cssi/SciSciGPT-SciSciNet huggingface dataset:
Multiple sclerosis, natalizumab therapy, and progressive multifocal leukoencephalopathy.

PURPOSE OF REVIEW Multiple sclerosis affects many people, often in early adulthood, and causes significant disability. Natalizumab is a novel agent to be evaluated for multiple sclerosis and Crohn's disease that has demonstrated unique efficacy but has unfortunately been implicated in three cases of progressive multifocal leukoencephalopathy. This review covers the mechanism of action of natalizumab and efficacy for multiple sclerosis, the three cases of natalizumab-associated progressive multifocal leukoencephalopathy, our understanding of progressive multifocal leukoencephalopathy, and the mechanisms that may account for these events. RECENT FINDINGS Natalizumab, an anti-alpha4-integrin antibody, binds to T-cell surface receptors to prevent migration from the circulation into the brain tissue. Phase II and III trials have been completed and demonstrate previously unseen efficacy in preventing relapses and disease progression. The cases of progressive multifocal leukoencephalopathy, two fatal and one disabling, resulted in the voluntary suspension of natalizumab and bring this entire class of agents into doubt. It is important to determine what led to the development of progressive multifocal leukoencephalopathy in the natalizumab-associated cases and to advance understanding and continue to develop therapies for the treatment of multiple sclerosis. SUMMARY With ongoing safety evaluations, natalizumab is being reevaluated by the US Food and Drug Administration for possible reapproval and return to the market. If natalizumab is reapproved, challenging questions and issues will remain in treating patients with multiple sclerosis.
Caveolae, ion channels and cardiac arrhythmias

Caveolae are specialized membrane microdomains enriched in cholesterol and sphingolipids which are present in multiple cell types including cardiomyocytes. Along with the essential scaffolding protein caveolin-3, a number of different ion channels and transporters have been localized to caveolae in cardiac myocytes including L-type Ca2+ channels (Ca(v)1.2), Na+ channels (Na(v)1.5), pacemaker channels (HCN4), Na+/Ca2+ exchanger (NCX1) and others. Closely associated with these channels are specific macromolecular signaling complexes that provide highly localized regulation of the channels. Mutations in the caveolin-3 gene (CAV3) have been linked with the congenital long QT syndrome (LQT9), and mutations in caveolar-localized ion channels may contribute to other inherited arrhythmias. Changes in the caveolar microdomain in acquired heart disease may also lead to dysregulation and dysfunction of ion channels, altering the risk of arrhythmias in conditions such as heart failure. This review highlights the existing evidence identifying and characterizing ion channels localized to caveolae in cardiomyocytes and their role in arrhythmogenesis.
Transient ischemic attacks caused by unruptured intracranial aneurysm

A case is reported of a 56-year-old man in whom an unruptured aneurysm of the left middle cerebral artery was the source of emboli resulting in transient ischemic attacks (TIAs). The potential relationship between TIAs and an unruptured aneurysm is discussed, and the literature is reviewed.
Sexual arousal in women: The development of a measurement device for vaginal blood volume

Undergraauate women were shown erotic and nonerotic films. A vaginal photoplethysmograph was developed and used to measure pressure pulse and vaginal blood volume during film presentations. All subjects yielded a visible increase in pressure pulse amplitude during the presentation of the erotic films. Statistical analyses of the pressure pulse data strongly confirmed (p <0.001) the visual impressions. In addition, total blood volume in the vaginal wall also increased (p <0.005) during the presentation of the erotic film. Subjective ratings of sexual arousal did not correlate with physiological measures. The results indicate that a simple and reliable device for measuring vaginal pressure pulse and blood volume is available. Measures obtained from the device appear to be useful for detecting sexual arousal in women.
The pharmacologic management of neuropathic pain

N reuropathic pain intrinsically differs from nociceptive pain. Nociceptive pain is mediated by activation of nociceptors (transduction) a~d transmission of electrochemical impulses along defined pathways to higher rostral centers. Modulation of afferent noxious input occurs at the level of the spinal cord. In contrast, neuropathic pain cannot occur de novo. By definition, the genesis of neuropathic pain implies damage to neural tissue. There are no predefined pathways, but pre-existent pathways may be damaged. Spontaneous discharge of damaged neurons or higher order neurons is responsible for the genesis of neuropathic pain. These changes become permanent because of the plasticity of the central nervous system. Despite these basic differences, nociceptive and neuropathic pain do share certain aspects of the physiologic processes of transduction, transmission, and modulation. While it is not the purpose of this article to exhaustibly review the neuroscience of neuropathic pain, it would be worthwhile to discuss some basic concepts. Nociceptors (nerves that transmit noxious impulses throughout the nervous system) differ from non-nociceptors in two discrete ways: ( I ) they are stimulated at higher threshaids than non-nociceptors, and (2) they have the ability to be sensitized. Sensitization refers to a decrease in the stimulation threshold as well as an increase in the magnitude of the response to that stimulation. Both peripheral and central nociceptors may become sensitized. Much has been written with respect to the central sensitization or "wind-up" of dorsal horn neurons. Release of excitatory amino acids (glutamate and aspartate) and neuropeptides (substance P, cal-
Prostate Cancer Gene Therapy Clinical Trials

