Changing fit and fat bias using an implicit retraining task.
To change implicit and explicit bias so that active obese people are regarded as more fit and normal weight sedentary people as less fit. Study one created a questionnaire that measured perceptions of active obese persons and sedentary normal weight persons on fitness-related items. Study two used a modified visual probe task to retrain perceptions regarding active obese persons and sedentary normal weight persons. Self-reported explicit bias was measured with a questionnaire and implicit bias was measured with response times collected during a visual probe task. The questionnaire reliably measured 'fitness and fatness' perceptions. In study two, pairing images of active obese persons with positive activity-related words resulted in active obese persons being explicitly rated more fit; pairing images of normal weight sedentary persons with negative words associated with sedentary lifestyles increased endorsement of normal weight people as unfit. There were no changes in implicit bias. Bias regarding how body weight is thought of relative to fitness can be altered by pairing images of obese persons being active with words such as 'health' and 'fit'. This is evidence that representations of persons of all body weight should be used when promoting physical activity.


Contactless hand tremor amplitude measurement using smartphones: development and pilot evaluation.
Background - Physiological tremor is defined as an involuntary and rhythmic shaking. Tremor of the hand is a key symptom of multiple neurological diseases, and its frequency and amplitude differs according to both disease type and disease progression. In routine clinical practice, tremor frequency and amplitude are assessed by expert rating using a 0 to 4 integer scale. Such ratings are subjective and have poor inter-rater reliability. There is thus a clinical need for a practical and accurate method for objectively assessing hand tremor.Objective - to develop a proof-of-principle method to measure hand tremor amplitude from smartphone videos.Methods - We created a computer vision pipeline that automatically extracts salient points on the hand and produces a 1-D time series of movement due to tremor, in pixels. Using the smartphones' depth measurement, we convert this measure into real distance units. We assessed the accuracy of the method using 60 videos of simulated tremor of different amplitudes from two healthy adults. Videos were taken at distances of 50, 75 and 100 cm between hand and camera. The participants had skin tone II and VI on the Fitzpatrick scale. We compared our method to a gold-standard measurement from a slide rule. Bland-Altman methods agreement analysis indicated a bias of 0.04 cm and 95% limits of agreement from -1.27 to 1.20 cm. Furthermore, we qualitatively observed that the method was robust to limited occlusion.Clinical relevance - We have demonstrated how tremor amplitude can be measured from smartphone videos. In conjunction with tremor frequency, this approach could be used to help diagnose and monitor neurological diseases.


The rabbit retina: a long-term model system for aluminum-induced neurofibrillary degeneration.
Aluminum (Al) was injected into the rabbit eye as a potential long-term model system for Al-induced neurofibrillary degeneration (NFD). Neurofibrillary tangles made up of 10 nm phosphorylated neurofilaments were observed in a subpopulation of retinal ganglion cells, located primarily in the peripheral retina. The distribution of affected cells suggested a differential susceptibility of ganglion cells to Al intoxication. Importantly, none of the animals demonstrated any of the central neurological dysfunctions characteristic of previous Al intoxication models. The retinal model should allow for long-term studies of Al intoxication and its potential relationship to neurofibrillary degenerative disorders such as Alzheimer's disease.


Genetic changes associated with the temporal shift in invasive non-typhoidal Salmonella serovars in Bamako Mali.
Invasive non-typhoidal Salmonella (iNTS) serovars S. Typhimurium and S. Enteritidis are major etiologic agents of invasive bacterial disease among infants and young children in sub-Saharan Africa, including in Mali. Early studies of iNTS serovars in several countries indicated that S. Typhimurium was more prevalent than S. Enteritidis, including in Mali before 2008. We investigated genomic and associated phenotypic changes associated with an increase in the relative proportion of iNTS caused by S. Enteritidis versus S. Typhimurium in Bamako, Mali, during the period 2002-2012. Comparative genomics studies identified homologs of tetracycline resistance and arsenic utilization genes that were associated with the temporal shift of serovars causing iNTS shift, along with several hypothetical proteins. These findings, validated through PCR screening and phenotypic assays, provide initial steps towards characterizing the genomic changes consequent to unknown evolutionary pressures associated with the shift in serovar prevalence. This work identified a shift to S. Enteritidis from the more classic S. Typhimurium, associated with iNTS in Bamako, Mali, during the period 2002-2012. This type of shift in underlying iNTS pathogens are of great importance to pediatric public health in endemic regions of sub-Saharan Africa. Additionally, this work demonstrates the utility of combining epidemiologic data, whole genome sequencing, and functional characterization in the laboratory to identify and characterize genomic changes in the isolates that may be involved with the observed shift in circulating iNTS agents.


MRI in the diagnosis of fetal developmental brain abnormalities: the MERIDIAN diagnostic accuracy study.
Ultrasonography has been the mainstay of antenatal screening programmes in the UK for many years. Technical factors and physical limitations may result in suboptimal images that can lead to incorrect diagnoses and inaccurate counselling and prognostic information being given to parents. Previous studies suggest that the addition of in utero magnetic resonance imaging (iuMRI) may improve diagnostic accuracy for fetal brain abnormalities. These studies have limitations, including a lack of an outcome reference diagnosis (ORD), which means that improvements could not be assessed accurately. To assess the diagnostic impact, acceptability and cost consequence of iuMRI among fetuses with a suspected fetal brain abnormality. A pragmatic, prospective, multicentre, cohort study with a health economics analysis and a sociological substudy. Sixteen UK fetal medicine centres. Pregnant women aged ≥ 16 years carrying a fetus (at least 18 weeks' gestation) with a suspected brain abnormality detected on ultrasonography. Participants underwent iuMRI and the findings were reported to their referring fetal medicine clinician. Pregnancy outcome was followed up and an ORD from postnatal imaging or postmortem autopsy/imaging collected when available. Developmental data from the Bayley Scales of Infant Development and questionnaires were collected from the surviving infants aged 2-3 years. Data on the management of the pregnancy before and after the iuMRI were collected to inform the economic evaluation. Two surveys collected data on patient acceptability of iuMRI and qualitative interviews with participants and health professionals were undertaken. The primary analysis consisted of 570 fetuses. The absolute diagnostic accuracies of ultrasonography and iuMRI were 68% and 93%, respectively [a difference of 25%, 95% confidence interval (CI) 21% to 29%]. The difference between ultrasonography and iuMRI increased with gestational age. In the 18-23 weeks group, the figures were 70% for ultrasonography and 92% for iuMRI (difference of 23%, 95% CI 18% to 27%); in the ≥ 24 weeks group, the figures were 65% for ultrasonography and 94% for iuMRI (difference of 29%, 95% CI 23% to 36%). Patient acceptability was high, with at least 95% of respondents stating that they would have iuMRI again in a similar situation. Health professional interviews suggested that iuMRI was acceptable to clinicians and that iuMRI was useful as an adjunct to ultrasonography, but not as a replacement. Across a range of scenarios, iuMRI resulted in additional costs compared with ultrasonography alone. The additional cost was consistently < £600 per patient and the cost per management decision appropriately changed was always < £3000. There is potential for reporting bias from the referring clinicians on the diagnostic and prognostic outcomes. Lower than anticipated follow-up rates at 3 years of age were observed. iuMRI as an adjunct to ultrasonography significantly improves the diagnostic accuracy and confidence for the detection of fetal brain abnormalities. An evaluation of the use of iuMRI for cases of isolated microcephaly and the diagnosis of fetal spine abnormalities is recommended. Longer-term follow-up studies of children diagnosed with fetal brain abnormalities are required to fully assess the functional significance of the diagnoses. Current Controlled Trials ISRCTN27626961. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 49. See the NIHR Journals Library website for further project information.


Progressive retinal vessel malformation in a premature infant with Sturge-Weber syndrome: a case report and a literature review of ocular manifestations in Sturge-Weber syndrome.
Sturge-Weber syndrome is a disorder marked by a distinctive facial capillary malformation, neurological abnormalities, and ocular abnormalities such as glaucoma and choroidal hemangioma. We report a case of progressively formed retinal vessel malformation in a premature male infant with Sturge-Weber syndrome and retinopathy of prematurity, after treatment with intravitreal anti-vascular endothelial growth factor (VEGF). The baby was born at 30 weeks gestation with a nevus flammeus involving his left eyelids and maxillary area. On postmenstrual age week 39, he received intravitreal anti-VEGF. Diffuse choroidal hemangioma became evident at 40 weeks, with the classic "tomato catsup fundus" appearance. These clinical findings characterized Sturge-weber syndrome. He presented with posterior retinal vessel tortuosity and vein-to-vein anastomoses at 44 weeks. This is a rare case of documented progression of retinal vessel malformations in a patient with Sturge-Weber syndrome and retinopathy of prematurity.


Preserved pulsatile insulin release from prediabetic mouse islets.
During the development of type I diabetes, the plasma insulin pattern changes. Because the islet secretory pattern has been implicated in this phenomenon, insulin release was measured from female nonobese diabetic (NOD) mouse islets isolated at different ages. Islets from 5-week-old mice were used as controls because they had no infiltrating mononuclear cells and insulin release rose almost 9-fold with maintained oscillatory frequency when the glucose concentration was raised from 3 to 11 mM. Islets isolated from 13- and 25-week-old mice were infiltrated with mononuclear cells. In these islets, increase in the glucose concentration from 3 to 11 mM only doubled insulin release. However, despite the cellular infiltration, insulin release was pulsatile. Islets from 13-week-old mice had reduced glucose oxidation rate. Culture of such islets for 7 days at 11.1 mM glucose causes a decrease in the number of mononuclear cells infiltrating the islets, which in the present study was accompanied by a normalization of both glucose oxidation and glucose-induced insulin release. In the presence of the mitochondrial substrate alpha-keto-isocaproate (5 mM) both control and infiltrated islets responded with pronounced insulin pulses with similar amplitudes. The results suggest that the deranged plasma insulin pattern observed during the development of type I diabetes may be related to decrease in the insulin pulse amplitude rather than loss of the pulsatile release from the islets.


