Crystal field effect induced topological crystalline insulators in monolayer IV-VI semiconductors.
Two-dimensional (2D) topological crystalline insulators (TCIs) were recently predicted in thin films of the SnTe class of IV-VI semiconductors, which can host metallic edge states protected by mirror symmetry. As thickness decreases, quantum confinement effect will increase and surpass the inverted gap below a critical thickness, turning TCIs into normal insulators. Surprisingly, based on first-principles calculations, here we demonstrate that (001) monolayers of rocksalt IV-VI semiconductors XY (X = Ge, Sn, Pb and Y = S, Se, Te) are 2D TCIs with the fundamental band gap as large as 260 meV in monolayer PbTe. This unexpected nontrivial topological phase stems from the strong crystal field effect in the monolayer, which lifts the degeneracy between p(x,y) and p(z) orbitals and leads to band inversion between cation pz and anion px,y orbitals. This crystal field effect induced topological phase offers a new strategy to find and design other atomically thin 2D topological materials.


Microorganisms in the atmosphere over Antarctica.
Antarctic microbial biodiversity is the result of a balance between evolution, extinction and colonization, and so it is not possible to gain a full understanding of the microbial biodiversity of a location, its biogeography, stability or evolutionary relationships without some understanding of the input of new biodiversity from the aerial environment. In addition, it is important to know whether the microorganisms already present are transient or resident - this is particularly true for the Antarctic environment, as selective pressures for survival in the air are similar to those that make microorganisms suitable for Antarctic colonization. The source of potential airborne colonists is widespread, as they may originate from plant surfaces, animals, water surfaces or soils and even from bacteria replicating within the clouds. On a global scale, transport of air masses from the well-mixed boundary layer to high-altitude sites has frequently been observed, particularly in the warm season, and these air masses contain microorganisms. Indeed, it has become evident that much of the microbial life within remote environments is transported by air currents. In this review, we examine the behaviour of microorganisms in the Antarctic aerial environment and the extent to which these microorganisms might influence Antarctic microbial biodiversity.


Plenty of motion at the bottom: atomically thin liquid gold membrane.
The discovery of graphene some ten years ago was the first proof of a free-standing two-dimensional (2D) solid phase. Here, using quantum molecular dynamics simulations of nanoscale gold patches suspended in graphene pores, we predict the existence of an atomically thin, free-standing 2D liquid phase. The liquid phase, enabled by the exceptional planar stability of gold due to relativistic effects, demonstrates extreme fluxionality of metal nanostructures and opens possibilities for a variety of nanoscale phenomena.


Role of adenosine in norepinephrine-induced coronary vasodilation.
Adenosine has been postulated to be the physiological transmitter coupling increases in coronary blood flow to increases in myocardial metabolism. The purpose of this experiment was to evaluate the role of adenosine in the coronary hyperemia due to norepinephrine. In 11 anesthetized, closed-chest canine preparations, the left main coronary artery was cannulated and perfused with blood at 100 mmHg. Coronary blood flow and myocardial oxygen consumption were measured, and interstitial adenosine concentration was estimated from arterial and coronary venous measurements using a distributed model. Adenosine receptor blockade with 8-phenyltheophylline (8-PT) was used to shift the adenosine dose-response curve 12-fold. During intracoronary norepinephrine infusion, coronary blood flow and myocardial oxygen consumption increased similarly before and after 8-PT, demonstrating a lack of an effect from the adenosine receptor blockade. Before 8-PT, estimated interstitial adenosine increased to a vasoactive concentration (220 nM); however, the temporal correlation with coronary blood flow was poor. After 8-PT, a similar increase in estimated interstitial adenosine was found, demonstrating that there was no augmentation in adenosine concentration to overcome the adenosine receptor blockade. Thus adenosine could not be responsible for the increase in coronary blood flow after adenosine receptor blockade and therefore is not required for norepinephrine-induced hyperemia.


Variation in lymph node assessment after colon cancer resection: patient, surgeon, pathologist, or hospital?
Evaluation of ≥ 12 lymph nodes after colon cancer resection has been adopted as a hospital quality measure, but compliance varies considerably. We sought to quantify relative proportions of the variation in lymph node assessment after colon cancer resection occurring at the patient, surgeon, pathologist, and hospital levels. The 1998-2005 Surveillance, Epidemiology, and End Results-Medicare database was used to identify 27,101 patients aged 65 years and older with Medicare parts A and B coverage undergoing colon cancer resection. Multilevel logistic regression was used to model lymph node evaluation as a binary variable (≥ 12 versus <12) while explicitly accounting for clustering of outcomes. Patients were treated by 4,180 distinct surgeons and 2,656 distinct pathologists at 1,113 distinct hospitals. The overall rate of 12-lymph node (12-LN) evaluation was 48%, with a median of 11 nodes examined per patient, and 33% demonstrated lymph node metastasis on pathological examination. Demographic and tumor-related characteristics such as age, gender, tumor grade, and location each demonstrated significant effects on rate of 12-LN assessment (all P < 0.05). The majority of the variation in 12-LN assessment was related to non-modifiable patient-specific factors (79%). After accounting for all explanatory variables in the full model, 8.2% of the residual provider-level variation was attributable to the surgeon, 19% to the pathologist, and 73% to the hospital. Compliance with the 12-LN standard is poor. Variation between hospitals is larger than that between pathologists or surgeons. However, patient-to-patient variation is the largest determinant of 12-LN evaluation.


Evidence for a role of the plasminogen activator--plasmin system in corneal ulceration.
Plasminogen is present in the cornea andcan be activated to plasmin by plasminogen activator. Plasmin is able, in turn, to activate latent collagenase. This system could initiate and perpetuate the collagen degradation of corneal ulceration. This report details evidence for such a system in the cornea. Plasmin has been found to activate latent collagenase from organ cultures of ulcerating rabbit corneas and from fibroblast cultures derived from such corneas. As in the case of activation by trypsin, activation by plasmin results in the conversion of the 40,000 MW latent form to an active species of 23,000 MW. Explants of normal or alkali-burned, ulcerating corneas demonstrated plasminogen-dependent lysis of fibrin clots; frozen sections of such corneas demonstrated that lysis begins in the superficial stroma near the periphery of the cornea. Multiply freeze-thawed ulcerating corneas, but not normal corneas, showed initial lysis, not peripherally but at the ulcer region containing polymorphonuclear leukocytes. The fact that the peripheral lytic pattern existed in corneas that were obtained from eyes prefrozen in liquid nitrogen before excision of the corneas would suggest that plasminogen activator is normally contained in cells in vivo and is not made only in response to tissue injury. There was no correlation between the location of blood vessels or the presence of the corneal endothelium and the plasminogen-dependent lysis. Plasminogen activator from the ulcerating cornea and from fibroblasts was characterized by sodium dodecyl sulfate--gel electrophoresis of its cleavage products of plasminogen. The activator cleaves plasminogen into heavy- and light-chain fragments similar to those produced from plasminogen by urokinase. Plasminogen activator activity was quantitated by a new assay that restricts diffusion of the enzyme to one dimension into a narrow bore tube. The addition of plasminogen daily to cultures of ulcerating corneas resulted in earlier rises of plasminogen activator, collagenase, and collagen degradation fragments in the culture media. Although total plasminogen activator levels were not increased by the addition of plasminogen to culture, levels of both collagenase and solubilized collagen were approximately doubled. It is concluded that the plasminogen activator--plasmin system might play an important role in the destruction of stromal matrix in corneal ulceration.


Metformin for the treatment of hyperandrogenism in adolescents with type 1 diabetes mellitus.
A high prevalence of hyperandrogenism has been reported in women with type 1 diabetes (T1D). Metformin has been used as a therapeutic agent in patients with polycystic ovarian syndrome and in T1D patients without hyperandrogenism. This study sought to determine the effect of metformin on hyperandrogenism and ovarian function in adolescents with T1D. We recruited 24 girls with T1D. The participants had hyperandrogenism and displayed suboptimal metabolic control. The patients were enrolled in a randomized, double-blind, placebo-controlled trial. One group received metformin (850 mg bid) and the other group received a placebo. Treatment was administered for 9 months. Ovulation, steroids and gonadotropin levels were evaluated. Metformin treatment was associated with decreases in testosterone, free androgen index, androstenedione, 17-OH progesterone and estradiol levels. The girls who were treated with placebo showed stable steroid, gonadotropin and sex hormone-binding globulin levels during the analysis. No differences were observed in the Ferriman-Gallwey scores, ovulation rates, HbA1c levels or daily insulin doses of the girls treated with metformin compared with the placebo group. Treating hyperandrogenic T1D adolescents with metformin significantly decreased the serum androgens compared to the placebo, but metformin therapy did not significantly affect clinical parameters, such as hirsutism, ovulation and metabolic control.