Despite recent advances in early detection and treatment, prostate cancer is still the second leading cause of cancer death in men in the United States, and approximately 27,000 men will die from it this year. Better treatments are needed for aggressive forms of localized disease and hormone-refractory metastatic disease. Recently, several gene therapy strategies have generated provocative results in early-stage clinical trials, raising the possibility that gene therapy may have the potential to affect both localized and metastatic disease. Much work lies ahead. Nevertheless, for the time being, these studies provide hope that gene therapy may someday earn a place in the management of prostate cancer.
Showing and telling asthma: Children teaching physicians with visual narrative

In this article we examine an innovative application of visual communication and social science methods, moving the study of indigenous media from the purely academic realm into pediatric health research. Through Video Intervention/Prevention Assessment (VIA), children and adolescents who share a medical condition create visual narratives of their lives with chronic disease to show and tell their illness experiences to health care providers. Clinicians routinely plan medical management with limited knowledge of how patients interact with disease in their “real life” physical, psychological, and social environments. VIA asks young patients to teach clinicians the realities of day‐to‐day life with illness, yielding unique insights that can guide the development of more realistic, more humane, and ultimately more effective medical care. We describe the VIA methodology, a pilot study of asthma, and the illness experiences shown and told by VIA Asthma participants. Not only did VIA generate useful research fin...
Interstaple Dithiol Cross-Linking in Au25(SR)18 Nanomolecules: A Combined Mass Spectrometric and Computational Study

A systematic study of cross-linking chemistry of the Au25(SR)18 nanomolecule by dithiols of varying chain length, HS–(CH2)n–SH where n = 2, 3, 4, 5, and 6, is presented here. Monothiolated Au25 has six [RSAuSRAuSR] staple motifs on its surface, and MALDI mass spectrometry data of the ligand exchanged clusters show that propane (C3) and butane (C4) dithiols have ideal chain lengths for interstaple cross-linking and that up to six C3 or C4 dithiols can be facilely exchanged onto the cluster surface. Propanedithiol predominately exchanges with two monothiols at a time, making cross-linking bridges, while butanedithiol can exchange with either one or two monothiols at a time. The extent of cross-linking can be controlled by the Au25(SR)18 to dithiol ratio, the reaction time of ligand exchange, or the addition of a hydrophobic tail to the dithiol. MALDI MS suggests that during ethane (C2) dithiol exchange, two ethanedithiols become connected by a disulfide bond; this result is supported by density functional t...
Fat and bone in children: Differential effects of obesity on bone size and mass according to fracture history

Fat mass predicts bone accrual in prepubertal children, but obese children have increased fracture risk. We hypothesised that bone size and mass would vary according to prior fracture in obese children. One hundred and three children (52 obese) underwent dual-energy X-ray absorptiometry (DXA) scanning of the lumbar spine, total body, and radial metaphysis and diaphysis. We derived body size-adjusted bone mineral density (BMD) estimates for each site using commonly employed procedures. Following adjustment for either age, age(2) and weight, or height and weight based on a reference group of nonobese controls without previous fracture, obese children with prior fracture showed a 0.8 to 1.2 SD reduction in total body areal BMD (aBMD), a 3.0 SD decrease in lumbar (L2-4) aBMD, and a 2.0 SD reduction in radial shaft aBMD. These changes were significant at p < .005. Lumbar volumetric BMD (vBMD) calculated by Carter and Kroger algorithms was significantly reduced in obese children with prior fracture (2.0 to 3.3 SD). Eighteen percent of obese children fulfilled the criteria for osteoporosis. Despite greater lean mass for height in obese children (p < .0001), total body bone mineral content (BMC) for lean mass was reduced (p = .002). Multiple regression models adjusting for height, weight, and gender demonstrated an inverse relationship between total body fat mass and total body, lumbar, and ultradistal radius BMC and aBMD. The data suggest that fat mass substantially inhibits bone accrual in children with prior fracture. These children may require targeted interventions to increase bone mass during adolescence to achieve optimal peak bone mass and reduce the risk of osteoporosis later in life.
Use of a three-phase model with hydroxypropyl-βy̧clodextrin for the direct determination of large octanol-water and cyclodextrin-water partition coefficients

Abstract A shake-flask method is presented which uses a three-phase model to measure octanol-water and cyclodextrin-water partition coefficients. Equations are derived which account for all equilibria and which relate the cyclodextrin-water partition coefficient to the formation constant for a cyclodextrin-solute complex. The partition coefficients of three aromatic solutes were determined and these values compared well with previously published partition coefficients. Solute concentration was determined using liquid chromatography.
A robust approach for automatic registration of aerial images with untextured aerial LiDAR data