Potential subtype-specific therapeutic approaches in small cell lung cancer.
Small cell lung cancer (SCLC) remains one of the most aggressive thoracic malignancies with an especially dismal prognosis. While the detection of various targetable driver mutations and immune checkpoints have revolutionized the treatment of non-small cell lung cancer (NSCLC), there has been only modest therapeutic innovation over the past decades in SCLC. In this review, we aim to provide a brief summary on the clinical relevance of recent research findings, which could soon pave the way towards a more personalized and targeted management of SCLC patients. Substantial research on the biological and molecular heterogeneity of SCLC has been conducted in the last years. Recent results from comprehensive profiling studies have shown that unique major SCLC subtypes can be distinguished based on the relative expression of key transcription regulators (ASCL1, NEUROD1, POU2F3) or distinct inflammatory features. Understanding the differing molecular characteristics of these distinct subtypes has resulted in the identification of specific therapeutic vulnerabilities. The recently introduced molecular SCLC subtype classification represents a substantial progress towards a personalized and more efficacious approach in SCLC. The consequences of this paradigm shift provide hope for improved patient care and clinical outcomes in this exceptionally lethal thoracic malignancy.


Expression of Fibrogenic Markers in Tumor and Tumor-Surrounding Tissue at Time of Transplantation Correlates with Recurrence of Hepatocellular Carcinoma in Patients Undergoing Liver Transplantation.
BACKGROUND Liver transplantation (LT) remains the only curative treatment option for patients with defined stages of hepatocellular carcinoma (HCC). Up to 25% of patients show a tumor recurrence following transplantation. The correlation of fibrogenic markers prior to LT with HCC recurrence has not been characterized. We explored the expression of fibrogenic markers in tumor tissue and tumor-surrounding liver tissue of patients undergoing LT and correlated these findings with tumor recurrence. MATERIAL AND METHODS Fibrogenic marker expression in explanted livers was assessed using tumor and tumor-surrounding liver tissue from patients who recently underwent liver transplantation at our center with a follow-up period of at least 3 years. Tissue was analyzed for the expression of fibrogenic proteins and genes, as well as collagen deposition into the extracellular matrix. Results were correlated with HCC recurrence. RESULTS Patients with recurrent HCC following LT exhibited increased levels of fibrogenic markers on both protein and RNA level within the non-tumorous liver tissue in comparison to the tumor tissue itself. Patients who did not develop tumor recurrence up to 4 years after LT showed a reversed expression pattern of fibrogenic markers with decreased levels of β-PDGFR, Collagen 1, and α-SMA in their non-tumorous liver tissue versus the tumor tissue at time of LT as assessed in protein and mRNA expression analysis. These findings correlated with analysis of collagen deposition in the liver. CONCLUSIONS Fibrogenic markers exhibit a differential expression pattern in HCC versus non-tumorous tissue in explanted livers of patients undergoing LT, showing a correlation with HCC recurrence.


A predictive algorithm to identify genes that discriminate individuals with fibromyalgia syndrome diagnosis from healthy controls.
Fibromyalgia syndrome (FMS) is a chronic and often debilitating condition that is characterized by persistent fatigue, pain, bowel abnormalities, and sleep disturbances. Currently, there are no definitive prognostic or diagnostic biomarkers for FMS. This study attempted to utilize a novel predictive algorithm to identify a group of genes whose differential expression discriminated individuals with FMS diagnosis from healthy controls. Secondary analysis of gene expression data from 28 women with FMS and 19 age-and race-matched healthy women. Expression of discriminatory genes were identified using fold-change differential and Fisher's ratio (FR). Discriminatory accuracy of the differential expression of these genes was determined using leave-one-out-cross-validation. Functional networks of the discriminating genes were described from the Ingenuity's Knowledge Base. The small-scale signature contained 57 genes whose expressions were highly discriminatory of the FMS diagnosis. The combination of these high discriminatory genes with FR higher than 1.45 provided a leave-one-out-cross-validation accuracy for the FMS diagnosis of 85.11%. The discriminatory genes were associated with 3 canonical pathways: hepatic stellate cell activation, oxidative phosphorylation, and airway pathology related to COPD. The discriminating genes, especially the 2 with the highest accuracy, are associated with mitochondrial function or oxidative phosphorylation and glutamate signaling. Further validation of the clinical utility of this finding is warranted.


Prolonged survival following the inadvertent intrathecal administration of vincristine: clinical and electrophysiologic analyses.
A 23-year-old man with a lymphoblastic lymphoma accidentally received 2.0 mg of vincristine intrathecally instead of intravenously. Although he underwent immediate CSF drainage, symptoms of an ascending myeloencephalopathy developed at 48 h. This progressed to coma, initially with a diffusely slow EEG, which evolved into alpha coma. He also developed a left frontal focus of epileptiform activity. He was transferred to our institution 1 month later. His court-appointed guardian refused to allow discontinuation of supportive treatment; therefore, the evolution of the disorder can be followed for 12 months. Although alpha coma remained the predominant pattern, some EEG evolution did occur, with a progressive decrease in amplitude being most prominent. An increase in amplitude in the 10th month was accompanied by the return of some nystagmoid eye movements. The patient's lymphoma then recurred, and further treatment was not attempted. This tragic case, in which transient exposure to a microtubular poison produced severe CNS toxicity, allows some insights into the mechanisms of alpha coma.


Being in a process of transition to psychosis, as narrated by adults with psychotic illnesses acutely admitted to hospital.
To assist in improving early interventions for psychosis, this study explored how adult people narrated their experience of becoming psychotic, and how contact with mental health personnel was established. Narrative interviews were conducted with 12 participants with psychotic illnesses recruited from acute psychiatric wards. The interviews were content analysed. Participants described being in a process of transition to psychosis as follows: experiencing changes as well-known signs of psychosis, experiencing sudden unexpected changes as signs of psychosis and experiencing unidentified changes as signs of illness. Our results show that participants and their close others who knew the signs of psychosis established a dialogue with mental health personnel and were better equipped to prevent and mitigate the psychosis. Our results demonstrate that participants who did not perceive the signs of psychosis and did not have other people to advocate for them were at risk for delayed treatment, poor communication and coercive interventions. Furthermore, participants who did not know the signs of psychosis perceived these changes as deterioration in their health and awareness of illness. We suggest that participants' experiential knowledge of transitioning to psychosis and an awareness of illness can be used to improve the communication during interventions for psychosis.


Reflection on the Role of a Hospital Chaplain as a Resource for Ethical Concerns.
As I take a legal approach to religion and spirituality, I reflect on how a chaplain can be beneficial as a resource to ethical concerns with which medical teams and patients/caregivers are confronted. This rather new approach can help medical professionals to understand the scope of a chaplain's work and to distinguish the work of a chaplain from that of clergy in organized religion.


Ethylene oxide and propylene oxide derived N7-alkylguanine adducts are bypassed accurately in vivo.
Adducts formed at the nucleophilic N7 position of guanine are the most abundant lesions produced by alkylating agents such as ethylene oxide (EO) and propylene oxide (PO). In order to investigate the intrinsic mutagenic potential of N7-alkylguanine adducts, we prepared single-stranded DNA probes containing a single well-defined N7-alkylguanine adduct under conditions that minimize the presence of depurinated molecules. Following introduction of these probes into Escherichia coli cells, the effect of the N7-alkylguanine adducts on the efficiency and fidelity of replication was determined. To investigate the effect on replication we monitored the relative transformation efficiency of the lesion containing constructs with respect to the control construct. The methyl adduct was found not to be toxic, while the N7-(2-hydroxyethyl)guanine (N7-heG) and N7-(2-hydroxypropyl)guanine (N7-hpG) adducts reduce the transformation efficiency to ≈70% and 40%, respectively. Within the detection limits of our assay, replication across the N7-alkylguanine adducts in vivo is essentially error-free, as no mutant colony was observed among ≈300 individual sequenced colonies (i.e., mutation frequency<0.3%).


[Effect of infrared low-intensity laser radiation on a mutation process and proliferative corneal activity in experimental cerebral hypoxia].
The paper deals with the impact of infrared low-intensity laser radiation (IRLILR) on a mutation process and the proliferative activity of the animal cornea during stimulation of circulatory brain hypoxia. During an experiment on laboratory albino rats, IRLILR was studied for its impact on the level of chromosomal rearrangements and the mitotic index in the corneal cells was calculated in circulatory brain hypoxia. Laser exposure during stimulation of circulatory brain hypoxia favors normalization of the level of chromosomal aberrations and a mitotic cycle in the rat corneal epithelial cells. The experimental findings suggest that IRLILR may be used in ophthalmological care for antihypoxic purposes.


Glycosylphosphatidylinositol-specific phospholipase C regulates transferrin endocytosis in the African trypanosome.
GPI-PLC (glycosylphosphatidylinositol-specific phospholipase C) is expressed in bloodstream-form Trypanosoma brucei, a protozoan that causes human African trypanosomiasis. Loss of genes encoding GPI-PLC reduces the virulence of a pleomorphic strain of the parasite, for reasons that are not clear. In the present paper, we report that GPI-PLC stimulates endocytosis of transferrin by 300-500%. Surprisingly, GPI-PLC is not detected at endosomes, suggesting that the enzyme does not interact directly with the endosomal machinery. We therefore hypothesized that a diffusible product of the GPI-PLC enzyme reaction [possibly DAG (diacylglycerol)] mediated the biological effects of the protein. Two sets of data support this assertion. First, a catalytically inactive Q81L mutant of GPI-PLC, expressed in a GPI-PLC-null background, had no effect on endocytosis, indicating that enzyme activity is essential for the protein to stimulate endocytosis. Secondly, the exogenous DAGs OAG (1-oleyl-2-acetyl-sn-glycerol) and DMG (dimyristoylglycerol) independently stimulated endocytosis of transferrin. Furthermore, the DAG mimic PMA, a phorbol ester, also activated endocytosis in T. brucei. DAG-stimulated endocytosis is a novel pathway in the trypanosome. We surmise that (i) GPI-PLC regulates transferrin endocytosis in T. brucei, (ii) GPI-PLC is a signalling enzyme, and (iii) DAG is a second messenger for GPI-PLC. We propose that regulation of endocytosis is a physiological function of GPI-PLC in bloodstream T. brucei.


[Bioamines of the sympathetic nervous system of the normal rat thyroid and in merkazolil exposure].
According to histochemical data (Falck method in modification), cytofluorimetric analysis, as well as the results of regressive modelling, localization and quantitative interaction of bioamines in the sympathetic nervous plexuses of the rat thyroid gland have been estimated. In the intact state a relatively firm correlation between serotonin and catecholamine concentrations is revealed in all parts investigated in the intraorganic nervous apparatus. Effect of thyrostatic--merkazolil--results in development of certain discrepancy between intensification of bioamines uptake and ability of thyrocytes to their functionally useful utilization. A suggestion is made that dynamic equilibrium of serotonin and catecholamines ratio in the thyroid sympathetic nervous fibers is one of the factors for maintenance of the function-proliferative balance of the gland working elements at the level, adequate to the active situation.


