantly to hepatic lipogenic gene expression.
Sterol regulatory element-binding protein (SREBP) 1, the master regulator of lipogenesis, was shown to be associated with non-alcoholic fatty liver disease, which is attributed to its major isoform SREBP1c. Based on studies in mice, the minor isoform SREBP1a is regarded as negligible for hepatic lipogenesis. This study aims to elucidate the expression and functional role of SREBP1a in human liver. mRNA expression of both isoforms was quantified in cohorts of human livers and primary human hepatocytes. Hepatocytes were treated with PF-429242 to inhibit the proteolytic activation of SREBP precursor protein. SREBP1a-specifc and pan-SREBP1 knock-down were performed by transfection of respective siRNAs. Lipogenic SREBP-target gene expression was analyzed by real-time RT-PCR. In human liver, SREBP1a accounts for up to half of the total SREBP1 pool. Treatment with PF-429242 indicated SREBP-dependent auto-regulation of SREBP1a, which however was much weaker than of SREBP1c. SREBP1a-specifc knock-down also reduced significantly the expression of SREBP1c and of SREBP-target genes. Regarding most SREBP-target genes, simultaneous knock-down of both isoforms resulted in effects of only similar extent as SREBP1a-specific knock-down. We here showed that SREBP1a is significantly contributing to the human hepatic SREBP1 pool and has a share in human hepatic lipogenic gene expression.


Platelet thrombospondin modulates endothelial cell adhesion, motility, and growth: a potential angiogenesis regulatory factor.
Components of the extracellular matrix have been shown to modulate the interaction of endothelial cells with their microenvironment. Here we report that thrombospondin (TSP), an extracellular matrix component, induces adhesion and spreading of murine lung capillary (LE-II) and bovine aortic (BAEC) endothelial cells. This TSP-induced spreading was inhibited by heparin and fucoidan, known to bind the amino-terminal globular domain of the molecule. In addition, endothelial cells were induced to migrate by a gradient of soluble TSP (chemotaxis). The chemotactic response was inhibited by heparin and fucoidan, as well as by the mAb A2.5, which also binds to the amino-terminal domain. These data are in agreement with our previous observation that the TSP aminoterminal heparin binding region is responsible for the induction of tumor cell spreading and chemotactic motility. The inhibition of chemotaxis and spreading by antibodies against the beta 3 but not the beta 1 chain of the integrin receptor points to a role for the integrins in the interaction of endothelial cells with TSP. We also found that TSP modulates endothelial cell growth. When added to quiescent LE-II cells, it inhibited the mitogenic effects of serum and the angiogenic factor bFGF, in a dose-dependent manner. The inhibition of DNA synthesis detected in the mitogenic assay resulted in a true inhibition of BAEC and LE-II cell growth, as assessed by proliferation assay. This work indicates that TSP affects endothelial cell adhesion, spreading, motility and growth. TSP, therefore, has the potential to modulate the angiogenic process.


Flexibility in starting ovarian stimulation at different phases of the menstrual cycle for treatment of infertile women with the use of in vitro fertilization or intracytoplasmic sperm injection.
To investigate flexibility in starting controlled ovarian stimulation at any phase of the menstrual cycle in infertile women undergoing treatment with assisted reproduction. Retrospective cohort study. Academic tertiary-care medical center. At total of 150 infertile patients undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment. Ninety of the women also underwent frozen embryo transfer (FET) procedures. Depending on the phase of the menstrual cycle when ovarian stimulation was started, three groups of patients were identified, namely: conventional group (ovarian stimulation started in the early follicular phase), late follicular phase group, and luteal phase group. When dominant follicles were observed, final oocyte maturation was triggered with the use of GnRH agonist and hCG. In all three groups, viable embryos were cryopreserved for subsequent transfer. number of mature oocytes retrieved. fertilization rate, viable embryo rate per oocyte retrieved, cancellation rate, and clinical pregnancy outcomes from FET cycles. There were no differences in the mean number of mature oocytes retrieved in the conventional group, late follicular phase group, and luteal phase group (5.7 ± 3.6, 5.2 ± 3.7, and 5.2 ± 3.9, respectively). Similarly, no significant differences were observed in the viable embryo rate per oocyte retrieved (37.9%, 38.5%, and 43.6%), clinical pregnancy rates (41.5%, 45.5%, and 38.9%), and implantation rates (30.7%, 30.2%, and 27.1%) in the three groups. All three ovarian stimulation protocols were observed to be equally effective. These results demonstrate that ovarian stimulation can be commenced on any day of the menstrual cycle. ChiCTR-OPN-15007332.