Airborne LiDAR technology draws increasing interest in large-scale 3D urban modeling in recent years. 3D LiDAR data typically has no texture information. To generate photo-realistic 3D models, oblique aerial images are needed for texture mapping, in which the key step is to obtain accurate registration between aerial images and untextured 3D LiDAR data. We present a robust automatic registration approach. A novel feature called 3CS is proposed which is composed of connected line segments. Putative line segment correspondences are obtained by matching 3CS features detected from both aerial images and 3D LiDAR data. Outliers are removed with a two-level RANSAC algorithm that integrates local and global processing to improve robustness and efficiency. The approach has been tested on 2290 aerial images that cover a variety of urban environments in Oakland and Atlanta areas. Its correct pose recovery rate is over 98%.
Incorporating ethics in computing courses extra class activities

Teaching ethics in undergraduate computing-oriented courses is important because the specific nature of the development and application of software products affects the professional and personal interests of so many people. Two different approaches in teaching ethics for computer science and information systems students are described here. The first approach consists of incorporating ethical concepts into the teaching material of several computing courses. The second approach implements miscellaneous forms of extra class activities. Both approaches can be united through service learning applications related to the respective academic community. The description of practical solutions relevant to the different methods of teaching cyberethics is discussed.
The application of MEMS technology for adaptive optics in vision science

Recent years have seen remarkable results in high-resolution imaging and testing of the human visual system. The ability to obtain in vivo images of the human fundus on the micrometer scale will allow for much earlier diagnosis and treatment of a range of retina diseases. These advances have been made possible in part through the use of adaptive optics (AO). In order to utilize the full numerical aperture and, hence, maximize the resolution of the eye, it is necessary to provide a means of correcting all of the ocular aberrations. The concept of AO has been used successfully to overcome this difficulty. A key component of such a system is an optical element that can be deformed to provide high-order correction of these aberrations. Existing AO systems make use of deformable mirrors that were developed for large ground-based telescopes. In a drive to reduce their size and cost, fabrication of this element using microelectromechanical systems (MEMS) has been actively pursued. This paper explains the challenges in high-resolution imaging of the human eye and details how MEMS technology has been used to further research in this area.
Changes in estimated right ventricular systolic pressure predict mortality and pulmonary hypertension in a cohort of scleroderma patients

Objectives Annual echocardiography screening is widely used in scleroderma, but the utility of longitudinal assessment is unknown. We evaluated whether change in right ventricular systolic pressure (RVSP) was a risk factor for mortality and development of pulmonary arterial hypertension (PAH) in a cohort of scleroderma patients. Methods The study population consisted of scleroderma patients who had at least three echocardiograms and pulmonary function tests (PFTs) over ≥1 year as part of routine care. The annual rate of change in RVSP was determined for each subject. Cox proportional hazards regression was performed to assess the association between PAH and mortality and change in RVSP/year, adjusted for relevant covariates. Results 613 scleroderma patients with 3244 echocardiograms were studied. The adjusted relative hazards of PAH and mortality were 1.08 (95% CI 1.05–1.11) and 1.12 (95% CI 1.08–1.15) per 1 mm Hg increase in RVSP/year, respectively. Compared with patients with a stable RVSP, the relative hazards for the development of PAH were 1.90 (95% CI 0.91–3.96), 5.09 (95% CI 2.53–10.26) and 6.15 (95% CI 3.58–10.56) for subjects whose RVSP increased at rates of 1–1.99, 2–2.99 and 3+ mm Hg/year. Compared with the same reference group, the relative hazards for death were 0.92 (95% CI 0.48–1.73), 2.16 (95% CI 1.16–4.01) and 5.05 (95% CI 3.47–7.34) for subjects whose RVSP increased at rates of 1–1.99, 2–2.99 and 3+ mm Hg/year. Conclusions In a population of scleroderma patients, the rate of increase in RVSP is a risk factor for mortality and PAH even after adjustment for clinical characteristics and longitudinal PFT data.
RITUAL: a performance driven placement algorithm

An algorithm for obtaining a placement of large scale cell-based ICs subject to performance constraints is described. The problem is formulated as a constrained programming problem and is solved in two phases: continuous and discrete. Constraints are placed on total path delays including cell and interconnect delays, and the behavior of all the paths is captured. Mathematical techniques and heuristics based on Lagrangian relaxation are used to find an approximate solution to the constrained problem. The algorithm yields good results, as shown on a set of real examples. On the average, between 8% and 30% improvement in the interconnect delay of these examples is obtained with little or no impact on chip area after routing by modifying the placement alone. >
Use of intracardiac echocardiography for prediction of chronic pulmonary vein stenosis after ablation of atrial fibrillation.