Attenuated adenosine-sensitivity and decreased adenosine-receptor number in adipocyte plasma membranes in human obesity.
Fat-cells were isolated from patients of body-mass indices (BMIs) ranging from 17.9 to 83.9 kg/m2. Isoprenaline-stimulated cyclic AMP accumulation in cells prepared from obese subjects as compared with normal-weight subjects, was less sensitive to inhibition by the adenosine agonist N6-(phenylisopropyl)adenosine (PIA) (P = 0.047). The inhibition of 7 beta-desacetyl-7 beta-[gamma-(N-methylpiperazino) butyryl]-forskolin-stimulated adenylate cyclase by PIA in the presence of adenosine deaminase was also much attenuated in crude plasma membranes of adipocytes prepared from massively obese patients as compared with lean controls (P = 0.0143). This difference was probably not due to different cell size, because adenylate cyclase of crude plasma membranes of large adipocytes was actually more sensitive to PIA than was adenylate cyclase of membranes of smaller fat-cells co-isolated from the same individual. The stimulatory effect of PIA on glucose uptake in the presence of adenosine deaminase was depressed in adipocytes prepared from obese subjects and correlated with BMI at r = -0.626 (P = 0.007) at 100 nM-PIA. The adenosine receptors were studied by using the adenosine antagonist 1,3-[3H]dipropyl-8-cyclopentylxanthine. The binding was rapid and proportional to protein concentration. There was no difference in the affinities of receptors in membranes of obese and normal-weight subjects; Kd values of all patients averaged 3.3 nM. Bmax values were 54 and 130 fmol/mg of protein in membranes prepared from seven obese and five control patients respectively. The Bmax values calculated per mg of protein correlated with BMI at r = -0.539 (P = 0.047). The adenosine content of adipose tissue was higher in obese than in control subjects. These results demonstrate an attenuated response of cyclic AMP accumulation, adenylate cyclase and glucose uptake to adenosine in fat-cells prepared from obese subjects, and suggest that this change is at least partly due to changes in the amount of adenosine receptors, but not their affinity. The decreased receptor number could be due to higher adenosine content. A higher adenosine concentration in adipose tissue could explain why lipolysis is inhibited in situ in obesity, and the desensitization could explain the diminished response to adenosine analogues in isolated fat-cells.


Financial protection from health spending in the Philippines: policies and progress.
The objective of this article is to assess the progress of the Philippines health sector in providing financial protection to the population, as measured by estimates of health insurance coverage, out-of-pocket spending, catastrophic payments and impoverishing health expenditures. Data are drawn from eight household surveys between 2000 and 2013, including two Demographic and Health Surveys, one Family Health Survey and five Family Income and Expenditure Surveys. We find that out-of-pocket spending increased by 150% (real) from 2000 to 2012, with the sharpest increases occurring in recent years. The main driver of health spending is medicines, accounting for almost two-thirds of total health spending, and as much as three-quarters among the poor. The incidence of catastrophic payments has tripled since 2000, from 2.5% to 7.7%. The percentage of people impoverished by health spending has also increased and, in 2012, out-of-pocket spending on health added 1.5 percentage points to the poverty rate, pushing more than 1.5 million people into poverty. In light of these findings, recent policies to enhance financial risk protection-such as the expansion of government-subsidized health insurance from the poor to the near-poor, a policy of zero copayments for the poor, a deepening of the benefit package and provider payment reform aimed at cost-containment-are to be commended. Indeed, between 2008 and 2013, self-reported health insurance coverage increased across all quintiles and its distribution became more pro-poor. To speed progress toward financial protection goals, quick wins could include issuing health insurance cards to the poor to increase awareness of coverage and limiting out-of-pocket spending by clearly defining a clear copayment structure for non-poor members. An in-depth analysis of the pharmaceutical sector would help to shed light on why medicines impose such a large financial burden on households.


Mechanical analysis of single myocyte contraction in a 3-D elastic matrix.
Cardiac myocytes experience mechanical stress during each heartbeat. Excessive mechanical stresses under pathological conditions cause functional and structural remodeling that lead to heart diseases, yet the precise mechanisms are still incompletely understood. To study the cellular and molecular level mechanotransduction mechanisms, we developed a new 'cell-in-gel' experimental system to exert multiaxial (3-D) stresses on a single myocyte during active contraction. Isolated myocytes are embedded in an elastic hydrogel to simulate the mechanical environment in myocardium (afterload). When electrically stimulated, the in-gel myocyte contracts while the matrix resists shortening and broadening of the cell, exerting normal and shear stresses on the cell. Here we provide a mechanical analysis, based on the Eshelby inclusion problem, of the 3-D strain and stress inside and outside the single myocyte during contraction in an elastic matrix. (1) The fractional shortening of the myocyte depends on the cell's geometric dimensions and the relative stiffness of the cell to the gel. A slender or softer cell has less fractional shortening. A myocyte of typical dimensions embedded in a gel of similar elastic stiffness can contract only 20% of its load-free value. (2) The longitudinal stress inside the cell is about 15 times the transverse stress level. (3) The traction on the cell surface is highly non-uniform, with a maximum near its ends, showing 'hot spots' at the location of intercalated disks. (4) The mechanical energy expenditure of the myocyte increases with the matrix stiffness in a monotonic and nonlinear manner. Our mechanical analyses provide analytic solutions that readily lend themselves to parametric studies. The resulting 3-D mapping of the strain and stress states serve to analyze and interpret ongoing cell-in-gel experiments, and the mathematical model provides an essential tool to decipher and quantify mechanotransduction mechanisms in cardiac myocytes.


Cloning and expression of two distinct high-affinity receptors cross-reacting with acidic and basic fibroblast growth factors.
The fibroblast growth factor (FGF) family consists of at least seven closely related polypeptide mitogens which exert their activities by binding and activation of specific cell surface receptors. Unanswered questions have been whether there are multiple FGF receptors and what factors determine binding specificity and biological response. We report the complete cDNA cloning of two human genes previously designated flg and bek. These genes encode two similar but distinct cell surface receptors comprised of an extracellular domain with three immunoglobulin-like regions, a single transmembrane domain, and a cytoplasmic portion containing a tyrosine kinase domain with a typical kinase insert. The expression of these two cDNAs in transfected NIH 3T3 cells led to the biosynthesis of proteins of 150 kd and 135 kd for flg and bek, respectively. Direct binding experiments with radiolabeled acidic FGF (aFGF) or basic FGF (bFGF), inhibition of binding with native growth factors, and Scatchard analysis of the binding data indicated that bek and flg bind either aFGF or bFGF with dissociation constants of (2-15) x 10(-11) M. The high affinity binding of two distinct growth factors to each of two different receptors represents a unique double redundancy without precedence among polypeptide growth factor-receptor interactions.


Fifty consecutive pancreatectomies without mortality.
to report the group's experience with a series of patients undergoing pancreatic resection presenting null mortality rates. we prospectively studied 50 consecutive patients undergoing pancreatic resections for peri-ampullary or pancreatic diseases. Main local complications were defined according to international criteria. In-hospital mortality was defined as death occurring in the first 90 postoperative days. patients' age ranged between 16 and 90 years (average: 53.3). We found anemia (Hb < 12g/dl) and preoperative jaundice in 38% and 40% of cases, respectively. Most patients presented with peri-ampullary tumors (66%). The most common surgical procedure was the Kausch - Whipple operation (70%). Six patients (12%) needed to undergo resection of a segment of the mesenteric-portal axis. The mean operative time was 445.1 minutes. Twenty two patients (44%) showed no clinical complications and presented mean hospital stay of 10.3 days. The most frequent complications were pancreatic fistula (56%), delayed gastric emptying (17.1%) and bleeding (16%). within the last three decades, pancreatic resection is still considered a challenge, especially outside large specialized centers. Nevertheless, even in our country (Brazil), teams seasoned in such procedure can reach low mortality rates.


Engineering Curvature-Induced Anisotropy in Thin Ferromagnetic Films.
We investigate the effect of large curvature and dipolar energy in thin ferromagnetic films with periodically modulated top and bottom surfaces on magnetization behavior. We predict that the dipolar interaction and surface curvature can produce perpendicular anisotropy which can be controlled by engineering special types of periodic surface structures. Similar effects can be achieved by a significant surface roughness in the film. We demonstrate that, in general, the anisotropy can point in an arbitrary direction depending on the surface curvature. Furthermore, we provide simple examples of these periodic surface structures to show how to engineer particular anisotropies in thin films.


Factors influencing outcome after emergency surgical repair of acute type A aortic dissection.
We retrospectively reviewed our more recent experience with acute type A aortic dissection in order to identify possible risk factors influencing current surgical results. Between January 1990 and January 1998, 122 patients (86 males and 36 females; mean age 60 +/- 12 years) underwent emergency repair of acute type A aortic dissection using a standard surgical approach. Seventy-four (61%) patients required isolated replacement of the dissected ascending aorta, 27 (22%) required additional replacement of the aortic arch and 21 (17%) required total aortic root replacement. Surgical outcome was evaluated in terms of operative mortality and morbidity. Results of patients presenting with preoperative complications (Group C) (i.e. cardiac tamponade, cerebral stroke, cardiogenic shock, acute myocardial infarction, anuria or visceral ischemia) were compared with those of uncomplications cases (Group U) and with a calculated risk of expected operative mortality (EOM-rate) based on an analysis of each patient set of preoperative risk factors. Sixteen preoperative and 18 perioperative variables were also analyzed to identify conditions influencing morbidity and mortality. Fifty-seven patients (47%) presented with preoperative complications (Group C) and 65 (53%) did not (Group U). Overall operative mortality was 22% (27 patients). Mortality within subgroups was 40 and 6% for complicated and uncomplications cases, respectively (p < 0.001). The 85% of the overall mortality occurred in Group C patients. During the experience, the operative mortality rate actually observed ranged from 0 to 38% and was similar to the calculated expected risk, thus proving a direct relationship with the amount of complicated cases operated on each year. Multivariate analysis revealed that older age and hemopericardium significantly increased the risk of operative death, while male gender, preoperative complications, postoperative bleeding, duration of circulatory arrest and aortic cross-clamp time significantly predicted morbidity (p = 0.02). Current results of emergency repair of acute type A aortic dissection are strictly dependent on the number of complicated cases referred for operation. Earlier diagnosis and prompt referral before development of preoperative complications appear essential to improve surgical results.