IgE binding to almond proteins in two CAP-FEIA-negative patients with allergic symptoms to almond as compared to three CAP-FEIA-false-positive subjects.
Allergy to almonds has been frequently reported, but data on the identification of the almond allergens, as well as on the reliability of the methods for in vitro detection of specific IgE for these allergens, are scant. This study aimed to identify the almond allergens and to evaluate the reliability of the CAP-FEIA as the standard system for detection of almond-specific IgE with clinical significance. Immunoblotting performed with an almond-protein extract was carried out on the sera of five patients who had previously been tested by the CAP-FEIA system; two of these patients had tested negative with the CAP-FEIA system but suffered life-threatening laryngeal edema after eating almonds, whereas the other three subjects, who had tested positive with CAP-FEIA, did not present any symptoms subsequent to almond ingestion. The sera of the two symptomatic CAP-FEIA-negative patients had IgE that bound only to a 37-kDa protein in immunoblotting. On the contrary, the sera of the three asymptomatic subjects all showed IgE binding to two almond proteins of 62 and 50 kDa, corresponding to the glycosylated components of the extract. The results here presented suggest that, at least for the examined subjects, the positivity to almond, as measured with a standard laboratory method, is due to the presence of the 62/50-kDa glycoproteins with little or no immunologic significance, and not to the binding to the 37-kDa polypeptide, which appears to be a true almond allergen.


The ontogeny of plant defense and herbivory: characterizing general patterns using meta-analysis.
Defense against herbivores often changes dramatically as plants develop. Hypotheses based on allocation theory and herbivore selection patterns predict that defense should increase or decrease, respectively, across ontogeny, and previous research partly supports both predictions. Thus, it remains unclear which pattern is more common and what factors contribute to variability among studies. We conducted a meta-analysis of 116 published studies reporting ontogenetic patterns in plant defense traits and herbivory. Patterns varied depending on plant life form (woody, herbaceous, grass), type of herbivore (insect, mollusk, mammal), and type of defense trait (secondary chemistry, physical defense, tolerance). In woody plants, chemical defense increased during the seedling stage, followed by an increase in physical defenses during the vegetative juvenile stage. Mammalian herbivores showed a strong preference for mature compared to juvenile tissues in woody plants. Herbs experienced a significant increase in secondary chemistry across the entire ontogenetic trajectory, although the magnitude of increase was greatest during the seedling stage. Correspondingly, mollusks preferred young compared to older herbs. Future research investigating growth/defense trade-offs, allometry, herbivore selection patterns, and ecological costs would shed light on the mechanisms driving the ontogenetic patterns observed.


Critical review of forensic trace evidence analysis and the need for a new approach.
The historical development, contributions and limitations of the two traditional approaches to trace evidence analysis are reviewed. The first approach was as generalist practitioner, looking broadly at an assemblage of many different particle types. The second was that of specialist practitioner, with attention focused on one specific particle type. Four factors have significantly impacted the effectiveness of these approaches: (1) increasing technological capabilities, (2) increasing complexity in the character of manufactured materials, (3) changes in forensic laboratory management, and (4) changing scientific and legal expectations. The effectiveness of each approach is assessed within the context of these changes. More recently, new technologies have been applied to some trace evidence problems, intended to address one or more limitations. This has led to a third approach founded on discrete, highly technical methods addressing specific analytical problems. After evaluating the contributions and limitations of this third approach, we consider the different ways that technologies could be developed to address unmet needs in forensic trace evidence analysis. The route toward effective use of new technologies is contrasted with how forensic science laboratories are currently choosing and employing them. The conclusion is that although new technologies are contributing, we are not on a path that will result in their most effective and appropriate use. A new approach is required. Based on an analysis of the contributions of each of the three exisiting approaches, seven characteristics of an effective trace evidence analysis capability were determined: (1) particle traces should be a major problem-solving tool, (2) there should be readily available, straightforward methods to enable their use, (3) all available and potentially useful particle types should be considered, (4) decisions to use them should be made in the context of each case, guided by what they can contribute to the case and how efficiently they can do so, (5) analyses should be conducted using appropriate technologies, (6) findings should be timely and directly integrated with case-specific problems, and (7) new technologies should be used to improve the overall effectiveness of the capability. Clearly new technologies have the potential to revolutionize forensic trace evidence, but just as clearly some of the traditional capabilities have been rendered ineffective, or lost entirely, by the way we have come to approach the problem. Having critically defined the current limitations of and the desired outcomes, the next focus should be consideration of alternative approaches that might achieve such a result.