Prediction of PV Stenosis After Ablation.Introduction: Measurements of pulmonary vein (PV) flow with intracardiac echocardiography (ICE) immediately before and after PV isolation may be a useful method for predicting which patients will develop chronic PV stenosis. Methods and Results: We assessed preablation and postablation flows in each of the four PVs using a phase-array ICE catheter in 95 patients (mean age 52 ± 13) undergoing atrial fibrillation ablation. The ostium of each of the PVs was defined using angiography, electrical mapping, and ICE imaging. Ostial electrical isolation of all PVs was achieved using a 4-mm cooled-tip radiofrequency ablation catheter. Change in PV flow, when present, was examined as both an absolute value and as a percentage of the baseline flow. All patients underwent spiral computed tomography (CT) scans of the PVs 3 months after the procedure for detection of stenosis. The average preablation diastolic flows for the left superior, left inferior, right superior, and right inferior veins were 0.56, 0.54, 0.47, and 0.45 m/sec, respectively. These values increased to 0.74, 0.67, 0.58, and 0.59 m/sec postablation (P 70%) stenosis, 13 (3%) with moderate (51%–70%) stenosis, and 62 (16%) with mild (≤ 50%) stenosis. The r value between flow and stenosis was only 0.09 (P = NS). Conclusion: Acute changes in PV flow immediately after ostial PV isolation do not appear to be a strong predictor of chronic PV stenosis.
Thermal resistance of human malignant melanoma modulated by prostaglandin E2

The inhibition of DNA synthesis in a human malignant melanoma cell line as measured by tritiated thymidine (3H-TdR) incorporation was both time- and temperature dependent. Two components of cell damage were identified: a cytostatic, temporary component from which cells recovered within 2-6 days, and a cytotoxic, permanent component from which no recovery was observed. Thermotolerance was induced in M14 cells by sublethal heat treatment at 41 degrees C for 1 hr. However, induction of thermotolerance was blocked by indomethacin, a prostaglandin synthetase inhibitor. Exogenous PGE2 at concentrations up to 10 micrograms/ml also protected cells from heat damage. These data suggest that prostaglandin synthesis increases during heat stress and may play a role in protecting cells from thermal damage.
CHILDREN'S PERSON PERCEPTION: THE GENERALIZATION FROM TELEVISION PEOPLE TO REAL PEOPLE

This study investigated children's perceptions of television people and the extent to which these perceptions are generalized to impressions of peers. Elementary school children (W=172) completed questionnaires measuring viewing, knowledge of, identification with, and the perceived reality of television characters, and ratings of peers on 11 traits (e.g., funny, attractive, kind, nice). Two criterion variables were studied: children's mean rating of peers on each of the traits and the variance in the ratings of peers on each trait. Multiple regression analyses (controlling for grade and sex) revealed that: (1) identification with television characters was a significant predictor of the mean evaluation of peers on the traits; (2) television viewing was a significant predictor of the variance in children's ratings of peers; and (3) the relationship between television viewing and the variance in trait ratings was lower for attributes found in past studies to be suggested by television presentations. Implications of these findings for the traditional concern that television standardizes perceptions of people through stereotyping are considered.
Obliteration of the tympanomastoid cavity: long term results of the Rambo operation.

Introduction Radical mastoidectomy and tympanomastoid obliteration with fat tissue, also called the Rambo operation, is proposed to those patients suffering chronic middle-ear disease, with or without cholesteatoma, who have no useful hearing in an ear which cannot be kept dry despite all conservative treatment. Methods We analysed retrospectively a series of 46 patients operated upon in our department. Information recorded included the surgical indications, surgical observations, post-operative care and complications. All patients were invited to comment on their long term anatomical and functional results and to express their degree of satisfaction with the procedure. Results Recurrent infectious episodes were observed in seven cases. Residual cholesteatoma were observed in three cases. After treatment, these patients did not present with further complications. One case presented with multiple episodes of infection with recurrences of cholesteatoma and finally had the obliterated cavity transformed into an open cavity again. For most of the patients, in the long term (i.e. one to 23 years post-operatively (mean eight years)), the operation resulted in a dry ear, ending the need for frequent consultations to clean and disinfect diseased ears or open cavities. Conclusion Obliteration of the tympanomastoid cavity, as proposed by Tom Rambo, shortens considerably the post-operative care period, in comparison with canal wall down mastoidectomy, and is therefore indicated if no serviceable hearing can be expected. In the long term, the rate of complications is low and patients are satisfied.
Evaluative and hedonic wellbeing among those with and without children at home

We document and interpret differences in life evaluation and in hedonic experience between those who live with children and those who do not; most previous literature has concluded that those with children have worse lives. For a sample of 1.8 million Americans of all ages, and without controls for other circumstances, we find little difference in subjective wellbeing between people with and without children. Among those most likely to be parents, life evaluation and all hedonic experiences except stress are markedly better among those living with a child. However, within this group, people who live with children are more likely to be married, richer, better educated, more religious, and healthier, all of which have well-documented positive associations with evaluative and hedonic wellbeing. With statistical controls for these background factors, the presence of a child has a small negative association with life evaluation, although it is associated with more of both positive and negative hedonics. These patterns are replicated in the English-speaking countries of the world, but not in other regions. We argue that the causal effect of children on parental wellbeing, which is the target for most of the literature, is not well defined. Instead, we interpret our rich-country results within a theory of children and wellbeing in which adults sort into parenthood according to their preferences. In poor, high-fertility countries, we find evidence that at least some people have children even when it diminishes their personal wellbeing.
Fate of oxytetracycline in streams receiving aquaculture discharges: Model simulations