High-throughput density-functional perturbation theory phonons for inorganic materials.
The knowledge of the vibrational properties of a material is of key importance to understand physical phenomena such as thermal conductivity, superconductivity, and ferroelectricity among others. However, detailed experimental phonon spectra are available only for a limited number of materials, which hinders the large-scale analysis of vibrational properties and their derived quantities. In this work, we perform ab initio calculations of the full phonon dispersion and vibrational density of states for 1521 semiconductor compounds in the harmonic approximation based on density functional perturbation theory. The data is collected along with derived dielectric and thermodynamic properties. We present the procedure used to obtain the results, the details of the provided database and a validation based on the comparison with experimental data.


Achalasia: a systematic review.
Achalasia significantly affects patients' quality of life and can be difficult to diagnose and treat. To review the diagnosis and management of achalasia, with a focus on phenotypic classification pertinent to therapeutic outcomes. Literature review and MEDLINE search of articles from January 2004 to February 2015. A total of 93 articles were included in the final literature review addressing facets of achalasia epidemiology, pathophysiology, diagnosis, treatment, and outcomes. Nine randomized controlled trials focusing on endoscopic or surgical therapy for achalasia were included (734 total patients). A diagnosis of achalasia should be considered when patients present with dysphagia, chest pain, and refractory reflux symptoms after an endoscopy does not reveal a mechanical obstruction or an inflammatory cause of esophageal symptoms. Manometry should be performed if achalasia is suspected. Randomized controlled trials support treatments focused on disrupting the lower esophageal sphincter with pneumatic dilation (70%-90% effective) or laparoscopic myotomy (88%-95% effective). Patients with achalasia have a variable prognosis after endoscopic or surgical myotomy based on subtypes, with type II (absent peristalsis with abnormal pan-esophageal high-pressure patterns) having a very favorable outcome (96%) and type I (absent peristalsis without abnormal pressure) having an intermediate prognosis (81%) that is inversely associated with the degree of esophageal dilatation. In contrast, type III (absent peristalsis with distal esophageal spastic contractions) is a spastic variant with less favorable outcomes (66%) after treatment of the lower esophageal sphincter. Achalasia should be considered when dysphagia is present and not explained by an obstruction or inflammatory process. Responses to treatment vary based on which achalasia subtype is present.


Sub-second dopamine detection in human striatum.
Fast-scan cyclic voltammetry at carbon fiber microelectrodes allows rapid (sub-second) measurements of dopamine release in behaving animals. Herein, we report the modification of existing technology and demonstrate the feasibility of making sub-second measurements of dopamine release in the caudate nucleus of a human subject during brain surgery. First, we describe the modification of our electrodes that allow for measurements to be made in a human brain. Next, we demonstrate in vitro and in vivo, that our modified electrodes can measure stimulated dopamine release in a rat brain equivalently to previously determined rodent electrodes. Finally, we demonstrate acute measurements of dopamine release in the caudate of a human patient during DBS electrode implantation surgery. The data generated are highly amenable for future work investigating the relationship between dopamine levels and important decision variables in human decision-making tasks.


Hitting a Moving Target: Glioma Stem Cells Demand New Approaches in Glioblastoma Therapy.
Glioblastoma multiforme (GBM) continues to devastate patients and outfox investigators and clinicians despite the preponderance of research directed at its biology, pathogenesis and therapeutic advances. GBM routinely outlasts multidisciplinary treatment protocols, almost inevitably recurring in a yet more aggressive and resistant form with distinct genetic differences from the original tumor. Attempts to glean further insight into GBM point increasingly toward a subpopulation of cells with a stem-like phenotype. These cancer stem cells, similar to those now described in a variety of malignancies, are capable of tumorigenesis from a population of susceptible cells. Glioma stem cells have thus become a prevalent focus in GBM research for their presumed role in development, maintenance and recurrence of tumors. Glioma stem cells infiltrate the white matter surrounding tumors and often evade resection. They are uniquely suited both biochemically and environmentally to resist the best therapy currently available, intrinsically and efficiently resistant to standard chemo- and radiotherapy. These stem cells create an extremely heterogenous tumor that to date has had an answer for every therapeutic question, with continued dismal patient survival. Targeting this population of glioma stem cells may hold the long-awaited key to durable therapeutic efficacy in GBM.


Accuracy and Usability of a Self-Administered 6-Minute Walk Test Smartphone Application.
The 6-minute walk test (6MWT) independently predicts congestive heart failure severity, death, and heart failure hospitalizations, but must be administered in clinic by qualified staff on a premeasured course. As part of the Health eHeart Study, we sought to develop and validate a self-administered 6MWT mobile application (SA-6MWTapp) for independent use at home by patients. We performed a validation study of an SA-6MWTapp in 103 participants. In phase 1 (n=52), we developed a distance-estimation algorithm for the SA-6MWTapp by comparing step counts from an Actigraph and measured distance on a premeasured 6MWT course with step counts and estimated distance obtained simultaneously from our SA-6MWTapp (best estimation algorithm, r=0.89 [95% confidence interval 0.78-0.99]). In phase 2, 32 participants (including those with congestive heart failure and pulmonary hypertension) used the SA-6MWTapp independently in clinic, and the distance estimated by the SA-6MWTapp was compared with the measured distance (r=0.83 [95% confidence interval 0.79-0.92]). In phase 3, 19 patients with congestive heart failure and pulmonary hypertension consecutively enrolled from clinic performed 3.2±1 SA-6MWTapp tests per week at home over 2 weeks. Distances estimated from the SA-6MWTapp during home 6MWTs were highly repeatable (coefficient of variation =4.6%) and correlated with in-clinic-measured distance (r=0.88 [95% confidence interval 0.87-0.89]). Usability surveys performed during the second (in-clinic) and third (at-home) phases demonstrated that the SA-6MWTapp was simple and easy to use independently. An SA-6MWTapp is easy to use and yields accurate repeatable measurements in the clinic and at home.


Coronary calcium scoring: are the results comparable to computed tomography coronary angiography for screening coronary artery disease in a South Asian population?
The need of having feasible screening tools like Coronary Calcium Scoring (CCS) and CT Coronary Artery (CTCA) for Coronary Artery Disease (CAD) has become paramount. We aimed to evaluate the accuracy of CCS in determining the degree of stenosis of coronary vessels as compared to that determined by CTCA in a South Asian population. A retrospective study was conducted at The Aga Khan University Hospital. A total of 539 patient records were reviewed who had undergone CCS and CTCA between 2008 and 2010. Patient records were reviewed by comparing their CCS and CTCA results. About 268 out of 301 (89%) patients with a CCS of 0-9 were found to be free of stenosis on CTCA. On a CCS of 10-99, 110 out of 121 (91%) patients were either free of stenosis or had mild stenosis. About 66 out of 79 (84%) patients had moderate or severe stenosis with a calcium score of 100-400 while none of the patients were free of stenosis. Around 28 out of 38 (74%) patients with a CCS of more than 400 had severe stenosis. However, only 04 patients (11%) were found to have mild stenosis. Spearman's rho revealed a correlation coefficient of 0.791 with a p-value of <0.001. Our study reaffirms that in South Asian population, low CCS (<100) is associated with no or minimal stenosis while high CCS warrants further investigation; hence, making it a reliable tool for screening patients with CAD.


Comparison of Quality Oncology Practice Initiative Metrics in Solid Tumor Oncology Clinic With or Without Concomitant Supportive Oncology Consultation.
The Quality Oncology Practice Initiative (QOPI) is a quality measurement and improvement program designed to assess practice performance for various consensus-based and evidence-based measures. In this study, we evaluated differences in QOPI metrics met among patients with advanced solid cancer receiving routine oncologic care alone (routine care) compared with patients receiving integrated oncology and specialty-level palliative care (supportive care). We conducted a retrospective chart review of 100 randomly selected patients treated between June 2013 and June 2015 from our supportive care group and matched these patients to 100 routine care group patients on the basis of tumor type and initial oncology visit date. We used the electronic medical record to collect data regarding patient demographics, palliative care-specific QOPI metrics, intensive care unit admissions, and hospice enrollment. We performed multivariate analysis comparing differences between the two groups. A total of 200 patients were included. Both groups had similar baseline characteristics. Supportive care consultation improved the absolute number of QOPI metrics met ( P = .01). The QOPI metrics more likely to be met included the following: pain appropriately addressed ( P < .01), advance care directives documented by third office visit ( P < .01), and longer hospice enrollment ( P < .01). Integrating palliative care consultation with routine oncologic care improved pain management and end-of-life planning and care. Properly addressing pain and guiding advance care discussions require specialized skills. These data support the need for increased primary palliative care education for oncologists and further development of supportive oncology practices.