Sidestepping the semantics of "consciousness"
Block explains the conflation of phenomenal consciousness and access consciousness by appeal to the ambiguity of the term "consciousness." However, the nature of ambiguity is not at all clear, and the thesis that "consciousness" is ambiguous between phenomenal consciousness and access consciousness is far from obvious. Moreover, the conflation can be explained without supposing that the term is ambiguous. Block's argument can thus be strengthened by avoiding controversial issues in the semantics of "consciousness."


[Functional morphology of pituitary adenoma in acromegaly].
Twenty-one pituitary adenomas removed from patients with acromegaly were studied electron microscopically. In 9 cases the tumors underwent immunohistochemical analysis by Coons' indirect immunofluorescent technique. Before the operation, all the patients were found by radioimmunoassay to have concentrations of pituitary hormones in the blood serum. A clinico-morphological analysis performed showed that in all cases of acromegaly pituitary adenoma consisted of somatotropocytes differing by the degree of cell granulation. The concentration of the somatotropic hormone (STH) in the blood serum of the patients did not depend on the intensity of the ultrastructural signs of the secretory activity of the cells. In 4 adenomas, a positive immunohistochemical reaction to two hormones, STH and prolactine, was demonstrated.


Mechanisms and energetics of potassium channel block by local anesthetics and antifungal agents.
Many drug molecules inhibit the conduction of several families of cation channels by binding to a small cavity just below the selectivity filter of the channel protein. The exact mechanisms governing drug-channel binding and the subsequent inhibition of conduction are not well understood. Here the inhibition of two K(+) channel isoforms, Kv1.2 and KCa3.1, by two drug molecules, lidocaine and TRAM-34, is examined in atomic detail using molecular dynamics simulations. A conserved valine-alanine-valine motif in the inner cavity is found to be crucial for drug binding in both channels, consistent with previous studies of similar systems. Potential of mean force calculations show that lidocaine in its charged form creates an energy barrier of ∼6 kT for a permeating K(+) ion when the ion is crossing over the drug, while the neutral form of lidocaine has no significant effect on the energetics of ion permeation. On the other hand, TRAM-34 in the neutral form is able to create a large energy barrier of ∼10 kT by causing the permeating ion to dehydrate. Our results suggest that TRAM-34 analogues that remain neutral and permeable to membranes under acidic conditions common to inflammation may act as possible drug scaffolds for combating local anesthetic failure in inflammation.


Costs and outcomes in evaluating management of unhealed surgical wounds in the community in clinical practice in the UK: a cohort study.
To evaluate the patient pathways and associated health outcomes, resource use and corresponding costs attributable to managing unhealed surgical wounds in clinical practice, from initial presentation in the community in the UK. This was a retrospective cohort analysis of the records of 707 patients in The Health Improvement Network (THIN) database whose wound failed to heal within 4 weeks of their surgery. Patients' characteristics, wound-related health outcomes and healthcare resource use were quantified, and the total National Health Service (NHS) cost of patient management was estimated at 2015/2016 prices. Inconsistent terminology was used in describing the wounds. 83% of all wounds healed within 12 months from onset of community management, ranging from 86% to 74% of wounds arising from planned and emergency procedures, respectively. Mean time to healing was 4 months per patient. Patients were predominantly managed in the community by nurses and only around a half of all patients who still had a wound at 3 months were recorded as having had a follow-up visit with their surgeon. Up to 68% of all wounds may have been clinically infected at the time of presentation, and 23% of patients subsequently developed a putative wound infection a mean 4 months after initial presentation. Mean NHS cost of wound care over 12 months was £7300 per wound, ranging from £6000 to £13 700 per healed and unhealed wound, respectively. Additionally, the mean NHS cost of managing a wound without any evidence of infection was ~£2000 and the conflated cost of managing a wound with a putative infection ranged from £5000 to £11 200. Surgeons are unlikely to be fully aware of the problems surrounding unhealed surgical wounds once patients are discharged into the community, due to inconsistent recording in patients' records coupled with the low rate of follow-up appointments. These findings offer the best evidence available with which to inform policy and budgetary decisions pertaining to managing unhealed surgical wounds in the community.