The potential aquatic fate of oxytetracycline (OTC) in streams receiving discharge from fish hatcheries was examined using the Water-Quality Analysis Simulation Program (WASP, Ver 6.1) model. The modeled 4.4-km stream network included a settling pond, a receiving segment, and two downstream segments. Attainment of quasi-steady state concentrations (concentration variation, <7.5 mg kg(-1)) in the sediment layers of the receiving segment and first downstream segment required several years. Median water-column concentrations (truly dissolved and colloid- and particle-associated) were 0, 0.57, 0.80, and 0.83 ng L(-1) in the settling pond, receiving segment, first downstream segment, and second downstream segment. Truly dissolved fractions in the water column during dosing were 16% in the settling pond, 64% in the receiving segment, and approximately 78% in the river segments. Concentrations declined 20- to 400-fold, depending on the segment considered, within 1 d of dosing. Truly dissolved fractions in the water column after cessation of dosing were 96% in the settling pond and approximately 78% in the river segments. Expected sediment-bound concentrations were approximately 4 mg kg(-1) in the receiving segment during dosing, with a median annual concentration of approximately 1.5 mg kg(-1) . Expected concentrations in downstream sediments were 0.2 mg kg(-1) or less. Sensitivity analyses indicated the most important factors influencing fate under the hydrodynamic conditions simulated were settling-pond biosolids load, biosolids settling velocity, OTC depuration kinetics from biosolids, and OTC river particle-water distribution coefficient(s).
Identification and characterization of intestinal antigen-presenting cells involved in uptake and processing of a nontoxic recombinant chimeric mucosal immunogen based on cholera toxin using imaging flow cytometry.

Intragastric immunization with recombinant chimeric immunogen, SBR-CTA2/B, constructed from the saliva-binding region (SBR) of Streptococcus mutans antigen AgI/II and the A2/B subunits of cholera toxin (CT) induces salivary and circulating antibodies against S. mutans that protect against dental caries. We previously found that SBR-CTA2/B activated dendritic cells (DC) in the Peyer's patches (PP) and mesenteric lymph nodes (MLN). To identify the cells involved in the intestinal uptake of SBR-CTA2/B and the initiation of immune responses, mice were immunized intragastrically with fluorescein-labeled SBR-CTA2/B or SBR, and intestinal cells were examined by imaging flow cytometry after fluorescent staining for cell surface markers. SBR-CTA2/B was preferentially taken up by CD103+ DC in the PP and by both CD103+ and CD11c+ DC in intestinal lamina propria (LP), whereas SBR was taken up to a lesser extent by PP CD11c+ DC, within 2 to 16 h. By 16 h, CD103+ and CD11c+ DC containing fluorescein-labeled SBR-CTA2/B were found in MLN and showed upregulation of the chemokine receptor CCR7. Large numbers of SBR-CTA2/B-containing DC were found interacting with CD4+ (T helper) cells, which costained for nuclear transcription factors T-bet or RORγt, identifying them as Th1 or Th17 cells. In contrast, SBR-containing CD11c+ DC interacted preferentially with GATA3+ (Th2) cells. No SBR- or SBR-CTA2/B-containing DC were found interacting with Foxp3+ (T regulatory) cells. We conclude that the coupling of SBR to CTA2/B enhances its immunogenicity by promoting uptake by DC in both PP and LP and that these antigen-containing DC migrated to MLN and interacted preferentially with Th1 and Th17 cells to induce active immune responses.
A Multiscale Assessment of Den Selection by Black Bears in Louisiana

Abstract Understanding den selection for the federally threatened Louisiana black bear (Ursus americanus luteolus) will assist managers in effectively managing bear populations and the landscapes they inhabit. We assessed den selection of 72 female Louisiana black bears at multiple spatial scales in northern and central Louisiana, USA. We used 230 den-years to examine den type preference, microhabitat characteristics of dens, and effects of landscape characteristics on den selection. We also evaluated reuse of tree dens and their availability across several study areas. Bears selected tree dens more frequently (65%) than ground dens. Most (55%) ground dens were associated with standing or downed trees, and most tree dens were in baldcypress (Taxodium distichum; 86%) or surrounded by water (80%). Selection of ground dens was positively associated with landscape metrics related to presence of water, whereas selection of tree dens was positively associated with proximity to edge and greater proportions of sw...
Metabolism of volatile compounds by lactic starter culture microorganisms. A review.

Abstract Cultured dairy products are accepted by the consumer primarily on the basis of flavor. During the last several years there has been a rapid proliferation of knowledge on the flavor compounds produced and utilized by starter culture organisms. This has led to a more thorough understanding of cultured product flavors and the role of starter bacteria in formation and degradation of these flavors. Volatile compounds produced by the common lactic culture organisms include acetaldehyde, diacetyl, ethanol, and volatile organic acids. Acetaldehyde arises from decarboxylation of pyruvate and it can be reduced to ethanol. Diacetyl is produced by citrate-fermenting organisms whieh also are able to reduce this compound to odorless products. Some of these organisms produce acetic acid by hydrolysis of acetylphosphate and by cleavage of citrate. This paper attempts to discuss recent findings in this area with reference to the most common microorganisms found in lactic starter cultures. A section on practical aspects of culture selection based on flavor compound production is included.
Cyclin alterations in diverse cancers: Outcome and co-amplification network