Imaging of filter-grown epithelial cells: MDCK Na(+)-H+ exchanger is basolateral.
We report a simple method for growing epithelial cells on permeable supports and for imaging the cells from the apical side using an inverted microscope. Madin-Darby canine kidney (MDCK) cells were either seeded onto the conventional side of Millipore-CM filters or onto "inverted" filters. The peak transepithelial resistance of confluent monolayers was the same with either system. Cells on inverted filters that were stained with various dyes and imaged by epifluorescence exhibited more distinct intercellular spaces, cell margins, nuclei, and subapical vesicles. We also perfused both sides of inverted filters with HCO3/CO2-free saline and measured intracellular pH (pHi) using 2',7'-bis(2-carboxyethyl)-5,6-carboxyfluorescein (BCECF) and digital imaging. The intrinsic buffer capacity of MDCK cells increased exponentially as pHi decreased. After an NH4Cl load, the H+ extrusion rate (JH+) in control saline was 2.42 +/- 0.62 mM/min. JH+ was completely blocked by 1 mM basolateral amiloride. In contrast, 1 mM apical amiloride had no effect. We conclude that 1) growth of epithelial cells on an inverted filter system is useful for the microspectrofluorimetric determination of pHi in single cells and for the imaging of apical/subapical structures, and 2) the Na(+)-H+ exchanger of MDCK cells is functionally polarized to the basolateral membrane.


Effect of NaCl-stressed Bacillus thuringiensis (Bt) cotton on the feeding behaviors and nutritional parameters of Helicoverpa armigera.
Saline-alkali soil is an arable land resource on which transgenic Bacillus thuringiensis (Bt) cotton has been planted on a large scale in accordance with food security strategies. There are, however, concerns about the insecticidal effects of Bt cotton on target insect pests. In this study, a Bt cotton variety, GK19, and its nontransgenic parent variety, Simian-3, were used as experimental models for investigating the effect of the expression of exogenous insecticidal proteins in Bt cotton under NaCl stress on the feeding behavior and nutritional parameters of Helicoverpa armigera. The results showed that the expression of exogenous insecticidal proteins in GK19 was significantly inhibited under NaCl stress. However, the feeding, crawling, resting and spinning down behavior of the 5th instar H. armigera larvae on GK19 Bt cotton, as well as the amount of food consumed and feces produced by these larvae, did not markedly differ under different NaCl concentrations. In contrast, the mean relative growth rate (MRGR), relative growth rate (RGR), approximate digestibility (AD), efficiency of conversion of ingested food (ECI) and efficiency of conversion of digested food (ECD) of the larvae markedly decreased in response to NaCl stress. Under the same concentration of NaCl, the nutritional parameters of the bollworm larvae on GK19 Bt cotton or Simian-3 nontransgenic cotton were different. However, the interaction between salt stress and cotton variety had no significant effect on the feeding behavior or nutritional parameters of H. armigera larvae. These results may provide a scientific basis for determining the effect of exogenous insecticidal protein expression in Bt cotton under NaCl stress on H. armigera and can therefore be useful for the effective application of Bt cotton in saline-alkali soils to prevent and control H. armigera.


Contribution of blood flow to leg glucose uptake during a mixed meal.
Insulin has important effects to increase skeletal muscle (leg) blood flow under euglycemic hyperinsulinemic clamp conditions and after oral glucose tolerance testing. The present studies examined the effects of mixed meal consumption on the components of leg glucose uptake (LGU) in lean, healthy adults. Seventeen men and women underwent measures of leg plasma flow and arteriovenous (AV) glucose difference before and for 6 h after a mixed meal providing one-third of daily energy expenditure. Another eight men and women underwent the same studies before and during the consumption of the same-size meal administered in small frequent feedings over 6 h. After the bolus meal, peak leg AV glucose gradient increased approximately fivefold (P < 0.001), whereas the peak increase in leg plasma flow was 20% (NS). No significant contribution of increased leg blood flow to the increase in postprandial LGU was apparent. Over the last 100 min of the frequent-feedings meal, the leg AV difference increased approximately fourfold (P < 0.001 vs. basal), whereas leg blood flow increased only by 16% (NS vs. basal). We conclude that after a mixed meal, leg (primarily skeletal muscle) blood flow does not increase enough for blood flow to be a major contributor to glucose uptake. These findings raise questions regarding the relative importance of insulin's hemodynamic effects in modulating glucose tolerance under more usual conditions.


Deal making 2.0: a guide to complex negotiations.
Most big deals--megamergers, major sales, infrastructure projects--are built on a series of smaller ones. Each component deal presents a tactical challenge, but sequencing the parts in a way that achieves the target outcome is a strategic challenge that can unfold over months or years. This process, which the authors call a negotiation campaign, must generally be conducted on several fronts, each involving multiple parties. A multifront campaign can be much more effective than direct negotiation. After failed talks between Longshoremen and the Pacific Maritime Association--a group of shippers and port operators--the PMA's president turned away from the bargaining table and embarked on a campaign to align member-firms, the business community, the U.S. government, and the public around his target outcome: the deployment of new information technologies to help unclog busy ports. The result was an agreement that was ultimately mutually beneficial. Designing and executing a negotiation campaign involves identifying the relevant parties, grouping them into fronts according to shared interests, determining whether to combine fronts (if, for instance, doing so would unite your allies), and deciding which fronts to approach early on and which to engage only after you've made progress elsewhere. The deal between the PMA and the Longshoremen involved high stakes, but many small-scale deals--such as gaining approval for a new product--also play out on multiple fronts. Going straight to a key decision maker often makes sense, but in many cases a multifront campaign is the only way.


Pharmacokinetic parameters of nandrolone (19-nortestosterone) after intramuscular administration of nandrolone decanoate (Deca-Durabolin) to healthy volunteers.
Nandrolone decanoate (Deca-Durabolin) was injected intramuscularly into healthy volunteers. One group of females received one injection of 100 mg and three groups of males received one injection of 200 mg, two repeat injections of 100 mg or four repeat injections of 50 mg respectively. The serum levels of nandrolone (19-nortestosterone) were determined by radioimmunoassay and used to estimate pharmacokinetic parameters. The following pharmacokinetic parameters were found: a mean half-life of 6 days for the release of the ester from the muscular injection depot into the general circulation; a mean half-life of 4.3 h for the combined processes of hydrolysis of nandrolone decanoate and of distribution and elimination of nandrolone; a mean nandrolone serum clearance of 1.55 1 X h-1 X kg-1. The half-life of hydrolysis of nandrolone decanoate in serum was of the order of one hour or less. The data are consistent with linear kinetics.


Hydrogen sulfide determination by solid surface luminescence.
In the analytical system suggested, atmospheric hydrogen sulfide reacts with the surface of a filter paper treated with aqueous cadmium chloride and yields a luminescent species whose intensity can be correlated with the analyte concentration in ambient air. It was shown that the luminescent species are CdS solid particles which were formed in a well defined size. The paper luminescence was also tried on polymeric surfaces; polyethyleneoxide, polyvinyl alcohol, ethylcellulose and carboxymethylcellulose were found to give a similar luminescence signal. The system can be used on the tip of an optical fiber for an irreversible, cumulative type of analytical device for hydrogen sulfide determination. The 3s detection limit for the paper luminescence detection system was 7.8 ppb H(2)S.


Nomograms to predict survival and the risk for developing local or distant recurrence in patients with rectal cancer treated with optional short-term radiotherapy.
In many European countries, short-term 5 × 5 Gy radiotherapy has become the standard preoperative treatment of patients with resectable rectal cancer. Individualized risk assessment might allow a better selection of patients who will benefit from postoperative treatment and intensified follow-up. From patient's data from three European rectal cancer trials (N = 2881), we developed multivariate cox nomograms reflecting the risk for local recurrence (LR), distant metastases (DM) and overall survival (OS). Evaluated variables were age, gender, tumour distance from the anal verge, the use of radiotherapy, surgical technique (total mesorectal excision/conventional surgery), surgery type (low anterior resection/abdominoperineal resection), time from randomization to surgery, residual disease (R0 versus R1 + 2), pT-stage, pN-stage and surgical complications. Pathological T- and N-status are of vital importance for an accurate prediction of LR, DM and OS. Short-course radiotherapy reduces the rate of LR. The developed nomograms are capable of predicting events with a validation c-index of 0.79 (LR), 0.76 (DM) and 0.75 (OS). The proposed stratification in risk groups allowed significant distinction between Kaplan-Meier curves for outcome. The developed nomograms can contribute to better individual risk prediction for LR, DM and OS for patients operated on rectal cancer. The practicality of the defined risk groups makes decision support in the consulting room feasible, assisting physicians to select patients for adjuvant therapy or intensified follow-up.