Aspirin reduces cutaneous flushing after administration of an optimized extended-release niacin formulation.
Niacin is an effective treatment for dyslipidemia due to its favorable effects on multiple lipid parameters. Clinical utility of niacin is sometimes limited, however, because of cutaneous flushing. A once-daily, extended-release (ER) niacin formulation has been shown to significantly reduce flushing compared to immediate-release niacin. An optimized (reformulated) version of niacin ER has recently been developed and was shown in a previous study to significantly reduce flushing intensity (severity) compared to the non-optimized (commercial) formulation. The current study was designed to evaluate the effect of aspirin on various indices of flushing when administered with the optimized niacin ER formulation. This was a randomized, double-blind, double-dummy, placebo-controlled flush provocation crossover study in healthy males. To increase the probability of flushing, subjects received a single dose of reformulated niacin ER 2,000 mg, which is the upper limit of the approved dosage range. Subjects received 650 mg aspirin orally either 30 minutes before or concomitantly with niacin ER, or placebo with niacin ER, in 3-way crossover fashion. The primary endpoint was the number of subjects who reported at least one flushing event. Secondary endpoints included the perceived intensity and duration of flushing symptoms. In the 148 men who completed all treatments, aspirin significantly reduced flushing incidence (the primary endpoint) following administration of niacin ER compared with placebo. Among subjects receiving placebo, 77% of subjects reported flushing with niacin ER. Among subjects receiving aspirin, 53-61% of subjects reported flushing (pretreatment and concomitant treatment, respectively, both p < 0.001 compared with placebo) with niacin ER. Aspirin also significantly reduced intensity and duration of flushing (by 30-40%) compared with no aspirin. The two aspirin-containing treatments (i.e. pre- or concomitant treatment) were similar in their effects on flushing incidence, intensity and duration. Median intensity on a 100 mm visual analogue scale (VAS) was reduced from 33 mm with placebo to 19-23 mm with aspirin. Median duration was reduced from approximately 1 hour with placebo to 37-48 minutes with aspirin. Aspirin significantly reduced the incidence, intensity and duration of flushing associated with reformulated niacin ER. These results support the administration of aspirin prophylactically to decrease niacin-induced cutaneous flushing and to improve patient adherence and acceptability of chronic niacin treatment at therapeutic doses.


Epidemiology of Pediatric Basketball Injuries Presenting to Emergency Departments: Sex- and Age-Based Patterns.
There is limited epidemiologic data on pediatric basketball injuries and the comparison of these injuries before and after adolescence and between male and female athletes. To assess common sex- and age-based injury patterns in pediatric basketball players. Descriptive epidemiology study. Injury data from the National Electronic Injury Surveillance System (NEISS) and participation data from the National Sporting Goods Association were used to complete this study. Data on pediatric basketball injuries between January 2012 and December 2018 in patients aged 7 to 11 years (childhood) and 12 to 17 years (adolescence) were extracted and used to calculate national injury incidence rates with 95% CIs. Sex and age group patterns were examined utilizing Pearson chi-square tests. Z tests were conducted for the comparison of injury rates between female and male athletes in each age group and overall injury rate across age groups. An average of 9582 basketball injuries were reported annually in the NEISS, which calculated to an annual national estimate of 294,920 injuries. The most common diagnoses were ankle strain/sprain (17.7%), finger strain/sprain/fracture (12.1%), concussion/head injury (9.4%), knee strain/sprain (4.5%), and facial laceration (3.3%). There was a significant increase in injury prevalence in adolescents (12- to 17-year-old category: 238,678 injuries per year) when compared with childhood (7- to 11-year-old category: 56,242 injuries per year) (P < .0001). Concussions/head injuries occurred at a high rate in childhood, second only to finger strain/sprain/fracture, and at a similar rate in females and males (injuries per 100,000 athlete-days: 4.9 [95% CI, 3.1-6.7] vs. 5.9 [4.3-7.5], respectively; P = .41). From childhood to adolescence, injury prevalence increased for all areas and across both sexes, except for female finger strain/sprain/fracture; however, the rate of increase for concussion/head injuries and knee injuries was significantly higher in female compared with male athletes (P < .0001 for both). In adolescents, ankle injuries were the most common injury overall. Ankle injuries continue to be the most predominant pediatric basketball injury. However, disproportionate rates of both knee and concussion/head injuries in female athletes during adolescent basketball are of concern and have implications for injury prevention.


The metabolism and toxicity of quinones, quinonimines, quinone methides, and quinone-thioethers.
Quinones are ubiquitous in nature and constitute an important class of naturally occurring compounds found in plants, fungi and bacteria. Human exposure to quinones therefore occurs via the diet, but also clinically or via airborne pollutants. For example, the quinones of polycyclic aromatic hydrocarbons are prevalent as environmental contaminants and provide a major source of current human exposure to quinones. The inevitable human exposure to quinones, and the inherent reactivity of quinones, has stimulated substantial research on the chemistry and toxicology of these compounds. From a toxicological perspective, quinones possess two principal chemical properties that confer their reactivity in biological systems. Quinones are oxidants and electrophiles, and the relative contribution of these properties to quinone toxicity is influenced by chemical structure, in particular substituent effects. Modification to the quinone nucleus also influences quinone metabolism. This review will therefore focus on the differences in structure and metabolism of quinones, and how such differences influence quinone toxicology. Specific examples will be discussed to illustrate the diverse manner by which quinones interact with biological systems to initiate and propagate a toxic response.


Imaging in diagnosis, outcome prediction and monitoring of large vessel vasculitis: a systematic literature review and meta-analysis informing the EULAR recommendations.
To perform a systematic literature review on imaging techniques for diagnosis, outcome prediction and disease monitoring in large vessel vasculitis (LVV) informing the European League Against Rheumatism recommendations for imaging in LVV. Systematic literature review (until 10 March 2017) of diagnostic and prognostic studies enrolling >20 patients and investigating ultrasound, MRI, CT or positron emission tomography (PET) in patients with suspected and/or established primary LVV. Meta-analyses were conducted, whenever possible, obtaining pooled estimates for sensitivity and specificity by fitting random effects models. Forty-three studies were included (39 on giant cell arteritis (GCA), 4 on Takayasu arteritis (TAK)). Ultrasound ('halo' sign) at temporal arteries (8 studies, 605 patients) and MRI of cranial arteries (6 studies, 509 patients) yielded pooled sensitivities of 77% (95% CI 62% to 87%) and 73% (95% CI 57% to 85%), respectively, compared with a clinical diagnosis of GCA. Corresponding specificities were 96% (95% CI 85% to 99%) and 88% (95% CI 81% to 92%). Two studies (93 patients) investigating PET for GCA diagnosis reported sensitivities of 67%-77% and specificities of 66%-100% as compared with clinical diagnosis or temporal artery biopsy. In TAK, one study each evaluated the role of magnetic resonance angiography and CT angiography for diagnostic purposes revealing both a sensitivity and specificity of 100%. Studies on outcome prediction and monitoring disease activity/damage were limited and mainly descriptive. Ultrasound and MRI provide a high diagnostic value for cranial GCA. More data on the role of imaging for diagnosis of extracranial large vessel GCA and TAK, as well as for outcome prediction and monitoring in LVV are warranted.


Search for dark matter produced in association with a leptonically decaying Z boson in proton-proton collisions at s = 13 Te .
A search for dark matter particles is performed using events with a Z boson candidate and large missing transverse momentum. The analysis is based on proton-proton collision data at a center-of-mass energy of 13 Te , collected by the CMS experiment at the LHC in 2016-2018, corresponding to an integrated luminosity of 137 fb - 1 . The search uses the decay channels Z → e e and Z → μ μ . No significant excess of events is observed over the background expected from the standard model. Limits are set on dark matter particle production in the context of simplified models with vector, axial-vector, scalar, and pseudoscalar mediators, as well as on a two-Higgs-doublet model with an additional pseudoscalar mediator. In addition, limits are provided for spin-dependent and spin-independent scattering cross sections and are compared to those from direct-detection experiments. The results are also interpreted in the context of models of invisible Higgs boson decays, unparticles, and large extra dimensions.


Efficacy of behavioral interventions to increase condom use and reduce sexually transmitted infections: a meta-analysis, 1991 to 2010.
In the absence of an effective HIV vaccine, safer sexual practices are necessary to avert new infections. Therefore, we examined the efficacy of behavioral interventions to increase condom use and reduce sexually transmitted infections (STIs), including HIV. Studies that examined a behavioral intervention focusing on reducing sexual risk, used a randomized controlled trial or a quasi-experimental design with a comparison condition, and provided needed information to calculate effect sizes for condom use and any type of STI, including HIV. Studies were retrieved from electronic databases (eg, PubMed, PsycINFO) and reference sections of relevant papers. Forty-two studies with 67 separate interventions (N = 40,665; M age = 26 years; 68% women; 59% Black) were included. Independent raters coded participant characteristics, design and methodological features, and intervention content. Weighted mean effect sizes, using both fixed-effects and random-effects models, were calculated. Potential moderators of intervention efficacy were assessed. Compared with controls, intervention participants increased their condom use [d+ = 0.17, 95% confidence interval (CI) = 0.04, 0.29; k = 67], had fewer incident STIs (d+ = 0.16, 95% CI = 0.04, 0.29; k = 62), including HIV (d+ = 0.46, 95% CI = 0.13, 0.79; k = 13). Sample (eg, ethnicity) and intervention features (eg, skills training) moderated the efficacy of the intervention. Behavioral interventions reduce sexual risk behavior and avert STIs and HIV. Translation and widespread dissemination of effective behavioral interventions are needed.