Cyclin genes are key regulatory components of the cell cycle. With the development of new agents, cyclin-related genes are becoming increasingly important as they can be targeted. Yet, the biological implications of these alterations have not been fully studied. Clinical characteristics and outcome parameters were compared for patients harboring cyclin alterations versus not. CCN alterations were found in 13% of our population (50/392; all amplifications) and were associated with breast cancer (P < 0.0001), a higher median number of concomitant molecular alterations (P < 0.0001), and liver metastases (P = 0.046). Harboring a cyclin amplification was not associated with overall survival, the time to metastasis/recurrence, nor with the best progression-free survival. In a Cox regression model, gastrointestinal histology (P < 0.0001), PTEN (P < 0.0001), and CDK alterations (P = 0.041) had a significant association with poorer overall survival. CCN amplifications significantly correlated with alterations in FGF/FGFR family genes as well as in MET and ARFRP1. An extended correlation study shed light on a network of co-amplifications influenced in part by genes that were localized on the same amplicons. CCN amplifications are common across cancers and had distinctive biological associations. Customized combinations targeting the cyclin pathway as well as the extended co-amplification network may be necessary in order to address resistance mechanisms.
Quantitative imaging of magnesium distribution at single-cell resolution in brain tumors and infiltrating tumor cells with secondary ion mass spectrometry (SIMS)

Glioblastoma multiforme (GBM) is one of the deadliest forms of human brain tumors. The infiltrative pattern of growth of these tumors includes the spread of individual and/or clusters of tumor cells at some distance from the main tumor mass in parts of the brain protected by an intact blood–brain-barrier. Pathophysiological studies of GBM could be greatly enhanced by analytical techniques capable of in situ single-cell resolution measurements of infiltrating tumor cells. Magnesium homeostasis is an area of active investigation in high grade gliomas. In the present study, we have used the F98 rat glioma as a model of human GBM and an elemental/isotopic imaging technique of secondary ion mass spectrometry, a CAMECA IMS-3f ion microscope, for studying Mg distribution with single-cell resolution in freeze-dried brain tissue cryosections. Quantitative observations were made on tumor cells in the main tumor mass, contiguous brain tissue, and infiltrating tumor cells in adjacent normal brain. The brain tissue contained a significantly lower total Mg concentration of 4.70 ± 0.93 mmol/kg wet weight (mean ± SD) in comparison to 11.64 ± 1.96 mmol/kg wet weight in tumor cells of the main tumor mass and 10.72 ± 1.76 mmol/kg wet weight in infiltrating tumor cells (p < 0.05). The nucleus of individual tumor cells contained elevated levels of bound Mg. These observations have established that there was enhanced influx and increased binding of Mg in tumor cells. They provide strong support for further investigation of altered Mg homeostasis and activation of Mg-transporting channels in GBMs as possible therapeutic targets.
Complete Genome Sequence of Kocuria palustris MU14/1.

ABSTRACT Presented here is the first completely assembled genome sequence of Kocuria palustris, an actinobacterial species with broad ecological distribution. The single, circular chromosome of K. palustris MU14/1 comprises 2,854,447 bp, has a G+C content of 70.5%, and contains a deduced gene set of 2,521 coding sequences.
Surgical Management of Esophageal Perforation

Esophageal perforations remain a challenging problem with significant morbidity and mortality. Accurate diagnosis to isolate the location and etiology of the injury, as well as associated upper gastrointestinal pathologies is vital to determine appropriate, prompt treatment plan. Management options include nonoperative resuscitation and medical management, endoscopic stenting and thoracoscopic decortication, primary repair with tissue flap buttress or esophageal diversion ± resection. Posterolateral thoracotomy and primary repair of the injury with reinforcement with a pedicled tissue flap is historically considered the standard treatment by which other treatments are measured. The thoracic surgeon should be skilled in all potential treatment algorithms to provide the best outcome for the patient in these difficult clinical scenarios.
Abstract 205: Protective Role for B-1 B Cells and IgM Antibodies in Obesity