PGRN exerts inflammatory effects via SIRT1-NF-κB in adipose insulin resistance.
Progranulin (PGRN), a multifunctional protein implicated in embryonic development and immune response, was recently introduced as a novel marker of chronic inflammation related with insulin resistance in obesity and type 2 diabetes mellitus. However, the potential mechanisms of PGRN on insulin signaling pathways are poorly understood. In this study, PGRN mediated the chemotaxis of RAW264.7, impaired insulin action and stimulated production of inflammatory factors in adipocytes, which was accompanied by increased c-Jun N-terminal kinase (JNK) activation and serine phosphorylation of insulin receptor substrate-1. PGRN knockdown partially led to an increase in insulin action as well as a decrease in the JNK activation and extracellular signal-regulated kinase phosphorylation in cells exposed to tumor-necrosis factor-α (TNF-α). Meanwhile, PGRN treatment resulted in an elevation of transcription factor nuclear factor κB (NF-κB) nuclear translocation and acetylation, and increased Il-1b, Il6, Tnf-a expression, whereas NF-κB inhibition reversed PGRN-induced insulin action impairment and inflammatory gene expression. Finally, we showed that sirtuin 1 (SIRT1) expression was downregulated by PGRN treatment, whereas SIRT1 overexpression improved PGRN-induced insulin resistance, NF-κB activation, and inflammatory gene expression. Our results suggest that PGRN regulates adipose tissue inflammation possibly by controlling the gain of proinflammatory transcription in a SIRT1-NF-κB dependent manner in response to inducers such as fatty acids and endoplasmic reticulum stress.


Long-term follow-up in patients with congenital myasthenic syndrome due to RAPSN mutations.
Rapsyn (RAPSN) mutations are a common cause of postsynaptic congenital myasthenic syndromes. We present a comprehensive description of the clinical and molecular findings of ten patients with CMS due to mutations in RAPSN, mostly with a long-term follow-up. Two patients were homozygous and eight were heterozygous for the common p.Asn88Lys mutation. In three of the heterozygous patients we have identified three novel mutations (c.869T > C; p.Leu290Pro, c.1185delG; p.Thr396Profs*12, and c.358delC; p.Gln120Serfs*8). In our cohort, the RAPSN mutations lead to a relatively homogeneous phenotype, characterized by fluctuating ptosis, occasional bulbar symptoms, neck muscle weakness, and mild proximal muscle weakness with exacerbations precipitated by minor infections. Interestingly, episodic exacerbations continue to occur during adulthood. These were characterized by proximal limb girdle weakness and ptosis, and not so much by respiratory insufficiency after age 6. All patients presented during neonatal period and responded to cholinergic agonists. In most of the affected patients, additional use of 3,4-diaminopyridine resulted in significant clinical benefit. The disease course is stable except for intermittent worsening.


In vivo recordings of spontaneous and odor-modulated dynamics in the Limax olfactory lobe.
The major central site of olfactory information processing in the terrestrial slug Limax maximus is the procerebral lobe of the cerebral ganglion, which exhibits oscillatory dynamics of its local field potential and propagates activity waves from its apex to its base, as determined by multisite optical and electrical measurements in vitro. The learning-dependent uptake of Lucifer yellow into procerebral neurons suggests that the procerebral lobe may form learned representations of odors. To determine the role of the procerebral lobe in odor processing and odor learning, we developed procedures to implant fine wire electrodes in the lobe, which allowed recordings of local field potential in freely behaving slugs. The procerebral lobe displays oscillatory dynamics of its local field potential in vivo; however the amplitude and frequency of the local field potential are much more variable in vivo than in vitro. Odor presentation leads to increased frequency and amplitude of the local field potential signal. Several lines of evidence indicate that the variations in the local field potential signal recorded in vivo are not due to movement artifacts or activity in adjacent muscles. Multiple amine, gaseous, and peptide neuromodulators known to be present in the procerebral lobe provide pathways by which activity or coupling of bursting neurons in the procerebral lobe could be altered, resulting in the observed amplitude and frequency modulation of the local field potential.


Ultra-high-field imaging reveals increased whole brain connectivity underpins cognitive strategies that attenuate pain.
We investigated how the attenuation of pain with cognitive interventions affects brain connectivity using neuroimaging and a whole brain novel analysis approach. While receiving tonic cold pain, 20 healthy participants performed three different pain attenuation strategies during simultaneous collection of functional imaging data at seven tesla. Participants were asked to rate their pain after each trial. We related the trial-by-trial variability of the attenuation performance to the trial-by-trial functional connectivity strength change of brain data. Across all conditions, we found that a higher performance of pain attenuation was predominantly associated with higher functional connectivity. Of note, we observed an association between low pain and high connectivity for regions that belong to brain regions long associated with pain processing, the insular and cingulate cortices. For one of the cognitive strategies (safe place), the performance of pain attenuation was explained by diffusion tensor imaging metrics of increased white matter integrity.


Physical Activity and Sedentary Time among Children with Disabilities at School.
Physical activity (PA) is important for the development of children with disabilities, but rarely does this population meet the recommended standards. Schools are salient locations for PA, but little is known about how specific school settings affect the PA of children with diverse disabilities. We assessed PA and sedentary time (ST) of children with disabilities in three school settings (physical education, recess, lunchtime). Participants included 259 children from 13 Hong Kong special schools for five primary disabilities: visual impairments, hearing impairments, physical disabilities, intellectual disabilities, and social development problems. Children wore accelerometers at school for 3 d, and the time (min and %) they engaged in moderate-to-vigorous PA (MVPA) and ST was extracted for each school setting by sex. Analyses included multiple linear mixed models to determine differences in MVPA and ST by sex across disability types, adjusting for body mass index, grade level, and duration in each setting. Overall, children spent 70% of their day at school being sedentary and accrued little MVPA (mean, 17 ± 4.2 min daily). Children with intellectual disabilities (severe) had especially low levels of MVPA. All three settings contributed significantly to both MVPA and ST, with recess contributing more to MVPA than physical education or lunchtime. This is the first study to examine MVPA and ST among different disability types at school using accelerometry. Given the low levels of PA, this population should receive priority in the development of cost-effective interventions to improve their PA opportunities.


Management of the geriatric trauma patient at risk of death: therapy withdrawal decision making.
The management of geriatric injured patients admitted to a trauma center includes the selective decision to provide comfort care only, including withdrawal of therapy, and a choice to not use full application of standard therapies. The decision makers in this process include multiple individuals in addition to the patient. Retrospective review of documentation by 2 blinded reviewers of the cohort of patients over a recent 5-year period (1993-1997). Trauma service of a level I trauma center. A convenience sample of patients aged 65 years and older who died, and whose medical record was available for review. Patients were categorized as having withdrawal of therapy, and documentation in the medical record of who made the assessment decisions and recommendations, and to what extent the processes of care were documented. Among 87 geriatric trauma patients who died, 47 had documentation interpreted as indicating a decision was made to withdraw therapy. In only a few circumstances was the patient capable of actively participating in these decisions. The other individuals involved in recommendations for withdrawal of therapy were, in order of prevalence, the treating trauma surgeon, family members (as proxy reporting the patient's preferences), or a second physician. Documentation regarding the end-of-life decisions was often fragmentary, and in some cases ambiguous. Copies of legal advance directives were rarely available in the medical record, and ethics committee participation was used only once. Withdrawal of therapy is a common event in the terminal care of geriatric injured patients. The process for reaching a decision regarding withdrawal of therapy is complex because in most circumstances patients' injuries preclude their full participation. Standards for documentation of essential information, including patients' preferences and decision-making ability, should be developed to improve the process and assist with recording these complicated decisions that often occur over several days of discussion.


Point/counterpoint: early-stage Hodgkin lymphoma and the role of radiation therapy.
The results of recent clinical trials for the management of limited-stage Hodgkin lymphoma have led to considerable debate, especially regarding the role of radiation therapy. This review highlights those recent trials and provides perspectives regarding their interpretation from a radiation oncologist and a hematologist. The trial protocol is available at http://www.nejm.org/doi/suppl/10.1056/NEJMoa1111961/suppl_file/nejmoa1111961_protocol.pdf.


Prenatal exposure to nicotine impairs performance of the 5-choice serial reaction time task in adult rats.
Cigarette smoking is associated with a wide variety of adverse reproductive outcomes, including increased infant mortality and decreased birth weight. Prenatal exposure to tobacco smoke, of which nicotine is a major teratogenic component, has also been linked to the acceleration of the risk for different psychiatric disorders, including conduct disorder and attention deficit hyperactivity disorder (ADHD). Whether this increased risk is influenced by the direct effects of gestational nicotine exposure on the developing fetus remains uncertain. In this study we provide experimental evidence for the effects of prenatal nicotine exposure on measures of attention and impulsivity in adult male rats. Offspring of females exposed during pregnancy to 0.06 mg/ml nicotine solution as the only source of water (daily consumption: 69.6±1.4 ml/kg; nicotine blood level: 96.0±31.9 ng/ml) had lower birth weight and delayed sensorimotor development measured by negative geotaxis, righting reflex, and grip strength. In the 5-choice serial reaction time test, adult rats showed increased numbers of anticipatory responses and omissions errors, more variable response times, and lower accuracy with evidence of delayed learning of the task demands when the 1 s stimulus duration was introduced. In contrast, prenatal nicotine exposure had no effect on exploratory locomotion or delay-discounting test. Prenatal nicotine exposure increased expression of the D5 dopamine receptor gene in the striatum, but did not change expression of other dopamine-related genes (DRD4, DAT1, NR4A2, and TH) in either the striatum or the prefrontal cortex. These data suggest a direct effect of prenatal nicotine exposure on important aspects of attention, inhibitory control, or learning later in life.