Dietary Prebiotics and Bioactive Milk Fractions Improve NREM Sleep, Enhance REM Sleep Rebound and Attenuate the Stress-Induced Decrease in Diurnal Temperature and Gut Microbial Alpha Diversity.
Severe, repeated or chronic stress produces negative health outcomes including disruptions of the sleep/wake cycle and gut microbial dysbiosis. Diets rich in prebiotics and glycoproteins impact the gut microbiota and may increase gut microbial species that reduce the impact of stress. This experiment tested the hypothesis that consumption of dietary prebiotics, lactoferrin (Lf) and milk fat globule membrane (MFGM) will reduce the negative physiological impacts of stress. Male F344 rats, postnatal day (PND) 24, received a diet with prebiotics, Lf and MFGM (test) or a calorically matched control diet. Fecal samples were collected on PND 35/70/91 for 16S rRNA sequencing to examine microbial composition and, in a subset of rats; Lactobacillus rhamnosus was measured using selective culture. On PND 59, biotelemetry devices were implanted to record sleep/wake electroencephalographic (EEG). Rats were exposed to an acute stressor (100, 1.5 mA, tail shocks) on PND 87 and recordings continued until PND 94. Test diet, compared to control diet, increased fecal Lactobacillus rhamnosus colony forming units (CFU), facilitated non-rapid eye movement (NREM) sleep consolidation (PND 71/72) and enhanced rapid eye movement (REM) sleep rebound after stressor exposure (PND 87). Rats fed control diet had stress-induced reductions in alpha diversity and diurnal amplitude of temperature, which were attenuated by the test diet (PND 91). Stepwise multiple regression analysis revealed a significant linear relationship between early-life Deferribacteres (PND 35) and longer NREM sleep episodes (PND 71/72). A diet containing prebiotics, Lf and MFGM enhanced sleep quality, which was related to changes in gut bacteria and modulated the impact of stress on sleep, diurnal rhythms and the gut microbiota.


Simulation-based medical education in clinical skills laboratory.
Clinical skills laboratories have been established in medical institutions as facilities for simulation-based medical education (SBME). SBME is believed to be superior to the traditional style of medical education from the viewpoint of the active and adult learning theories. SBME can provide a learning cycle of debriefing and feedback for learners as well as evaluation of procedures and competency. SBME offers both learners and patients a safe environment for practice and error. In a full-environment simulation, learners can obtain not only technical skills but also non-technical skills, such as leadership, team work, communication, situation awareness, decision-making, and awareness of personal limitations. SBME is also effective for integration of clinical medicine and basic medicine. In addition, technology-enhanced simulation training is associated with beneficial effects for outcomes of knowledge, skills, behaviors, and patient-related outcomes. To perform SBME, effectively, not only simulators including high-fidelity mannequin-type simulators or virtual-reality simulators but also full-time faculties and instructors as professionals of SBME are essential in a clinical skills laboratory for SBME. Clinical skills laboratory is expected to become an integrated medical education center to achieve continuing professional development, integrated learning of basic and clinical medicine, and citizens' participation and cooperation in medical education.


Reprogramming human retinal pigmented epithelial cells to neurons using recombinant proteins.
Somatic cells can be reprogrammed to an altered lineage by overexpressing specific transcription factors. To avoid introducing exogenous genetic material into the genome of host cells, cell-penetrating peptides can be used to deliver transcription factors into cells for reprogramming. Position-dependent C-end rule (CendR) cell- and tissue-penetrating peptides provide an alternative to the conventional cell-penetrating peptides, such as polyarginine. In this study, we used a prototypic, already active CendR peptide, RPARPAR, to deliver the transcription factor SOX2 to retinal pigmented epithelial (RPE) cells. We demonstrated that RPE cells can be directly reprogrammed to a neuronal fate by introduction of SOX2. Resulting neuronal cells expressed neuronal marker mRNAs and proteins and downregulated expression of RPE markers. Cells produced extensive neurites and developed synaptic machinery capable of dye uptake after depolarization with potassium. The RPARPAR-mediated delivery of SOX2 alone was sufficient to allow cell lineage reprogramming of both fetal and stem cell-derived RPE cells to become functional neurons.


[Tuberculosis in children in Romania].
According to the World Health Organization and Stop TB Partnership, tuberculosis among children often remains undiagnosed, the main reported causes being lack of access to health services or because health professionals unrecognizing the signs and symptoms of tuberculosis in this age group. In Romania, consistent with TB endemic levels, the overall incidence progressively decreased from 142.2%ooo in 2002 to 82.8%ooo in 2011, incidence of TB in children 0-14 years dropped steadily from 47.2 %ooo (1784 cases) in the same "peak year"2002 to 23.6% ooo (766 cases) in 2011. The distribution of TB disease in children by counties shows variations between these, the explanations may be related both to differences in offer of the bacilli between different areas (prevalence of pulmonary patients smear and/or culture positive) and by deficiencies in the detection of cases and lack of rigor in diagnosis (variation in the incidence of TB in 0-14 years from 2.S%ooo in Sălaj county up to 53.2%ooo in Maramures county in 2011). The number of serious cases of TB in children (meningoencephalitis, miliary, cavitary) still maintains a constant high annual rate (65 cases in 2011), which demonstrates the severity of endemic TB in our country. Prompt assurance of TB diagnostic and also the accurate management of TB treatment constitute the guarantee of the decrease of this disease, goal applies to all age groups.


The effects of topical alpha-hydroxyacids on the normal skin barrier of hairless mice.
alpha-hydroxyacids (AHA), such as glycolic acid and lactic acid, have recently been used in cosmetic and dermatological formulations. However, the mechanisms of action of these substances have not been well documented. This study was done to investigate the effects of AHA on the skin barrier of hairless mice and to clarify the contribution of AHA to the formation and secretion of the lamellar bodies (LB), which are known to be the critical structure for barrier function in the epidermis. 5% Lactic acid and 5% glycolic acid were applied to normal skin of the mice daily for 14 days. Changes in transepidermal water loss (TEWL), capacitance and electron microscopic findings of the epidermis of hairless mice were compared with those in which only the vehicle was applied. There were no significant differences in TEWL, capacitance or epidermal thickness between the epidermis of the mice to which AHA or vehicle only had been applied. On electron micrographs, the normal epidermis to which AHA had been applied showed an increase in the number and secretion of LB and a decrease in the number of stratum corneum (SC) layers in comparison with the epidermis to which the vehicle only had been applied. The lipid layers of the SC intercellular spaces and calcium gradient in both the epidermis with application of AHA and that with vehicle only were normal. These results suggest that AHA, in low concentration (5%), may improve the skin barrier in hairless mice by inducing enhanced desquamation, and by increasing the number and secretion of LB without increasing TEWL.


Cardiac synthesis, processing, and coronary release of enkephalin-related peptides.
Although preproenkephalin mRNA is abundant in the heart, the myocardial synthesis and processing of proenkephalin is largely undefined. Isolated working rat hearts were perfused to determine the rate of myocardial proenkephalin synthesis, its processing into enkephalin-containing peptides, their subsequent release into the coronary arteries, and the influence of prior sympathectomy. Enkephalin-containing peptides were separated by gel filtration and quantified with antisera for specific COOH-terminal sequences. Proenkephalin, peptide B, and [Met(5)]enkephalin-Arg(6)-Phe(7) (MEAP) comprised 95% of the extracted myocardial enkephalins (35 pmol/g). Newly synthesized enkephalins, estimated during a 1-h perfusion with [(14)C]phenylalanine (4 pmol x h(-1) x g wet wt(-1)), were rapidly cleared from the heart during a second isotope-free hour. Despite a steady release of enkephalins into the coronary effluent (4 pmol x h(-1) x g wet wt(-1)), enkephalin replacement apparently exceeded its release, and tissue enkephalins actually accumulated during hour 2. In contrast to the tissue, methionine-enkephalin accounted for more than half of the released enkephalin. Chemical sympathectomy produced an increase in total enkephalin content similar to that observed after 2-h control perfusion. This observation suggested that the normal turnover of myocardial enkephalin may depend in part on continued sympathetic influences.


Recent experience with laparoscopic appendectomy in a Canadian teaching centre.
Laparoscopic appendectomy (LA) remains controversial in our city, in part because of results obtained early in the learning curve. In 1995, our centre reported that LA took 30 minutes longer and yet resulted in similar length of hospital stay, compared with open appendectomy (OA). The purpose of the current study is to reexamine LA now that more experience has been gained with the procedure and to document the learning curve at a typical Canadian teaching centre. We undertook a retrospective chart review of patients undergoing nonelective appendectomy between January 2001 and June 2004; this yielded 201 charts that satisfied the inclusion criteria. The 201 cases were divided into 3 groups, each consisting of 67 consecutive cases, to allow for comparison between early, middle and late experience. The main outcomes of interest were operative time, length of stay and the changes over time that occurred in these 2 measures. An intent-to-treat analysis was performed. The mean operative time differed by only minutes: 54.9 (standard error of mean [SEM] 1.9) minutes for LA and 48.8 (SEM 1.4) minutes for OA (p = 0.004). Length of stay was 1.3 (SEM 0.1) days and 2.9 (SEM 0.2) days for LA and OA groups, respectively (p 0.0001). Analysis of the 3 time periods (early, middle and late) revealed significant improvements in operative time and length of stay for LA in the middle, compared with the early, time periods. These data suggest that, with experience, LA operative time approaches that of OA and length of stay decreases. A shortened hospital stay and similar operative time, along with educational advantages, support the use of the LA in teaching centres.


New strategy for selective and sensitive assay of cathepsin B using a dityrosine-based material.
The increasing number of reports for disease-related proteases has necessitated materials for the fast, sensitive, and specific assessment of protease activities. The purpose of this study was to synthesize and test a dityrosine-based substrate for the selective assay of a specific cysteine cathepsin. DBDY-Gly-INH)2 was synthesized from the conjugation of N,N'-diBoc-dityrosine (DBDY) with two molecules of glycine and isoniazid (INH) for this purpose. The fluorescence of DBDY (λex=284-320nm, λem=400-420nm) disappeared due to the quenching effect of INH. However, the protease-catalyzed hydrolysis resulted in the release of INH and recovered the fluorescence of DBDY. When reacted with 13 proteases, DBDY-Gly-INH)2 was hydrolyzed by the cysteine proteases only. Meeting the growing need to discriminate cysteine cathepsins (e.g., cathepsins B, L, and S found at high levels in various cancers), DBDY-Gly-INH)2 was tested as a substrate for cathepsins B, L, and S. Only cathepsin B catalyzed the hydrolysis reaction among the three cathepsins. The reaction rate followed the Michaelis-Menten kinetics, and the KM and kcat/KM values were 2.88μM and 3.87×10(3)M(-1)s(-1), respectively, which were comparable to those for the materials reported for the selective assay of cathepsin B. Considering the simple preparation of DBDY-(Gly-INH)2, DBDY-(Gly-INH)2 is believed to be valuable for the sensitive and selective assay of cathepsin B activity.