Innate B-1 B cells can protect against inflammatory disease through production of natural IgM antibodies, but little is known regarding their role in obesity-induced metabolic dysfunction. In this study, we explore the role murine B-1 B cells play in regulating diet-induced glucose intolerance. In addition, we examine bariatric surgery samples for the presence of B cells in human adipose tissue and circulating natural IgM antibodies. We show that mice with increased visceral adipose tissue B-1b B cells due to B cell specific deletion of Id3 (Id3BcellKO) have attenuated high-fat diet-induced glucose intolerance compared to littermate controls. Omental visceral adipose tissue from Id3BcellKO mice had enhanced local natural IgM antibody secretion (49.0 ± 5.9 vs. 17.5 ± 4.2 U/mg fat), and demonstrated attenuated HFD-induced secretion of TNFa (2.5 ± 0.3 vs. 6.7 ± 1.3 pg/mg fat) and IFNg (0.10 ± 0.02 vs. 0.48 ± 0.14 pg/mg fat). Adoptive transfer of B-1b B cells null for Id3 protected against diet-induced glucose intolerance in Rag1-/- hosts, while B-1b B cells unable to secrete IgM had no effect. Additional studies in humans undergoing bariatric surgery showed CD20+CD27+CD43+ B cells, previously shown to have B-1-like characteristics, within omental adipose tissue. A correlation was found between their presence and serum natural IgM levels (r=0.52). In addition, natural IgM levels were inversely associated with the inflammatory chemokine, MCP-1 (r=-0.21). Finally, IgM, but not IgG, natural antibodies were inversely associated with insulin resistance (r=0.32). Together, our findings provide the first evidence that B-1b B cells protect against diet-induced glucose intolerance in an IgM-dependent manner in mice, and suggest that anti-inflammatory natural IgM antibodies may modulate the inflammatory and metabolic consequences of obesity in humans.
Synthesis of Biotinylated Inositol Hexakisphosphate To Study DNA Double-Strand Break Repair and Affinity Capture of IP6-Binding Proteins

Inositol hexakisphosphate (IP6) is a soluble inositol polyphosphate, which is abundant in mammalian cells. Despite the participation of IP6 in critical cellular functions, few IP6-binding proteins have been characterized. We report on the synthesis, characterization, and application of biotin-labeled IP6 (IP6-biotin), which has biotin attached at position 2 of the myo-inositol ring via an aminohexyl linker. Like natural IP6, IP6-biotin stimulated DNA ligation by nonhomologous end joining (NHEJ) in vitro. The Ku protein is a required NHEJ factor that has been shown to bind IP6. We found that IP6-biotin could affinity capture Ku and other required NHEJ factors from human cell extracts, including the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XRCC4, and XLF. Direct binding studies with recombinant proteins show that Ku is the only NHEJ factor with affinity for IP6-biotin. DNA-PKcs, XLF, and the XRCC4:ligase IV complex interact with Ku in cell extracts and likely interact indirectly with IP6-biotin. IP6-biotin was used to tether streptavidin to Ku, which inhibited NHEJ in vitro. These proof-of-concept experiments suggest that molecules like IP6-biotin might be used to molecularly target biologically important proteins that bind IP6. IP6-biotin affinity capture experiments show that numerous proteins specifically bind IP6-biotin, including casein kinase 2, which is known to bind IP6, and nucleolin. Protein binding to IP6-biotin is selective, as IP3, IP4, and IP5 did not compete for binding of proteins to IP6-biotin. Our results document IP6-biotin as a useful tool for investigating the role of IP6 in biological systems.
Standardization of the δ-Endotoxin Produced by Several Varieties of Bacillus thuringiensis. 1. Enzyme Kinetics of the Trypsin-Azoalbumin- δ-Endotoxin System

Studies on the kinetics of the inhibition of bovine pancreatic trypsin by the δ-endotoxin produced by Bacillus-thuringiensis var. dendrolimus Talalaev revealed that the probable action is the reversible mixed type (partially competitive and partially noncompetitive) whereby Km and Vm are both affected, and the trypsin-δ-endotoxin-azoalbumin complex formed breaks down at a rate greater than the trypsin-azoalbumin complex at high substrate concentration. The investigations of other workers on the degradation of the δ-endotoxin by proteolytic enzymes are also discussed.
Early results of Charnley-Müller total hip reconstruction.

SUMMARY The early results of a prospective study of 80 cases of Charnley-Muller total hip arthroplasty are reported. The two year follow-up shows good or excellent results in more than 90 per cent of the cases. The most impressive gains were achieved in relief of pain, enhanced functional capacity, and improved hip motion. It is mandatory to recognize that overenthusiasm for total hip reconstruction can easily occur. All forms of treatment of the arthritic hip must be carefully considered by the orthopedic surgeon, and he must maintain his perspective when adding total hip joint reconstruction to his therapeutic choices.
Cysts of the Tunica Albuginea Testis: A Report of 3 Cases with a Review of the Literature

AbstractWe report 3 cases of cysts of the tunica albuginea. A review of the literature yielded only 12 similar cases. In all cases described testicular neoplasm was suspected preoperatively and orchiectomy was planned. We used a conservative surgical approach that permitted preservation of the testes.
State Characteristics and Economic Internationalization

The American states differ widely in their economic characteristics and capabilities and their international orientation (“outward look”), which, in combination, may affect their relative competitiveness and performance in international economic activities. The present paper focused on state characteristics associated with two important elements of state economic internationalization: inward foreign direct investment and export intensity. Multivariate analyses identified two state characteristics that are significantly related to both elements of economic internationalization: lower levels of unionization and state spending targeted for promoting international economic activities (e.g. trade development, export promotion, inward/outward foreign direct investment). On the other hand, different sets of other state characteristics were found to be associated with high performance on the two selected elements of internationalization: lower state and local taxes, better interstate and airport infrastructure capabilities and higher consumer buying power were associated with higher inward foreign direct investment, while higher patent registrations, extensive water transportation capabilities, higher hourly wages and higher state and local taxes were associated with higher export intensity of the states. Further research is underway to examine the consistency of the findings for specific groups of industries and trading partner countries.
Struggle for Identity: The Bavarian People’s Party and Federalist Reichsreform, 1919–33