Flow morphometry to assess the red blood cell storage lesion.
We present a novel automated system for morphology analysis of red blood cells (RBC) under flow. RBC concentrates collected by blood banks for transfusions are stored for periods of up to several weeks, during which time a number of changes occur, collectively termed the storage lesion. Typically the extent of hemolysis is the defining criterion to determine the acceptability of the RBCs for transfusions. Morphological changes are related with biochemical alteration during the storage of RBCs. The typical blood smear procedure for determining such changes is a labor-intensive and potentially biased manual process. The advantage of the flow morphometry system presented here is that it provides fully automated morphological classification of RBCs with large sample numbers in a short time. Our system uses a commercially available flow cell and flow conditions that prevent adhesion of RBCs, thus eliminating the need for blocking agents such as albumin that affect the distribution of cell shapes. Our morphometry results are validated by comparison with standard biochemical assays (hemolysis, ATP) for blood from 17 donors stored under blood bank conditions for 13 weeks. We show that the percentage of spherocytes present can be used to estimate the status of RBC concentrates. © 2017 International Society for Advancement of Cytometry.


Systemic Infusion of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells in Peritoneal Dialysis Patients: Feasibility and Safety.
Using mesenchymal stem cells (MSCs) is regarded as a new therapeutic approach for improving fibrotic diseases. the aim of this study to evaluate the feasibility and safety of systemic infusion of autologous adipose tissue-derived MSCs (AD-MSCs) in peritoneal dialysis (PD) patients with expected peritoneal fibrosis. This study was a prospective, open-label, non-randomized, placebo-free, phase I clinical trial. Case group consisted of nine eligible renal failure patients with more than two years of history of being on PD. Autologous AD-MSCs were obtained through lipoaspiration and expanded under good manufacturing practice conditions. Patients received 1.2 ± 0.1×106 cell/kg of AD-MSCs via cubital vein and then were followed for six months at time points of baseline, and then 3 weeks, 6 weeks, 12 weeks, 16 weeks and 24 weeks after infusion. Clinical, biochemical and peritoneal equilibration test (PET) were performed to assess the safety and probable change in peritoneal solute transport parameters. No serious adverse events and no catheter-related complications were found in the participants. 14 minor reported adverse events were self-limited or subsided after supportive treatment. One patient developed an episode of peritonitis and another patient experienced exit site infection, which did not appear to be related to the procedure. A significant decrease in the rate of solute transport across peritoneal membrane was detected by PET (D/P cr=0.77 vs. 0.73, P=0.02). This study, for the first time, showed the feasibility and safety of AD-MSCs in PD patients and the potentials for positive changes in solute transport. Further studies with larger samples, longer follow-up, and randomized blind control groups to elucidate the most effective route, frequency and dose of MSCs administration, are necessary (Registration Number: IRCT2015052415841N2).


Comparison of the effects of daily and intermittent-dose calcitriol on serum parathyroid hormone and ionized calcium concentrations in normal cats and cats with chronic renal failure.
Chronic renal failure is complicated by secondary hyperparathyroidism, which traditionally has been controlled by dietary restriction of phosphorus and administration of phosphorus binders. Early treatment of patients with chronic renal failure with calcitriol may be indicated because once established, parathyroid gland hyperplasia does not readily resolve with therapy. Daily and intermittent dosing of calcitriol will decrease plasma parathyroid hormone concentration in normal cats and cats with chronic renal failure without causing ionized hypercalcemia. Ten normal cats; 10 cats with chronic renal failure. Phase 1 was daily calcitriol administration (2.5 ng/kg PO q24h) for 14 days. Phase 2 was intermittent calcitriol administration (8.75 ng/kg PO q84h) for 14 days. A 7-day washout period separated phases 1 and 2. Before each phase, calcitriol, parathyroid hormone, and ionized calcium concentrations were measured. On days 1, 2, and 3 of both phases, serum ionized calcium concentrations were measured. On the last day of both phases, calcitriol, parathyroid hormone, and ionized calcium concentrations were measured 0, 2, 4, and 6 hours after calcitriol administration. Overall, serum parathyroid hormone concentrations were significantly higher in cats with chronic renal failure than in normal cats (P = .022), but serum parathyroid hormone concentrations for both normal cats and cats with chronic renal failure were not significantly different before and after 14 days of treatment with calcitriol, regardless of whether calcitriol was administered daily or intermittently. Adverse effects of calcitriol administration (specifically ionized hypercalcemia) were not seen in either feline group during either phase of the study over the 3-day evaluation after calcitriol administration was initiated. At the dosages used, calcitriol treatment did not result in significant differences in serum parathyroid hormone concentrations before and after treatment in both normal cats and cats with chronic renal failure. With these dosages, adverse affects of calcitriol administration were not seen. Potential reasons for lack of apparent effect include small sample size, insufficient duration of study, insufficient dosage of calcitriol, problems with formulation or administration of calcitriol, and variable gastrointestinal absorption of calcitriol.


L-palmitylcarnitine and calcium ions act similarly on excitatory ionic currents in avian ventricular muscle.
Palmitylcarnitine, an amphiphile that accumulates in and leaks from ischemic heart tissue, affected the fast sodium ion channel and the slow calcium channel in avian ventricular muscle. In the presence of 5.4 mM external potassium ion, palmitylcarnitine reduced the maximum rate of rise of the action potential and increased action potential duration at the plateau level without changing the resting potential. Steady state inactivation of the maximum rate of rise, an index of fast sodium ion current, was shifted by 3-6 mV to more positive potentials by palmitylcarnitine. Elevation of external calcium ion to 5.4 mM (normal = 1.8 mM), like palmitylcarnitine, reduced the maximum rate of rise and shifted the voltage at which the action potential was half maximum by 3 mV to more positive potentials without changing the resting potential. Elevated external calcium ion, unlike palmitylcarnitine, reduced the duration of action potentials initiated from a resting potential of -80 mV. Palmitylcarnitine and elevated external calcium ion increased the amplitude, the maximum rate of rise, and duration of calcium ion dependent action potentials recorded in the presence of 25 mM [K+]0 that completely inactivated the fast sodium ion channel. Steady state inactivation of the maximum rate of rise of calcium-dependent action potentials was consistently shifted to more positive potentials by palmitylcarnitine (3 mV) and by elevated external calcium ion (6 mV) when the initial external calcium ion was 0.9 mM. Palmitylcarnitine, like elevated calcium, evoked a positive inotropic effect in the presence of propranolol. The similarity of the effects of palmitylcarnitine (3 X 10(-5) to 3 X 10(-4)M) with those of elevated external calcium is consistent with the hypothesis that palmitylcarnitine, like elevated external calcium, influences sodium and calcium channel operation by an effect on membrane surface charge.


Advanced oxidation protein product levels as a marker of oxidative stress in paediatric patients with chronic tonsillitis.
We aimed to determine whether advanced oxidation protein product (AOPP) levels can serve as a marker of oxidative stress in paediatric patients with chronic tonsillitis. Thirty children with chronic tonsillitis and 30 healthy children (control group) were recruited from the Otorhinolaryngology (ORL) and Paediatric Surgery departments, respectively, of Dumlupinar University Hospital. In the patient group, blood samples were collected before tonsillectomy, and tonsil tissue was sampled during the operation. Blood samples were also obtained from the control subjects. AOPP levels in the serum and tonsil tissue were measured by the spectrophotometric method. Serum AOPP levels were significantly higher in the patient group (13.1 ± 3.3 ng/ml) than in the control group (11.6 ± 2.3 ng/ml; P < 0.05). In addition, the mean AOPP level (41.9 ± 13.5 ng/mg protein) in the tonsil tissue in the patient group was significantly higher than the mean serum AOPP levels in the control and patient groups (P < 0.05). AOPP levels are elevated in the tonsil tissue and serum of patients with chronic tonsillitis compared to the serum AOPP levels in healthy controls. AOPPs may represent a novel class of pro-inflammatory molecules that are involved in oxidative stress in chronic tonsillitis. AOPPs may be used as a marker of oxidative stress in paediatric patients with chronic tonsillitis.