The within host dynamics of Mycobacterium avium ssp. paratuberculosis infection in cattle: where time and place matter.
Johne's disease or paratuberculosis, caused by Mycobacterium avium subsp. paratuberculosis (MAP), occurs in domestic and wild animals worldwide, causing a significant economic loss to livestock industries. After a prolonged incubation time, infected cattle shed MAP bacilli into feces and spread the disease to an uninfected animal population. It is largely unknown how (or whether) the interplay between the pathogen and the host immunity determines timing of shedding after the long incubation time. Such information would provide an understanding of pathogenesis in individual animals and the epidemiology of MAP infection in animal populations. In this review, we summarize current knowledge of bovine Johne's disease pathology, pathogenesis, immunology and genetics. We discuss knowledge gaps that direly need to be addressed to provide a science-based approach to diagnostics and (immuno)prophylaxis. These knowledge gaps are related to anatomical/clinical manifestation of MAP invasion, interaction of bacteria with phagocytes, granuloma formation, shedding, establishment and kinetics of adaptive immune responses in the pathogenesis of the disease. These topics are discussed at the molecular, cellular and tissue levels with special attention to the within host dynamics including the temporal and the spatial context relevant for the various host-pathogen interactions.


Complete Sequences of mcr-1-Harboring Plasmids from Extended-Spectrum-β-Lactamase- and Carbapenemase-Producing Enterobacteriaceae.
Here we completely sequenced four mcr-1-haboring plasmids, isolated from two extended-spectrum-β-lactamase (ESBL)-producing Escherichia coli and two carbapenemase-producing Klebsiella pneumoniae clinical isolates. The mcr-1-harboring plasmids from an E. coli sequence type 2448 (ST2448) isolate and two K. pneumoniae ST25 isolates were identical (all pMCR1-IncX4), belonging to the IncX4 incompatibility group, while the plasmid from an E. coli ST2085 isolate (pMCR1-IncI2) belongs to the IncI2 group. A nearly identical 2.6-kb mcr-1-pap2 element was found to be shared by all mcr-1-carrying plasmids.


Bisindolylmaleimide IX Induces Reversible and Time-Dependent Tumor Necrosis Factor Receptor Family-Mediated Caspase Activation and Cell Death.
We have previously shown that Bisindolylmaleimide (Bis) IX is localized in mitochondria but also acts as an inhibitor of transcription and facilitates tumor necrosis factor receptor family-mediated apoptosis. In this study, we found that Bis IX is freely distributed both within cells and extracellular medium and acts as a reversible apoptosis-inducing agent. Bis IX was found to induce time-dependent apoptosis in combination with TNF-a, TRAIL, and anti-Fas Ab. Using human prostatic carcinoma cell lines DU145 and LNCaP that are resistant to treatment with TNF family death-inducing ligands, we have shown that different, albeit still unidentified, inhibitory factors are responsible for the resistance to TRAIL-, Fas-, and TNF-a-mediated apoptosis. Our data also suggest that the turnover of apoptosis suppressor factors is much faster in DU145 compared to LNCaP. Lastly, we have found that Bis IX can override the apoptosis-inhibitory effects of Bcl-2 overexpression. In conclusion, Bis IX could be used as a drug to facilitate apoptosis of cancer cells that are resistant to treatment with death-inducing ligands as well as a valuable tool to discern the factors that mediate resistance to different death-inducing ligands.


Identifying barriers for implementation of computer based nursing documentation.
This study was undertaken in the planning phase for the introduction of a comprehensive computer based nursing documentation system at Erlangen University Hospital. There, we expect a wide range of difficult organizational changes, because the nurses currently neither used computer based nursing documentation nor did they follow strongly the nursing process model within paper based documentation. Thus we were eager to recognize potential pitfalls early and to identify potential barriers for digital nursing documentation. In a questionnaire study we surveyed all German university hospitals for their experience with the implementation of computer based nursing documentation implementation. We received answers from 11 of the 23 hospitals. Furthermore we performed a questionnaire study about expectations and fears among the nurses of four pilot wards of our hospital. Most respondents stated a positive attitude towards the nursing process documentation, but many respondents note technical (e.g. bad performance of the software) and organizational barriers (e.g. lack of time).


Strengthening the Combinational Immunotherapy from Modulating the Tumor Inflammatory Environment via Hypoxia-Responsive Nanogels.
Despite the success of immuno-oncology in clinical settings, the therapeutic efficacy is lower than the expectation due to the immunosuppressive inflammatory tumor microenvironment (TME) and the lack of functional lymphocytes caused by exhaustion. To enhance the efficacy of immuno-oncotherapy, a synergistic strategy should be used that can effectively improve the inflammatory TME and increase the tumor infiltration of cytotoxic T lymphocytes (CTLs). Herein, we developed a TME hypoxia-responsive nanogel (NG) to enhance the delivery and penetration of diacerein and (-)-epigallocatechin gallate (EGCG) in tumors. After systemic administration, diacerein effectively improved the tumor immunosuppressive condition through a reduction of MDSCs and Tregs in TME, and induced tumor cells apoptosis via the inhibition of IL-6/STAT3 signal pathway, realizing a strong anti-tumor effect. Additionally, EGCG could effectively inhibit the expression of PD-L1, restoring the tumor-killing function of CTLs. The infiltration of CTLs increased at the tumor site with activation of systemic immunity after the combination of TIM3 blockade therapy, ultimately resulting in a strong anti-tumor immune response. This study provides valuable insights for future research on eliciting effective anti-tumor immunity by suppressing adverse tumor inflammation. The feasible strategy proposed in this work may solve the urgent clinical concerns of the dissatisfactory checkpoint-based immuno-oncotherapy. This article is protected by copyright. All rights reserved.


The role of meniscal root pathology and radial meniscal tear in medial meniscal extrusion.
The purpose of our study was twofold: to better understand the relationship between medial meniscal extrusion (MME) and degenerative joint disease (DJD), and to determine whether a relationship exists between MME and medial meniscal root (MMR) pathology, radial tear and joint effusion. Two hundred and five consecutive MR imaging examinations of the knee were prospectively evaluated, regardless of indication, for the presence and degree of MME, medial compartment marginal osteophytes, medial compartment articular cartilage loss, joint effusion, medial meniscal tear and MMR pathology. MME >or=3 mm was considered abnormal. All studies were performed using a 1.5 T GE Signa MR unit with a quadrature knee coil. The standard protocol included oblique sagittal, coronal and axial imaging. We found a strong association ( P<0.0001) between >or=3 mm MME and medial joint line osteophytosis (77%), medial compartment articular cartilage loss (69%), MMR pathology (64%) and radial tear (58%) when compared with knees without these findings. Fifty-one percent of cases with a moderate/large joint effusion had <3 mm MME. We found that 20% (31/155) of patients with minimal or no evidence of DJD had >or=3 mm MME. Of this group, 62% (19/31) had either MMR pathology and/or radial tear, 13% (4/31) had joint effusion as their only abnormality and 6% (2/31) had a normal examination (other than the presence of MME). The remaining 19% consisted of three cases of different types of meniscal tear and three cases of small joint effusions but no other detectable pathology. MME >or=3 mm is strongly associated with DJD, MMR pathology and radial tear. A significant number of cases with no or minimal evidence of DJD (20%) had >or=3 mm MME, suggesting that MME precedes, rather than follows, the development of DJD. We also found that joint effusion was not strongly associated with >or=3 mm MME.


Biochemical and immunological characterization of renal protein kinase C.
Protein kinase C (PKC) plays an important role in regulation of renal transport and metabolic function. To understand the role of a specific PKC isozyme in renal homeostasis, alpha-PKC content, regulation, and localization have been characterized. Immunoadsorption assays were used to determine that 34% of the total rat kidney PKC (measured as phorbol ester receptors) was alpha-PKC. Immunohistochemical staining with alpha-PKC-specific monoclonal antibodies determined that alpha-PKC was present throughout the nephron and was especially concentrated in proximal tubules and papillary collecting ducts. In general, the S3 segment of the proximal tubule stained more intensely than the S1-S2 segments. Cortical collecting ducts stained poorly for alpha-PKC. Interstitial cells of the papilla also stained for alpha-PKC. Subcellular distribution of alpha-PKC could not be determined in tissue sections; however, in cultured proximal tubule epithelial cells, alpha-PKC was localized not only in cytoplasm but also in cell-cell borders and focal contacts. Chromatography of rat kidney soluble fraction revealed two endogenous kinase inhibitors, one which is PKC specific and one which is a more general kinase inhibitor. The presence of negative regulators of PKC activity suggests that both activation and inactivation of PKC are important for normal renal function.


Substance P accelerates hypercellularity and angiogenesis in tendon tissue and enhances paratendinitis in response to Achilles tendon overuse in a tendinopathy model.
Tenocytes produce substance P (SP), and its receptor (neurokinin-1 receptor (NK-1R)) is expressed throughout the tendon tissue, especially in patients with tendinopathy and tissue changes (tendinosis) including hypercellularity and vascular proliferation. Considering the known effects of SP, one might ask whether SP contributes to these changes. To test whether development of tendinosis-like changes (hypercellularity and angiogenesis) is accelerated during a 1-week course of exercise with local administration of SP in an established Achilles tendinopathy model. Rabbits were subjected to a protocol of Achilles tendon overuse for 1 week, in conjunction with SP injections in the paratenon. Exercised control animals received NaCl injections or no injections, and unexercised, uninjected controls were also used. Tenocyte number and vascular density, as well as paratendinous inflammation, were evaluated. Immunohistochemistry and in situ hybridisation to detect NK-1R were conducted. Results There was a significant increase in tenocyte number in the SP-injected and NaCl-injected groups compared with both unexercised and exercised, uninjected controls. Tendon blood vessels increased in number in the SP-injected group compared with unexercised controls, a finding not seen in NaCl-injected controls or in uninjected, exercised animals. Paratendinous inflammation was more pronounced in the SP-injected group than in the NaCl controls. NK-1R was detected in blood vessel walls, nerves, inflammatory cells and tenocytes. SP accelerated the development of tendinosis-like changes in the rabbit Achilles tendon, which supports theories of a potential role of SP in tendinosis development; a fact of clinical interest since SP effects can be effectively blocked. The angiogenic response to SP injections seems related to paratendinitis.