The problem of Bavaria’s relationship to the German Reich in the twentieth century is one whose roots may be found in the establishment of the German Empire in 1871. In that year Bavaria already possessed a tradition reaching back to the eighth century, a tradition from which, for all its vagaries, she consciously drew self-identity and a sense of purpose in German affairs. Historically the strongest and most influential south German state, excepting only Austria, Bavaria had grown from an early medieval geographic core bounded roughly by the rivers Lech, Danube, Inn, Salzach, and the spine of the Alps. On to this core were grafted, over time, substantial areas of Swabia and Franconia, these acquisitions being primarily the results of Bavaria’s involvement in the great-power politics of France, Prussia and Austria. Becoming in the nineteenth century a monarchy in her own right, Bavaria was linked to the North German Confederation in an offensive/defensive alliance following the Austro-Prussian War. When, in 1871, Bavaria joined the German Empire, it was only on the condition that the member states be granted special rights and privileges under the terms of the federal constitution of the Reich.
Genomic control of neuronal demographics in the retina

The mature retinal architecture is composed of various types of neuron, each population differing in size and constrained to particular layers, wherein the cells achieve a characteristic patterning in their local organization. These demographic features of retinal nerve cell populations are each complex traits controlled by multiple genes affecting different processes during development, and their genetic determinants can be dissected by correlating variation in these traits with their genomic architecture across recombinant-inbred mouse strains. Using such a resource, we consider how the variation in the numbers of twelve different types of retinal neuron are independent of one another, including those sharing transcriptional regulation as well as those that are synaptically-connected, each mapping to distinct genomic loci. Using the populations of two retinal interneurons, the horizontal cells and the cholinergic amacrine cells, we present in further detail examples where the variation in neuronal number, as well as the variation in mosaic patterning or in laminar positioning, each maps to discrete genomic loci where allelic variants modulating these features must be present. At those loci, we identify candidate genes which, when rendered non-functional, alter those very demographic properties, and in turn, we identify candidate coding or regulatory variants that alter protein structure or gene expression, respectively, being prospective contributors to the variation in phenotype. This forward-genetic approach provides an alternative means for dissecting the molecular genetic control of neuronal population dynamics, with each genomic locus serving as a causal anchor from which we may ultimately understand the developmental principles responsible for the control of those traits.
Approaches to Environmental Education

This chapter provides an overview of various approaches that exist within the field of environmental education (EE). Like science education, environmental education is an interdisciplinary and complex field that offers a multitude of strategies for learning, dependent on the variables of resources, time, space, curriculum, student characteristics, plus a full range of factors that can affect any kind of educational implementation. Seven approaches are briefly described: EE and the schoolyard; place-based education; the Projects curricula (PLT, WILD, and WET) and Population Connection; science and EE in nature centers, zoos, and museums; investigating and evaluating environmental issues and actions; action research and EE; and the Science-Technology-Society approach to EE. Each of these approaches individually addresses several important goals of EE, but none of these is totally prescriptive or comprehensive. There are many different EE teaching and learning approaches one can select from. It is up to the individual educator to select and apply the approach that will be most effective in specific settings.
Urban energy flux: Spatiotemporal fluctuations of building energy consumption and human mobility-driven prediction

Urbanization is causing a significant increase in the amount, diversity, and complexity of human activities, all of which have a substantial impact on energy consumption. Current approaches to predicting energy demand at different spatiotemporal levels are functions of the characteristics of either individual buildings or cities and their occupancy levels, or are data-driven, typically taking the form of sensor-based modeling. Nevertheless, accounting for both the spatial and temporal effects of heterogeneous human behavior patterns on buildings’ energy use at the city level remains a challenge. In this paper, we examine the temporal manifestation of the fluctuations of energy use in urban buildings driven by spatial mobility patterns of the population. We then present an urban-level spatiotemporal approach for predicting buildings’ energy demand. Using a full year of individual positional records from an online social networking platform (Twitter), we introduce a multivariate autoregressive model in reduced principle component analysis space to create monthly predictions of residential building electricity demand generated across 801 spatial divisions that account for 68% of the electricity used by buildings in the City of Chicago, through a spatial autoregressive model. This model represents an important step forward, incorporating the spatiotemporal energy use fluctuations of urban population activities to create more reliable predictions of demand in future cities.
Ascending aortic slide for interrupted aortic arch repair: a new approach to maintain native tissue continuity

Interrupted aortic arch (IAA) is characterized by the absence of luminal continuity between segments of the aortic arch and the proximal descending aorta (1,2). It is a rare congenital malformation that is often associated with a ventricular septal defect (VSD), and may coexist with severe intracardiac congenital anomalies such as common arterial trunk (CAT), transposition of the great arteries (TGA), aortopulmonary window (APW) or hearts with single ventricle connection (1-3).