Cervical cytology biobanking in Europe.
A cervical cytology biobank (CCB) is an extension of current cytopathology laboratory practice consisting in the systematic storage of Pap smears or liquid-based cytology samples from women participating in cervical cancer screening with the explicit purpose to facilitate future scientific research and quality audit of preventive services. A CCB should use an internationally agreed uniform cytology terminology, be integrated in a national or regional screening registry, and be linked to other registries (histology, cancer, vaccination). Legal and ethical principles concerning personal integrity and data safety must be respected strictly. Biobank-based studies require approval of ethical review boards. A CCB is an almost inexhaustible resource for fundamental and applied biological research. In particular, it can contribute to answering questions on the natural history of HPV infection and HPV-induced lesions and cancers, screening effectiveness, exploration of new biomarkers, and surveillance of the short- and long-term effects of the introduction of HPV vaccination. To understand the limitations of CCB, more studies are needed on the quality of samples in relation to sample type, storage procedures, and duration of storage.


[Quality of life in multiple sclerosis and other chronic autoimmune and non-autoimmune diseases].
Diseases that involve the nervous system and the musculoskeletal system are particularly likely to produce different limitations and deficits, and to affect the individual conception of quality of life. To determine the impact on quality of life generated by chronic autoimmune diseases like multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), ankylosing spondylitis (AS) and chronic musculotendinous diseases like osteoarthritis (OA) and fibromyalgia (FM), using the Short Form 36-item (SF-36) health questionnaire. A descriptive cross-sectional study was conducted between January 2004 and June 2006 and included 509 individuals, of whom 56 had MS, 36 SS, 24 AS, 200 RA, 65 SLE, 54 OA and 74 FM. Guided interviews were conducted to evaluate each sphere of the SF-36 health questionnaire. The statistical analysis was performed using the general lineal model, with means differences according to each diagnosis. Compared to patients with RA, those with MS showed significant differences in the physical functioning and social functioning dimensions. The lowest score was recorded in those with FM, except in physical functioning, where MS had the lowest mean. No differences were found in the mean scores on general conception of the state of health in each condition analysed. Different neurological functions deteriorate progressively in MS, which has repercussions on the musculoskeletal system; this leads to a poorer quality of life, mainly in the physical and social functions. The disability generated is not only defined by deficit but also by the degrees of functional limitation within the context of personal health. Quality of life thus becomes a global biopsychosocial phenomenon.


Autoregulation of spinal cord blood flow: is the cord a microcosm of the brain?
The autoregulatory capability of regional areas of the brain and spinal cord was demonstrated in 18 rats anesthetized with a continuous infusion of intravenous pentothal. Blood flow was measured by the injection of radioactive microspheres (Co57, Sn113, Ru103, Sc46). Blood flow measurements were made at varying levels of mean arterial pressure (MAP) which was altered by neosynephrine to raise MAP or trimethaphan to lower MAP. Autoregulation of the spinal cord mirrored that of the brain, with an autoregulatory range of 60 to 120 mm Hg for both tissues. Within this range, cerebral blood flow (CBF) was 59.2 +/- 3.2 ml/100 g/min (SEM) and spinal cord blood flow (SCBF) was 61.1 +/- 3.6. There was no significant difference in CBF and SCBF in the autoregulatory range. Autoregulation was also demonstrated regionally in the left cortex, right cortex, brainstem, thalamus, cerebellum, hippocampus and cervical, thoracic and lumbar cord. This data provides a coherent reference point in establishing autoregulatory curves under barbiturate anesthesia. Further investigation of the effects of other anesthetic agents on autoregulation of the spinal cord is needed. It is possible that intraspinal cord compliance, like intracranial compliance, might be adversely affected by the effects of anesthetics on autoregulation.


The Influence of Arthritis in Other Major Joints and the Spine on the One-Year Outcome of Total Hip Replacement: A Prospective, Multicenter Cohort Study (EUROHIP) Measuring the Influence of Musculoskeletal Morbidity.
Although arthritis in other affected major joints and back pain are known to lead to worse outcomes following total hip replacement, to our knowledge, these risk factors have not previously been operationalized as a musculoskeletal morbidity profile. The aim of this study was to measure the influence of other major joints and the spine (as grades of musculoskeletal morbidity) on the 1-year outcome of primary total hip replacement. The EUROHIP study consists of 1,327 patients undergoing primary total hip replacement for arthritis across 20 European orthopaedic centers. The primary outcome was the responder rate at 12 months calculated with the relative effect per patient for total hip replacement using the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score. The primary predictor of interest was different combinations of arthritis of major joints and the spine grouped into 4 musculoskeletal morbidity grades: 1 (single major joint), 2 (multiple major joints), 3 (single major joint and spine), and 4 (multiple major joints and spine). The confounders adjusted for were age, sex, body mass index, living situation, years of hip pain, American Society of Anesthesiologists (ASA) class, anxiety or depression, and preoperative WOMAC subscales. For this analysis, 845 patients were included with complete 12-month follow-up WOMAC scores. The mean patient age was 65.7 years, and 55.2% of patients were female. The involvement of other major joints and the spine assessed as 1 of 4 musculoskeletal morbidity grades had a strong influence on the 1-year outcome after total hip replacement. The effect size was large compared with other risk factors. Even so, the majority of patients in musculoskeletal morbidity grade 4 had favorable outcomes from the surgical procedure (>74% response to surgical procedures). Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Antigen-driven long term-cultured T cells proliferate in vivo, distribute widely, mediate specific tumor therapy, and persist long-term as functional memory T cells.
Mice bearing disseminated syngeneic FBL-3 leukemia were treated with cyclophosphamide plus long term-cultured T cells immune to FBL-3. The cultured T cells for therapy had been induced to grow in vitro for 62 d by intermittent stimulation with irradiated FBL-3. At the time of therapy, such antigen-driven long term-cultured T cells were greatly expanded in number, proliferated in vitro in response to FBL-3, and were specifically cytotoxic. Following adoptive transfer, donor T cells persisting in the host were identified and counted using donor and host mice congenic for the T cell marker Thy-1. The results show that antigen-driven long term-cultured T cells proliferated rapidly in vivo, distributed widely in host lymphoid organs, and were effective in tumor therapy. Moreover, the already rapid in vivo growth rate of donor T cells could be augmented by administration of exogenous IL-2. When cured mice were examined 120 d after therapy, donor L3T4+ T cells and donor Lyt-2+ T cells could be found in large numbers in host ascites, spleen, and mesenteric and axillary lymph nodes. The persisting donor T cells proliferated in vitro, and became specifically cytotoxic in response to FBL-3, demonstrating that antigen-driven long term-cultured T cells can persist long term in vivo and provide immunologic memory.


The initial peopling of the Americas: a growing number of founding mitochondrial genomes from Beringia.
Pan-American mitochondrial DNA (mtDNA) haplogroup C1 has been recently subdivided into three branches, two of which (C1b and C1c) are characterized by ages and geographical distributions that are indicative of an early arrival from Beringia with Paleo-Indians. In contrast, the estimated ages of C1d--the third subset of C1--looked too young to fit the above scenario. To define the origin of this enigmatic C1 branch, we completely sequenced 63 C1d mitochondrial genomes from a wide range of geographically diverse, mixed, and indigenous American populations. The revised phylogeny not only brings the age of C1d within the range of that of its two sister clades, but reveals that there were two C1d founder genomes for Paleo-Indians. Thus, the recognized maternal founding lineages of Native Americans are at least 15, indicating that the overall number of Beringian or Asian founder mitochondrial genomes will probably increase extensively when all Native American haplogroups reach the same level of phylogenetic and genomic resolution as obtained here for C1d.


Oligomeric state and structural stability of two hyperthermophilic β-glucosidases from Thermotoga petrophila.
The β-glucosidases are enzymes essential for several industrial applications, especially in the field of plant structural polysaccharides conversion into bioenergy and bioproducts. In a recent study, we have provided a biochemical characterization of two hyperthermostable β-glucosidases from Thermotoga petrophila belonging to the families GH1 (TpBGL1) and GH3 (TpBGL3). Here, as part of a continuing investigation, the oligomeric state, the net charge, and the structural stability, at acidic pH, of the TpBGL1 and TpBGL3 were characterized and compared. Enzymatic activity is directly related to the balance between protonation and conformational changes. Interestingly, our results indicated that there were no significant changes in the secondary, tertiary and quaternary structures of the β-glucosidases at temperatures below 80 °C. Furthermore, the results indicated that both the enzymes are stable homodimers in solution. Therefore, the observed changes in the enzymatic activities are due to variations in pH that modify protonation of the enzymes residues and the net charge, directly affecting the interactions with ligands. Finally, the results showed that the two β-glucosidases displayed different pH dependence of thermostability at temperatures above 80 °C. TpBGL1 showed higher stability at pH 6 than at pH 4, while TpBGL3 showed similar stability at both pH values. This study provides a useful comparison of the structural stability, at acidic pH, of two different hyperthermostable β-glucosidases and how it correlates with the activity of the enzymes. The information described here can be useful for biotechnological applications in the biofuel and food industries.