High expression ITGA2 affects the expression of MET, PD-L1, CD4 and CD8 with the immune microenvironment in pancreatic cancer patients.
Pancreatic cancer is characterized by a grim prognosis and is regarded as one of the most formidable malignancies. Among the genes exhibiting high expression in different tumor tissues, ITGA2 stands out as a promising candidate for cancer therapy. The promotion of cancer in pancreatic cancer is not effective. The objective of this study is to assess the presence of ITGA2, EMT and PD-L1 in pancreatic cancer. We examined the expression of ITGA2, MET, E-cadherin, PD-L1, CD4, and CD8 proteins in 62 pancreatic cancer tissue samples using multi-tissue immunofluorescence and immunohistochemistry techniques. Functional assays, such as the cell migration assay and transwell assay, were used to determine the biological role of ITGA2 in pancreatic cancer. The relationship of ITGA2,EMT and PD-L1 were examined using Western blot analysis and RT-qPCR assay. In our study, we observed the expression of ITGA2, E-cadherin, and PD-L1 in both tumor and stroma tissues of pancreatic cancer. Additionally, a positive correlation between ITGA2, E-cadherin, and PD-L1 in the tumor region (r=0.559, P<0.001 and r=0.511, P<0.001), and PD-L1 in the stroma region (r=0.512, P<0.001).The expression levels of ITGA2, CD4, and CD8 were found to be higher in pancreatic cancer tissues compared to adjacent tissues (P < 0.05). Additionally, ITGA2 was negatively correlated with CD4 and CD8 (r = -0.344, P < 0.005 and r = -0.398, P < 0.005).Furthermore, ITGA2, CD4, and CD8 were found to be correlated with the survival time of patients (P < 0.05). Blocking ITGA2 inhibited the proliferation and invasion ability of pancreatic cancer cells significantly, Additionally, sh-ITGA2 can down-regulate the expression of EMT and PD-L1. We identified a novel mechanism in which ITGA2 plays a crucial role in the regulation of pancreatic cancer growth and invasion. This mechanism involves the upregulation of MET and PD-L1 expression in pancreatic cancer cells. Additionally, we found that increased expression of ITGA2 is associated with a poor prognosis in pancreatic cancer patients. Furthermore, ITGA2 also affects immune regulation in these patients. Therefore, targeting ITGA2 is an effective method to enhance the efficacy of checkpoint immunotherapy and prohibiting tumor growth against pancreatic cancer.


Awaiting a new era of cancer immunotherapy.
A major challenge in cancer therapy is the lack of specificity for cancer cells. Antibody-based therapies have better specificity and, thus, improved efficacy over standard chemotherapy regimens. Monoclonal antibodies (mAb) constitute the most rapidly growing class of human therapeutics and are proven agents for recognizing and destroying malignant cells. However, the development of antibody therapies has focused only on targeting extracellular (cell-surface or secreted) proteins rather than intracellular targets (within cells, such as phosphatases and/or kinases and transcription factors), because antibodies are generally believed to be too large to enter cells, resulting in a large untapped source of intracellular therapeutic targets. Recently, we presented evidence that suggests that intracellular proteins with high expression in cancer cells are useful targets for mAb-based or vaccination immunotherapies, thus challenging current understanding. Here, we further discuss the concept and future uses of these immunotherapies against a large pool of intracellular oncoproteins for cancer therapy. This line of research has the potential to vastly expand the field of antibody therapy and usher in a new era of cancer vaccines.


Characterization of a neuregulin-related gene, Don-1, that is highly expressed in restricted regions of the cerebellum and hippocampus.
Members of the epidermal growth factor family of receptors have long been implicated in the pathogenesis of various tumors, and more recently, apparent roles in the developing heart and nervous system have been described. Numerous ligands that activate these receptors have been isolated. We report here on the cloning and initial characterization of a second ligand for the erbB family of receptors. This factor, which we have termed Don-1 (divergent of neuregulin 1), has structural similarity with the neuregulins. We have isolated four splice variants, two each from human and mouse, and have shown that they are capable of inducing tyrosine phosphorylation of erbB3, erbB4, and erbB2. In contrast to those of neuregulin, high levels of expression of Don-1 are restricted to the cerebellum and dentate gyrus in the adult brain and to fetal tissues.


Surface wettability of (3-aminopropyl)triethoxysilane self-assembled monolayers.
The (3-aminopropyl)triethoxysilane (APTES) self-assembled monolayer (SAM) has been widely used in fundamental research and engineering applications; however, characterization of its surface wetting properties remains problematic. Surface wetting properties of the APTES SAM were systematically investigated using different contact angle measurement techniques. The observed unique nonideal wetting was related to the APTES SAM structure, including surface hydrogen bond formation, the surface roughness, and the effect of water penetration. The contact angle decreased dramatically with the residence time on the APTES SAM surface, and a special contact angle hysteresis phenomenon was observed. The contact angle could be distorted by the calculation method used for the nonideal APTES SAM surface. Values calculated by the tangent-leaning method were thought to be more accurate and credible. Our findings demonstrated that static advancing contact angles were the most stable and credible for characterizing the APTES SAM surface wettability.


Molecular hybridization with cloned fragments of tick-borne encephalitis (TBE) virus cDNA in acute and chronic TBE infection.
Recombinant plasmid DNA was used as a probe to detect tick-borne encephalitis (TBE) virus RNA during incubation period, acute disease and persistent infection of syrian hamsters. Within the first three weeks post-infection the results of direct virus isolation and RNA detection in the brain agreed by a rate of 100%, the virus titre ranging between 10(1.9) to 10(10.5) LD50/ml and viral RNA concentration at 1-1000 pg. At the same time TBE virus RNA was detected in the spleen when the virus titre was greater than or equal to 10(6.5) LD50/ml. By 8 months post infection (p.i.) viral RNA was found in the brain, liver, and spleen in the absence of infectious TBE virus. No viral RNA was present in the thymus. In addition, electron microscopic findings in hamster brain confirmed the hypothesis that TBE virus persistence was accompanied by formation of virus-specific structures but impaired virion maturation.


Linear-selective hydroarylation of unactivated terminal and internal olefins with trifluoromethyl-substituted arenes.
We report a series of hydroarylations of unactivated olefins with trifluoromethyl-substituted arenes that occur with high selectivity for the linear product without directing groups on the arene. We also show that hydroarylations occur with internal, acyclic olefins to yield linear alkylarene products. Experimental mechanistic data provide evidence for reversible formation of an alkylnickel-aryl intermediate and rate-determining reductive elimination to form the carbon-carbon bond. Labeling studies show that formation of terminal alkylarenes from internal alkenes occurs by initial establishment of an equilibrating mixture of alkene isomers, followed by addition of the arene to the terminal alkene. Computational (DFT) studies imply that the aryl C-H bond transfers to a coordinated alkene without oxidative addition and support the conclusion from experiment that reductive elimination is rate-determining and forms the anti-Markovnikov product. The reactions are inverse order in α-olefin; thus the catalytic reaction occurs, in part, because isomerization creates a low concentration of the reactant α-olefin.


NLS-tagging: an alternative strategy to tag nuclear proteins.
The characterization of transcription factor complexes and their binding sites in the genome by affinity purification has yielded tremendous new insights into how genes are regulated. The affinity purification requires either the use of antibodies raised against the factor of interest itself or by high-affinity binding of a C- or N-terminally added tag sequence to the factor. Unfortunately, fusing extra amino acids to the termini of a factor can interfere with its biological function or the tag may be inaccessible inside the protein. Here, we describe an effective solution to that problem by integrating the 'tag' close to the nuclear localization sequence domain of the factor. We demonstrate the effectiveness of this approach with the transcription factors Fli-1 and Irf2bp2, which cannot be tagged at their extremities without loss of function. This resulted in the identification of novel proteins partners and a new hypothesis on the contribution of Fli-1 to hematopoiesis.


Assessing Risks of Polypharmacy Involving Medications With Anticholinergic Properties.
Anticholinergic burden (ACB), the cumulative effect of anticholinergic medications, is associated with adverse outcomes in older people but is less studied in middle-aged populations. Numerous scales exist to quantify ACB. The aims of this study were to quantify ACB in a large cohort using the 10 most common anticholinergic scales, to assess the association of each scale with adverse outcomes, and to assess overlap in populations identified by each scale. We performed a longitudinal analysis of the UK Biobank community cohort (502,538 participants, baseline age: 37-73 years, median years of follow-up: 6.2). The ACB was calculated at baseline using 10 scales. Baseline data were linked to national mortality register records and hospital episode statistics. The primary outcome was a composite of all-cause mortality and major adverse cardiovascular event (MACE). Secondary outcomes were all-cause mortality, MACE, hospital admission for fall/fracture, and hospital admission with dementia/delirium. Cox proportional hazards models (hazard ratio [HR], 95% CI) quantified associations between ACB scales and outcomes adjusted for age, sex, socioeconomic status, body mass index, smoking status, alcohol use, physical activity, and morbidity count. Anticholinergic medication use varied from 8% to 17.6% depending on the scale used. For the primary outcome, ACB was significantly associated with all-cause mortality/MACE for each scale. The Anticholinergic Drug Scale was most strongly associated with mortality/MACE (HR = 1.12; 95% CI, 1.11-1.14 per 1-point increase in score). The ACB was significantly associated with all secondary outcomes. The Anticholinergic Effect on Cognition scale was most strongly associated with dementia/delirium (HR = 1.45; 95% CI, 1.3-1.61 per 1-point increase). The ACB was associated with adverse outcomes in a middle- to older-aged population. Populations identified and effect size differed between scales. Scale choice influenced the population identified as potentially requiring reduction in ACB in clinical practice or intervention trials.


Stimulation of DNA synthesis and cell proliferation in the liver of rats fed a choline-devoid diet and their suppression by phenobarbital.
Feeding of choline-devoid (CD) diet and dietary administration of phenobarbital (PHB) are efficient promoters of liver carcinogenesis in the rat. Furthermore, inclusion of PHB in a CD diet results in a synergistic effect, inasmuch as the promoting action of their combination is greater than the sum of those exerted by either agent alone. To investigate the mechanism(s) of action of the two promoters, liver DNA synthesis and liver cell proliferation were studied in rats fed a CD diet, a choline-supplemented diet, or the same diets to which 0.06% PHB was added. DNA synthesis was determined by [3H]thymidine incorporation into DNA and autoradiography, and cell proliferation was determined by mitosis counts. Feeding the CD diet caused an increase of both DBA synthesis and cell proliferation over those present in rats fed the choline-supplemented diet. Inclusion of PHB in the CD diet, on the other hand, inhibited DNA synthesis and cell proliferation. These results indicate that stimulation of cell proliferation per se may not be a sufficient condition for an agent to act as a promoter of liver carcinogenesis.