Mechanisms of mammary cancer chemoprevention by organoselenium compounds.
Searching for optimal diets and for naturally occurring agents in routinely consumed foods that may inhibit cancer development, although challenging, constitutes a valuable and plausible approach to finding ways to control and prevent cancer. To date, the use of the micronutrient selenium in human clinical trials is limited but the outcome of these investigations indicates that selenium is one of the most promising agents. Data presented in this mini-review indicate that the dose and the form (structure) in which selenium is used are the most critical determinants of success in future clinical trials. The focus of this mini-review is on the mechanisms of mammary cancer chemoprevention by organoselenium compounds. Among the naturally occurring organoselenium compounds, Se-Methylselenocysteine is more efficacious than the most extensively studied forms, such as selenomethionine. However, we showed that synthetic organoselenium compounds can be tailored to achieve greater chemopreventive efficacy with minimal side effects by structural modifications; it is evident that synthetic agents are superior to the inorganic selenite, naturally occurring selenium compounds and their sulfur-containing analogs. We have demonstrated that 1,4-phenylenebis (methylene) selenocyanate (p-XSC) and its putative metabolite glutathione conjugate (p-XSeSG) are highly promising agents in the chemoprevention of mammary carcinogenesis in the 7,12-dimethylbenz[a]anthracene (DMBA)-rat mammary tumor model system. Both compounds inhibit the initiation phase of carcinogenesis by inhibiting DMBA-DNA adduct formation in the target organ in vivo. cDNA microarray analysis indicates that both selenium compounds alter genes in a manner that leads to inhibition of cell proliferation and induction of apoptosis; modulation of apoptosis and cell proliferation can account for chemoprevention during the post-initiation phase of mammary carcinogenesis. Using a rat mammary cancer cell line, we compared p-XSC and p-XSeSG as inhibitors of cell proliferation; depending on the selenium dose and time point selected, p-XSC was comparable to or better than p-XSeSG. Collectively, the results described here, suggest that the molecular targets modulated by organoselenium compounds are highly useful indicators of success in clinical cancer chemoprevention trials.


Inference of stochastic time series with missing data.
Inferring dynamics from time series is an important objective in data analysis. In particular, it is challenging to infer stochastic dynamics given incomplete data. We propose an expectation maximization (EM) algorithm that iterates between alternating two steps: E-step restores missing data points, while M-step infers an underlying network model from the restored data. Using synthetic data of a kinetic Ising model, we confirm that the algorithm works for restoring missing data points as well as inferring the underlying model. At the initial iteration of the EM algorithm, the model inference shows better model-data consistency with observed data points than with missing data points. As we keep iterating, however, missing data points show better model-data consistency. We find that demanding equal consistency of observed and missing data points provides an effective stopping criterion for the iteration to prevent going beyond the most accurate model inference. Using the EM algorithm and the stopping criterion together, we infer missing data points from a time-series data of real neuronal activities. Our method reproduces collective properties of neuronal activities such as correlations and firing statistics even when 70% of data points are masked as missing points.