The Team Nutrition pilot study: lessons learned from implementing a comprehensive school-based intervention.
Team Nutrition (TN) is an educational and promotional initiative developed by the US Department of Agriculture to change children's eating behaviors through social marketing techniques. This article reports on the process evaluation of a TN pilot project targeting students in kindergarten to grade 4 and systematically documents the implementation experience. Even with a very short start-up period, schools implemented most components of this multichannel nutrition intervention and formed new, supportive relationships with local media and community partners. School teachers and administrators, along with foodservice professionals, generally expressed support for and satisfaction with TN, citing the positive experience and gains for students. The lessons learned from this study highlight the management and organizational issues involved in a comprehensive intervention. These include the importance of local coordinators to support and create a bridge between teachers and cafeteria staff and to forge links with key external partners. To function effectively, coordinators themselves may need training in coalition building and working with media. Relationships formed with parents, local businesses, other educational institutions, health organizations, and the media offer promise for helping to sustain nutrition education efforts. The TN process evaluation identified multiple ideas for pursuing these partnerships more successfully.


Ankyrin G overexpression in Hutchinson-Gilford progeria syndrome fibroblasts identified through biological filtering of expression profiles.
Hutchinson-Gilford progeria syndrome (HGPS; MIM 176670) is a rare disease characterized by accelerated aging. In this study, light and immunofluorescence microscopy were used to assess morphological changes, measures of cell growth kinetics and gene expression profiles in HGPS cells and normal fibroblasts in culture. A filtering strategy was developed based on differentially expressed transcripts seen consistently across three culture stages based on cell passage number. This filtering strategy produced a list of 66 unique differentially expressed genes, of which approximately 40% were upregulated in HGPS cells compared to normal fibroblasts. The increased mRNA expression in HGPS cells that was seen for one gene defined using this strategy--namely ANK3--was validated using quantitative reverse-transcriptase amplification, Western analysis and immunofluorescence microscopy, all of which showed significantly increased ankyrin G expression. These findings demonstrate differences in morphology, growth kinetics and mRNA expression profiles in HGPS cells compared to normal fibroblasts in culture, including increased expression of ANK3/ankyrin G. Furthermore, other genes that co-clustered with ANK3 might provide mechanistic clues regarding senescence in cultured HGPS cells.


Cigarette packaging and health warnings: the impact of plain packaging and message framing on young smokers.
This study examined the impact of pictorial cigarette-warning labels, warning-label message framing and plain cigarette packaging, on young adult smokers' motivation to quit. Smokers aged 18-30 years (n=740) from a consumer research panel were randomised to one of four experimental conditions where they viewed online images of four cigarette packs with warnings about lung disease, cancer, stroke/heart disease and death, respectively. Packs differed across conditions by warning-message framing (gain vs loss) and packaging (branded vs plain). Measures captured demographics, smoking behaviour, covariates and motivation to quit in response to cigarette packs. Pictorial warnings about lung disease and cancer generated the strongest motivation to quit across conditions. Adjusting for pretest motivation and covariates, a message framing by packaging interaction revealed gain-framed warnings on plain packs generated greater motivation to quit for lung disease, cancer and mortality warnings (p<0.05), compared with loss-framed warnings on plain packs. Warnings combining pictorial depictions of smoking-related health risks with text-based messages about how quitting reduces risks, may achieve better outcomes among young adults, especially in countries considering or implementing plain packaging regulations.


Fine particulate matter and risk of preterm birth and pre-labor rupture of membranes in Perth, Western Australia 1997-2007: a longitudinal study.
A recent longitudinal study reported an association between fine particulate (PM2.5) exposure and preterm birth (PTB) in a US cohort. We applied the same design to an Australian cohort to investigate associations with PTB and pre-labor rupture of membranes (PROM). From 287,680 births, we selected 39,189 women who had singleton births at least twice in Western Australia in 1997-2007 (n=86,844 births). Analyses matched pregnancies to the same women with conditional logistic regression. For PROM adjusted odds ratios (ORs) for a 1 μg/m(3) increase in PM2.5 in the first trimester, second trimester, third trimester, and whole pregnancy were 1.00 (95% confidence interval (CI): 0.97, 1.03), 1.03 (95% CI: 1.00, 1.06), 1.02 (95% CI: 1.00, 1.05), and 1.02 (95% CI: 0.99, 1.05) respectively. For PTB, corresponding ORs were 1.00 (95% CI: 0.96, 1.04), 1.00 (95% CI: 0.96, 1.04), 0.98 (95% CI: 0.94, 1.02), and 0.99 (95% CI: 0.95, 1.04) respectively. Risk of PROM was greater for pregnancies with elevated PM2.5 exposure in the second trimester than were other pregnancies to the same Australian women at lower exposure. There was insufficient evidence for an association with PTB, indicating that a longer time period might be needed to observe an association if a causal effect exists.


Characterization of an in vivo concentration-effect relationship for piperaquine in malaria chemoprevention.
A randomized, placebo-controlled trial conducted on the northwest border of Thailand compared malaria chemoprevention with monthly or bimonthly standard 3-day treatment regimens of dihydroartemisinin-piperaquine. Healthy adult male subjects (N = 1000) were followed weekly during 9 months of treatment. Using nonlinear mixed-effects modeling, the concentration-effect relationship for the malaria-preventive effect of piperaquine was best characterized with a sigmoidal Emax relationship, where plasma concentrations of 6.7 ng/ml [relative standard error (RSE), 23%] and 20 ng/ml were found to reduce the hazard of acquiring a malaria infection by 50% [that is, median inhibitory concentration (IC50)] and 95% (IC95), respectively. Simulations of monthly dosing, based on the final model and published pharmacokinetic data, suggested that the incidence of malaria infections over 1 year could be reduced by 70% with a recently suggested dosing regimen compared to the current manufacturer's recommendations for small children (8 to 12 kg). This model provides a rational framework for piperaquine dose optimization in different patient groups.


Integrated text mining and chemoinformatics analysis associates diet to health benefit at molecular level.
Awareness that disease susceptibility is not only dependent on genetic make up, but can be affected by lifestyle decisions, has brought more attention to the role of diet. However, food is often treated as a black box, or the focus is limited to few, well-studied compounds, such as polyphenols, lipids and nutrients. In this work, we applied text mining and Naïve Bayes classification to assemble the knowledge space of food-phytochemical and food-disease associations, where we distinguish between disease prevention/amelioration and disease progression. We subsequently searched for frequently occurring phytochemical-disease pairs and we identified 20,654 phytochemicals from 16,102 plants associated to 1,592 human disease phenotypes. We selected colon cancer as a case study and analyzed our results in three directions; i) one stop legacy knowledge-shop for the effect of food on disease, ii) discovery of novel bioactive compounds with drug-like properties, and iii) discovery of novel health benefits from foods. This works represents a systematized approach to the association of food with health effect, and provides the phytochemical layer of information for nutritional systems biology research.


Air Pollution and Noncommunicable Diseases: A Review by the Forum of International Respiratory Societies' Environmental Committee, Part 1: The Damaging Effects of Air Pollution.
Air pollution poses a great environmental risk to health. Outdoor fine particulate matter (particulate matter with an aerodynamic diameter < 2.5 μm) exposure is the fifth leading risk factor for death in the world, accounting for 4.2 million deaths and > 103 million disability-adjusted life years lost according to the Global Burden of Disease Report. The World Health Organization attributes 3.8 million additional deaths to indoor air pollution. Air pollution can harm acutely, usually manifested by respiratory or cardiac symptoms, as well as chronically, potentially affecting every organ in the body. It can cause, complicate, or exacerbate many adverse health conditions. Tissue damage may result directly from pollutant toxicity because fine and ultrafine particles can gain access to organs, or indirectly through systemic inflammatory processes. Susceptibility is partly under genetic and epigenetic regulation. Although air pollution affects people of all regions, ages, and social groups, it is likely to cause greater illness in those with heavy exposure and greater susceptibility. Persons are more vulnerable to air pollution if they have other illnesses or less social support. Harmful effects occur on a continuum of dosage and even at levels below air quality standards previously considered to be safe.


Emotional processing and executive functions in major depressive disorder: dorsal prefrontal activity correlates with performance in the intra-extra dimensional set shift.
Heinzel A, Northoff G, Boeker H, Boesiger P, Grimm S. Emotional processing and executive functions in major depressive disorder: dorsal prefrontal activity correlates with performance in the intra-extra dimensional set shift. Major depressive disorder (MDD) is characterised by predominately negatively valenced emotional symptoms that are often accompanied by cognitive impairments. We posited that cognitive impairments in MDD are related to altered emotional processing in prefrontal cortex. We compared 20 medication-free patients with MDD and 29 matched healthy controls. Both groups performed an emotional task during functional magnetic resonance imaging (fMRI). Furthermore, they completed the intra-extra dimensional set shift (IED) test probing for cognitive impairments. Then we correlated the results of the IED with the changes in fMRI BOLD signal in MDD patients and healthy subjects. The subcategory of the IED applying extradimensional shift (EDS) showed a divergent performance of the MDD group committing significantly more errors than the control group. Correlating the EDS errors with fMRI signal changes, the healthy subjects showed a positive correlation with the right ventrolateral prefrontal cortex and the right orbitofrontal cortex. MDD subjects, in contrast, showed a positive correlation in right dorsolateral prefrontal cortex (DLPFC) and a negative correlation in the left dorsomedial prefrontal cortex (DMPFC). We hypothesise that the differential correlation in healthy controls and MDD patients may reflect the use of different strategies in their performance. The impaired executive functions, as reflected by altered processing in right DLPFC and left DMPFC, may implicitly influence emotional processing in patients suffering from MDD.