Grafting of PEO to glass, nitinol, and pyrolytic carbon surfaces by gamma irradiation.
Glass, nitinol, and pyrolytic carbon surfaces were grafted with poly (ethylene oxide) (PEO) and PEO-containing Pluronic surfactants by gamma irradiation. These substrates were coated with a primer layer of trichlorovinylsilane (TCVS), which allows grafting of organic polymers. The TCVS-coated substrates were adsorbed with PEO or Pluronics and exposed to 0.3 Mrad of gamma radiation to graft the polymer to the surface. PEO-grafted substrates were characterized by contact angle measurement, X-ray photoelectron spectroscopy, fibrinogen adsorption, and platelet adhesion and activation. Surface modification with PEO reduced fibrinogen adsorption by as much as 99%. Platelet adhesion was significnatly reduced or prevented on the modified surfaces. Protein- and platelet-resistance effects were independent of hydrophilicity of the PEO-grafted surfaces. Polymer grafting by gamma radiation to TCVS-coated substrates provides a facile process to improve thromboresistance of inorganic biomaterials.


Stereospecific Decarboxylative Benzylation of Enolates: Development and Mechanistic Insight.
A palladium-catalyzed decarboxylative coupling of enol carbonates with diarylmethyl electrophiles that are derived from secondary benzylic alcohols has been developed. This method allows the generation of a variety of β-diaryl ketones through an efficient and highly stereospecific coupling. In addition, detailed mechanistic insight into the coupling suggests that the reaction is a rare example of an intramolecular decarboxylative coupling that proceeds without crossover between reactants.


Adaptive pacing during ventricular fibrillation.
While it has been shown that pacing during ventricular fibrillation (VF) can capture a portion of the epicardium, little is known about the characteristics of the area captured or about whether adaptively changing the pacing rate during VF will increase the area captured. In six open-chested pigs, pacing during VF was performed from the center of a plaque containing 504 electrodes 2 mm apart in a21 x 24 array on the anterior right ventricle. Simultaneous recordings from the 504 electrodes were used to construct activation maps from which the area of epicardium captured by pacing was determined. Four pacing algorithms were examined: (1) fixed rate pacing at 95% of the median VF activation rate, (2 and 3) adaptive pacing in which the pacing timing and/or rate is reset in real time if capture is not obtained, and (4) pacing at a slowly increasing rate after initial capture. Regional capture, defined as control of the myocardium under at least 10 plaque electrodes, was achieved in 71% (92/129) of pacing episodes. The incidence of capture was not significantly different for pacing algorithms 1-3. The maximum area captured for each pacing episode with algorithms 1-3 was 3.8 +/- 2.0 cm2(mean +/- SD). Within each animal, the pattern of capture was similar among all pacing episodes, no matter which algorithm was use dr = 0.85 +/- 0.25). The region of greatest capture extended away from the pacing site along the long axis of the myocardial fibers. However, the area of captured epicardium toward the right ventricular side of the pacing electrode was 9.7 times greater than toward the left ventricular side. This principal direction toward the right ventricular side of the pacing electrode was the same direction traveled by the majority of VF activation fronts before capture occurred. The absence of recorded activations at the pacing site for 20 consecutive stimuli predicted 83% of the time that regional capture was present. With algorithm 4, the pacing rate could be increased 7.1%+/- 4.3%while maintaining capture; however, the area of capture progressively decreased as the pacing rate increased. While pacing from the anterior right ventricular epicardium during VF, the area of capture is repeatable and is markedly asymmetrical with almost 10 times as much epicardium captured on the side of the pacing electrode closest to the acute margin of the right ventricle as on the opposite side. This marked asymmetry is associated both with myofiber orientation and with the direction of spread of activation and hence the direction of dispersion of refractoriness during VF just before pacing is initiated. It is possible to perform adaptive pacing algorithms in real time during VF; however, the two adaptive algorithms tested did not capture significantly more epicardium than a simple fixed-rate pacing algorithm. Although it is possible to maintain capture while increasing the pacing rate during VF, the area of capture decreases.


Bottleneck Problems: An Information and Estimation-Theoretic View.
Information bottleneck (IB) and privacy funnel (PF) are two closely related optimization problems which have found applications in machine learning, design of privacy algorithms, capacity problems (e.g., Mrs. Gerber's Lemma), and strong data processing inequalities, among others. In this work, we first investigate the functional properties of IB and PF through a unified theoretical framework. We then connect them to three information-theoretic coding problems, namely hypothesis testing against independence, noisy source coding, and dependence dilution. Leveraging these connections, we prove a new cardinality bound on the auxiliary variable in IB, making its computation more tractable for discrete random variables. In the second part, we introduce a general family of optimization problems, termed "bottleneck problems", by replacing mutual information in IB and PF with other notions of mutual information, namely f-information and Arimoto's mutual information. We then argue that, unlike IB and PF, these problems lead to easily interpretable guarantees in a variety of inference tasks with statistical constraints on accuracy and privacy. While the underlying optimization problems are non-convex, we develop a technique to evaluate bottleneck problems in closed form by equivalently expressing them in terms of lower convex or upper concave envelope of certain functions. By applying this technique to a binary case, we derive closed form expressions for several bottleneck problems.


Optimizing the sensitivity of high repetition rate broadband transient optical spectroscopy with modified shot-to-shot detection.
A major limitation of transient optical spectroscopy is that relatively high laser fluences are required to enable broadband, multichannel detection with acceptable signal-to-noise levels. Under typical experimental conditions, many condensed phase and nanoscale materials exhibit fluence-dependent dynamics, including higher order effects such as carrier-carrier annihilation. With the proliferation of commercial laser systems, offering both high repetition rates and high pulse energies, have come new opportunities for high sensitivity pump-probe measurements at low pump fluences. However, experimental considerations needed to fully leverage the statistical advantage of these laser systems have not been fully described. Here, we demonstrate a high repetition rate, broadband transient spectrometer capable of multichannel shot-to-shot detection at 90 kHz. Importantly, we find that several high-speed cameras exhibit a time-domain fixed pattern noise resulting from interleaved analog-to-digital converters, which is particularly detrimental to the conventional "ON/OFF" modulation scheme used in pump-probe spectroscopy. Using a modified modulation and data processing scheme, we achieve a noise level of 10-5 in 4 s for differential transmission, an order of magnitude lower than for commercial 1 kHz transient spectrometers for the same acquisition time. We leverage the high sensitivity of this system to measure the differential transmission of monolayer graphene at low pump fluence. We show that signals on the order of 10-6 OD can be measured, enabling a new data acquisition regime for low-dimensional materials.


Implementation of Supervised Exercise Therapy for Patients With Symptomatic Peripheral Artery Disease: A Science Advisory From the American Heart Association.
Patients with lower-extremity peripheral artery disease (PAD) have greater functional impairment, faster functional decline, increased rates of mobility loss, and poorer quality of life than people without PAD. Supervised exercise therapy (SET) improves walking ability, overall functional status, and health-related quality of life in patients with symptomatic PAD. In 2017, the Centers for Medicare & Medicaid Services released a National Coverage Determination (CAG-00449N) for SET programs for patients with symptomatic PAD. This advisory provides a practical guide for delivering SET programs to patients with PAD according to Centers for Medicare & Medicaid Services criteria. It summarizes the Centers for Medicare & Medicaid Services process and requirements for referral and coverage of SET and provides guidance on how to implement SET for patients with PAD, including the SET protocol, options for outcome measurement, and transition to home-based exercise. This advisory is based on the guidelines established by the Centers for Medicare & Medicaid Services for Medicare beneficiaries in the United States and is intended to assist clinicians and administrators who are implementing SET programs for patients with PAD.


High-Quality Inorganic Red Pigment Prepared by Aluminum Deposition on Biogenous Iron Oxide Sheaths.
Naturally occurring tubular iron oxides produced by aquatic bacteria in Leptothrix spp. are promising raw materials for hematite-based red pigments because of the higher heat resistance as compared with chemically synthesized hematite compounds. Here, we report iron oxide red pigments prepared through an additive deposition of aluminum on culture-based biogenous iron oxide (cBIOX) sheaths using an artificial culture system of L. cholodnii strain OUMS1. The heat-treated Al-containing cBIOXs exhibited elevated chroma and lightness along with increasing Al contents and enhanced thermal stability of color tones to repetitive heat treatments. XRD analysis showed a monophasic pattern of hematite in the Al-rich cBIOX after heating at a wide range of high temperatures. Micromorphology analyses revealed that putative Al oxide regions present among hematite particles plausibly prevented the grain growth of hematite during heat treatments. The results therefore demonstrate that the bioderived Al-rich iron oxide sheaths can serve as innovative inorganic red pigments feasible for industrial applications.


Relation of antimullerian hormone with the clinical signs of hyperandrogenism and polycystic ovary morphology.
The relation of antimullerian hormone (AMH) levels with the clinical and biochemical markers of polycystic ovary syndrome (PCOS) could be different. A total of 463 PCOS patients were evaluated in this cross-sectional study. Groups were constructed according to polycystic ovarian morphology (PCOM) and menstrual cycle-length. The relation of serum AMH with androgenic hormones, menstrual cycle-length and clinical signs of PCOS were investigated. A powerful positive relation was found between the PCOM and AMH levels (odds ratio = 2.49). There was a negative correlation between age and AMH level (p < 0.001, r[correlation coefficent] = -0.155). Positive correlations were found between luteinizing hormone (LH) and AMH (p < 0.001, r = 0.25) and also between cycle length and AMH (p < 0.01, r = 0.27). We found a negative week correlation between AMH and follicle-stimulating hormone (FSH) (p = 0.01, r = -0.19). After controlling main androgenic hormones, AMH was found to be correlated with the Ferriman-Gallway score (p = 0.03, r = 0.18). There was a positive relationship between hirsutism and AMH (odds ratio = 1.43), but no correlation between AMH and other parameters of clinical hyperandrogenism like hair-loss, acne and seborrhea were identified. The strongest relation was presented between the AMH levels and PCOM. Also, cycle-length correlated well with the AMH levels. The relationship between hirsutism and AMH is found to be independent from androgenic hormones.