[The effect of the subchronic administration of calcium-channel blockers on CNS excitability].
The effect of a single day administration of nifedipine (10 mg/kg), cinnarizine (25 mg/kg), verapamile (25 mg/kg), fendiline (10 mg/kg), dilthiazem (10 mg/kg), and diazepam (0.5 mg/kg) on the dynamics of changing a convulsive dose of convulsant was studied on a model of intermittent intracutaneous administration of Corazole (10 mg/kg until convulsions) during 5 days. Repeated intermittent Corazole administrations were found to increase the sensitivity of animals with respect to convulsive effect of the drug. All calcium channel blockers and diazepam increased the convulsive dose of Corazole. In accordance with the hypothesis of anxiety disturbances based on nonspecific CNS activation, a possibility of application of calcium channel blockers as potential anxiolytics is considered.


Prostate cancer progression correlates with increased humoral immune response to a human endogenous retrovirus GAG protein.
Human endogenous retroviruses (HERV) encode 8% of the human genome. While HERVs may play a role in autoimmune and neoplastic disease, no mechanistic association has yet been established. We studied the expression and immunogenicity of a HERV-K GAG protein encoded on chromosome 22q11.23 in relation to the clinical course of prostate cancer. In vitro expression of GAG-HERV-K was analyzed in panels of normal and malignant tissues, microarrays, and cell lines, and effects of demethylation and androgen stimulation were evaluated. Patient sera were analyzed for seroreactivity to GAG-HERV-K and other self-antigens by ELISA and seromics (protein array profiling). GAG-HERV-K expression was most frequent in prostate tissues and regulated both by demethylation of the promoter region and by androgen stimulation. Serum screening revealed that antibodies to GAG-HERV-K are found in a subset of patients with prostate cancer (33 of 483, 6.8%) but rarely in male healthy donors (1 of 55, 1.8%). Autoantibodies to GAG-HERV-K occurred more frequently in patients with advanced prostate cancer (29 of 191 in stage III-IV, 21.0%) than in early prostate cancer (4 of 292 in stages I-II, 1.4%). Presence of GAG-HERV-K serum antibody was correlated with worse survival of patients with prostate cancer, with a trend for faster biochemical recurrence in patients with antibodies to GAG-HERV-K. Preferential expression of GAG-HERV-K ch22q11.23 in prostate cancer tissue and increased frequency of autoantibodies observed in patients with advanced prostate cancer make this protein one of the first bona fide retroviral cancer antigens in humans, with potential as a biomarker for progression and biochemical recurrence rate of prostate cancer. Clin Cancer Res; 19(22); 6112-25. ©2013 AACR.


Factors influencing the use of energy conservation strategies by persons with multiple sclerosis.
To examine the factors influencing the implementation and continued use of energy conservation strategies among persons with multiple sclerosis. A qualitative research design was used. Eight persons with multiple sclerosis who participated in a 6-week energy conservation educational course delivered by teleconference were interviewed using a semistructured, open-ended format. Participants were asked about their thoughts, feelings, and actions resulting from course participation. They also were engaged in a card-sort activity to promote discussion about using the energy conservation strategies. The data were analyzed thematically. Three themes directly addressed and interacted to enhance or hinder the use of energy conservation strategies: (1) experience with the disease, (2) sense of self, and (3) environmental factors. The fourth theme of education emphasized how participation in the educational course and use of the strategies afterward gave participants a new ability to manage their lives with multiple sclerosis. The findings of this study demonstrated that the use of energy conservation strategies is not dependent on a single factor but rather on complex, interrelated contextual factors.


Interview Mode and Measurement of Sexual Behaviors: Methodological Issues.
Studies of sexual and other sensitive behaviors are often fraught with a variety of reporting biases. When IAQs are used to collect data, respondents may underreport certain sensitive behaviors and overreport normative behaviors. SAQs can also pose problems: requiring that respondents be literate and able to follow skip patterns. In recent years, the development of computerized technologies--audio-CASI and T-ACASI--have begun to overcome some of the limitations of IAQs and SAQs. By providing a more private mode for data collection and standardized delivery of all questions, as well as automated skip patterns and range checks, audio-CASI and T-ACASI have been tested in a number of studies and found to be an effective way of reducing response bias, and thus, contributing to a better understanding of the prevalence and patterns of sexual and other sensitive behaviors.


Effect of insulin on intracellular pH and phosphate metabolism in human skeletal muscle in vivo.
1. 31P nuclear magnetic resonance spectroscopy and the hyperinsulinaemic-euglycaemic clamp were used simultaneously to assess the effect of insulin on intracellular pH and the major phosphorus-containing metabolites of normal human skeletal muscle in vivo in four normal subjects. 2. Insulin and glucose were infused for 120 min. Plasma insulin increased approximately 10-fold over preclamp levels (5.6 +/- 0.9 m-units/l pre-clamp and 54 +/- 5 m-units/l over the last hour of infusion; mean +/- SEM, n = 4). Plasma glucose concentration did not change significantly (5.4 +/- 0.2 mmol/l pre-clamp and 5.5 +/- 0.1 mmol/l over the last hour of infusion). 3. Insulin and glucose infusion resulted in a decline in the intracellular pH of forearm muscle of 0.027 +/- 0.007 unit/h (P less than 0.01), whereas in control studies of the same subjects, pH rose by 0.046 +/- 0.005 unit/h (P less than 0.001). 4. In the clamp studies, intracellular inorganic phosphate concentration rose by 18%/h, whereas ATP, phosphocreatine and phosphomonoester concentrations did not change. In plasma, inorganic phosphate concentration was 1.16 +/- 0.05 mmol/l before infusion, and this decreased by a mean rate of 0.14 mmol h-1 l-1. No change was observed in any of these intracellular metabolites in the control studies. 5. The results show that, under physiological conditions, insulin does not raise intracellular pH in human muscle, and thus cannot influence muscle metabolism by this mechanism. The results also suggest that insulin causes a primary increase in the next flux of inorganic phosphate across the muscle cell membrane.


A national scheme for public access defibrillation in England and Wales: early results.
Automated external defibrillators (AEDs) operated by lay persons are used in the UK in a National Defibrillator Programme promoting public access defibrillation (PAD). Two strategies are used: (1) Static AEDs installed permanently in busy public places operated by those working nearby. (2) Mobile AEDs operated by community first responders (CFRs) who travel to the casualty. One thousand five hundred and thirty resuscitation attempts. With static AEDs, return of spontaneous circulation (ROSC) was achieved in 170/437 (39%) patients, hospital discharge in 113/437 (26%). With mobile AEDs, ROSC was achieved in 110/1093 (10%), hospital discharge in 32 (2.9%) (P<0.001 for both variables). More shocks were administered with static AEDS 347/437 (79%) than mobile AEDs 388/1093 (35.5%) P<0.001. Highly significant advantages existed for witnessed arrests, administration of shocks, bystander CPR before arrival of AED and short delays to start CPR and attach AED. These factors were more common with static AEDs. For CFRs, patients at home did less well than those at other locations for ROSC (P<0.001) and survival (P=.006). Patients at home were older, more arrests were unwitnessed, fewer shocks were given, delays to start CPR and attach electrodes were longer. PAD is a highly effective strategy for patients with sudden cardiac arrest due to ventricular fibrillation who arrest in public places where AEDs are installed. Community responders who travel with an AED are less effective, but offer some prospect of resuscitation for many patients who would otherwise receive no treatment. Both strategies merit continuing development.


Therapeutic potential of bone marrow-derived mesenchymal stem cells for cutaneous wound healing.
Despite advances in wound care, many wounds never heal and become chronic problems that result in significant morbidity and mortality to the patient. Cellular therapy for cutaneous wounds has recently come under investigation as a potential treatment modality for impaired wound healing. Bone marrow-derived mesenchymal stem cells (MSCs) are a promising source of adult progenitor cells for cytotherapy as they are easy to isolate and expand and have been shown to differentiate into various cell lineages. Early studies have demonstrated that MSCs may enhance epithelialization, granulation tissue formation, and neovascularization resulting in accelerated wound closure. It is currently unclear if these effects are mediated through cellular differentiation or by secretion of cytokines and growth factors. This review discusses the proposed biological contributions of MSCs to cutaneous repair and their clinical potential in cell-based therapies.


Joint Object Detection and Re-Identification for 3D Obstacle Multi-Camera Systems.
The growing on-board processing capabilities have led to more complex sensor configurations, enabling autonomous car prototypes to expand their operational scope. Nowadays, the joint use of LiDAR data and multiple cameras is almost a standard and poses new challenges for existing multi-modal perception pipelines, such as dealing with contradictory or redundant detections caused by inference on overlapping images. In this paper, we address this last issue in the context of sequential schemes like F-PointNets, where object candidates are obtained in the image space, and the final 3D bounding box is then inferred from point cloud information. To this end, we propose the inclusion of a re-identification branch into the 2D detector, i.e., Faster R-CNN, so that objects seen from adjacent cameras can be handled before the 3D box estimation takes place, removing duplicates and completing the object's cloud. Extensive experimental evaluations covering both the 2D and 3D domains affirm the effectiveness of the suggested methodology. The findings indicate that our approach outperforms conventional Non-Maximum Suppression (NMS) methods. Particularly, we observed a significant gain of over 5% in terms of accuracy for cars in camera overlap regions. These results highlight the potential of our upgraded detection and re-identification system in practical scenarios for autonomous driving.


'Feeling sad and useless': an investigation into personal acceptance of disability and its association with depression following stroke.
To study the association of acceptance of disability with depression following stroke and its ability to predict depression at follow-up. A prospective cohort mixed (quantitative and qualitative) design was used. Patients admitted to a stroke unit were consecutively recruited. Eighty-nine participated at one month and 81 were followed up nine months post stroke. Depressive disorder was assessed using a structured clinical interview. Disability and acceptance of disability were measured using self-report scales. At one month post stroke, 60 consecutive participants also participated in open-ended interviews exploring their individual concerns about having had a stroke and their responses were analysed qualitatively. One-third of participants were found to have depression (29/89; 33% at one month and 24/81; 30% at nine months). Non-acceptance of disability remained associated with depression after controlling for age, gender, original stroke severity and current disability at one month (odds ratio (OR) = 1.27, 95% confidence interval (CI) 1.09-1.47) and nine months (OR = 1.46, 95% CI 1.22-1.75). Also, non-acceptance of disability measured at one month independently predicted depression measured at nine months (OR = 1.19, 95% CI 1.05-1.35). The qualitative findings illustrated a self-reproachful element to non-acceptance of disability. Patients with depression often said that they 'should still' be capable and sometimes referred to themselves as 'useless'; whereas patients who were not depressed commonly reported having accepted stroke-related disability. These finding suggest that personal beliefs about accepting disability are associated with and predict emotional adaptation following stroke.


Cleavage of foot-and-mouth disease virus polyprotein is mediated by residues located within a 19 amino acid sequence.
The 2A region of the foot-and-mouth disease virus (FMDV) polyprotein is only 16 amino acids in length. During synthesis of the FMDV polyprotein a primary proteolytic processing event occurs between the 2A and 2B regions of the polyprotein. The activity responsible for this cleavage is not known but it is thought that either an unidentified virus-encoded proteinase may be responsible, or that 2A acts as a substrate for a host cell proteinase. A series of recombinant FMDV polyproteins has been constructed in which sequences to the N- or C-terminal side of the 2A region have been deleted. Analysis of the processing of these polyproteins shows that a 19 amino acid sequence spanning 2A is sufficient to mediate polyprotein cleavage at a site immediately C-terminal to 2A, whereas deletions extending into the 2A region prevent cleavage.


Effects of caroxazone, a reversible monoamine oxidase inhibitor, on the pressor response to intravenous tyramine in man.
1 Caroxazone is a new antidepressant drug with reversible MAO-inhibitory activity. 2 The pressor effect of intravenously injected tyramine has been evaluated in six male healthy volunteers before, during oral treatment with caroxazone 200 mg three times daily and at different time intervals after discontinuation of treatment. 3 Caroxazone produces a moderate tyramine supersensitivity. 4 The reversibility of MAO-inhibition produced by caroxazone is clearly reflected by the time-course of tyramine supersensitivity. In fact, tyramine potentiation does not accumulate with caroxazone cumulative dose, while it is correlated to drug plasma levels and disappears rapidly (half-life 1.5 days) upon discontinuation of treatment. 5 caroxazone seems to be safer and more manageable than all other clinically available MAO-inhibitors which produce irreversible inactivation of MAO.