Diagnostic approaches to predict persistent post-traumatic symptoms after mild traumatic brain injury - a literature review.
Mild traumatic brain injury (mTBI) is one of the most frequently diagnosed neurological disorders in emergency departments. Although there are established recommendations for the diagnosis and treatment in the acute stage, there is an on-going debate in which diagnostic methods and risk factors predict unfavourable long-term outcome after mTBI. This literature review addresses the question, which diagnostic approaches may best predict persistent post-traumatic symptoms (pPTS). A literature search for experimental studies from January 2000 to September 2014 evaluating the following diagnostic approaches (1) susceptibility weighted imaging (SWI), (2) diffusion tensor imaging (DTI), (3) magnetic resonance spectroscopy (MRS), (4) functional magnetic resonance imaging (fMRI), as predictive factors of pPTS or unfavourable cognitive outcome in adult populations with mTBI was performed. DTI has been proved to be a valuable tool to identify diffuse axonal injury (DAI) after mTBI. Additionally, some studies showed associations between DAI and unfavourable cognitive outcome. SWI has shown to be a highly sensitive imaging method to identify microbleeds. The presence and quantity of microbleeds in this imaging technique can further provide aetiological evidence for pPTS. MRS provides information about local neurons metabolism and preliminary data show that creatine-phosphocreatine levels measured after mTBI are predictive of cognitive outcome and emotional distress. The results of one study have shown fMRI as a useful tool to differentiate mTBI patients with pPTS from controls and mTBI patients without pPTS in a resting-state condition. From the evaluated diagnostic approaches to predict pPTS after mTBI, DTI, SWI, MRS, and fMRI seem to have adequate sensitivity and specificity as predictive diagnostic tools for pPTS. Large longitudinal clinical trials are warranted to validate the prognostic applicability and practicability in daily clinical practice.


Manipulation of length and lexicality localizes the functional neuroanatomy of phonological processing in adult readers.
In a previous study of single word reading, regions in the left supramarginal gyrus and left angular gyrus showed positive BOLD activity in children but significantly less activity in adults for high-frequency words [Church, J. A., Coalson, R. S., Lugar, H. M., Petersen, S. E., & Schlaggar, B. L. A developmental fMRI study of reading and repetition reveals changes in phonological and visual mechanisms over age. Cerebral Cortex, 18, 2054-2065, 2008]. This developmental decrease may reflect decreased reliance on phonological processing for familiar stimuli in adults. Therefore, in the present study, variables thought to influence phonological demand (string length and lexicality) were manipulated. Length and lexicality effects in the brain were explored using both ROI and whole-brain approaches. In the ROI analysis, the supramarginal and angular regions from the previous study were applied to this study. The supramarginal region showed a significant positive effect of length, consistent with a role in phonological processing, whereas the angular region showed only negative deflections from baseline with a strong effect of lexicality and other weaker effects. At the whole-brain level, varying effects of length and lexicality and their interactions were observed in 85 regions throughout the brain. The application of hierarchical clustering analysis to the BOLD time course data derived from these regions revealed seven clusters, with potentially revealing anatomical locations. Of note, a left angular gyrus region was the sole constituent of one cluster. Taken together, these findings in adult readers (1) provide support for a widespread set of brain regions affected by lexical variables, (2) corroborate a role for phonological processing in the left supramarginal gyrus, and (3) do not support a strong role for phonological processing in the left angular gyrus.


Hybrid genetic and variational expectation-maximization algorithm for gaussian-mixture-model-based brain MR image segmentation.
The expectation-maximization (EM) algorithm has been widely applied to the estimation of gaussian mixture model (GMM) in brain MR image segmentation. However, the EM algorithm is deterministic and intrinsically prone to overfitting the training data and being trapped in local optima. In this paper, we propose a hybrid genetic and variational EM (GA-VEM) algorithm for brain MR image segmentation. In this approach, the VEM algorithm is performed to estimate the GMM, and the GA is employed to initialize the hyperparameters of the conjugate prior distributions of GMM parameters involved in the VEM algorithm. Since GA has the potential to achieve global optimization and VEM can steadily avoid overfitting, the hybrid GA-VEM algorithm is capable of overcoming the drawbacks of traditional EM-based methods. We compared our approach to the EM-based, VEM-based, and GA-EM based segmentation algorithms, and the segmentation routines used in the statistical parametric mapping package and FMRIB Software Library in 20 low-resolution and 17 high-resolution brain MR studies. Our results show that the proposed approach can improve substantially the performance of brain MR image segmentation.


To lie or not to lie: resident physician attitudes about the use of deception in clinical practice.
Physicians face competing values of truth-telling and beneficence when deception may be employed in patient care. The purposes of this study were to assess resident physicians' attitudes towards lying, explore lie types and reported reasons for lying. After obtaining institutional review board review (OSR# 58013) and receiving exempt status, posts written by Loma Linda University resident physicians in response to forum questions in required online courses were collected from 2002 to 2007. Responses were blinded and manually coded by two investigators using NVivo software. Qualitative and quantitative analyses of the data were performed with links to various attributes. A 95% binomial proportion CI was used to analyse the attribute data. The study found that the majority of residents (90.3%) would disclose the truth about medical errors. Similarly, many residents (55.7%) would disclose the truth regarding unanticipated events, especially if the error was serious enough to result in a malpractice suit (74.7%). However, many residents (40.9%) would not reveal a near miss event because they believe it has no impact on patient health. Some residents (47.3%) would deceive the insurance company for additional patient benefits. Of those willing to lie, only a small group (4.2%) gave self-serving reasons. This study demonstrates that the ethical issues related to deception that trouble attending physicians also exist at the resident physician level. Residents primarily lie for altruistic reasons and rarely for egoistic or self-serving purposes that may or may not result in harm to patients, insurance companies and/or physicians themselves.


Cardiac resynchronization therapy in a case with single ventricle and concommitant noncompaction cardiomyopathy.
A 32-year-old male patient was admitted to the hospital with syncope. An electrocardiogram revealed complete atrioventricular (AV) block and a right bundle branch block with a QRS duration of 218 milliseconds. The heart rate was 40 beats/minute. Echocardiography revealed that both AV valves opened to a single ventricle as well as noncompaction of the myocardium. Due to New York Heart Association class III heart failure, cardiac resynchronization therapy with a defibrillator device (CRT-D) was performed. After the implantation, the electrocardiography QRS duration was reduced to 183 ms. To our knowledge, this was the first reported case of CRT-D implantation in a patient with a noncompacted single ventricle and complete AV block.


A physical activity, nutrition and oral health intervention in nursery settings: process evaluation of the NAP SACC UK feasibility cluster RCT.
The nutrition and physical activity self-assessment for childcare (NAP SACC) intervention has demonstrated effectiveness in the USA. A feasibility randomised controlled trial was conducted in England to adapt the intervention to the UK context. An embedded process evaluation focused on three key questions. 1. Was it feasible and acceptable to implement the intervention as planned? 2. How did the intervention affect staff and parent mediators? 3. Were the trial design and methods acceptable? Twelve nurseries in south-west England were recruited and randomised to intervention or control. The intervention comprised: NAP SACC UK Partner (Health Visitor) support to nurseries to review practice and policies against best practice, and then set goals to improve physical activity, nutrition and oral health; two staff training workshops; and a web-based parent support element. The process evaluation comprised: observations of Partner training (n = 1), Partner/manager meetings (n = 5) and staff workshops (n = 10); semi-structured interviews with Partners (n = 4), managers (n = 12), staff (n = 4) and parents (n = 20); analysis of self-assessment forms, goal setting forms and Partner logbooks; and assessment of staff and parent knowledge, motivation and self-efficacy mediators. Overall, NAP SACC UK was feasible to implement and acceptable to nursery staff, managers, Partners and parents. The intervention was implemented as planned in five of the six intervention nurseries. Partners and managers appreciated the opportunity to review and improve nursery practices and valued the relationship forged between them. Staff rated the training workshops highly, despite attending outside of working hours. Most goals set by nurseries were achieved. However, Partners raised concerns about Health Visitors' capacity to deliver the intervention in any subsequent roll out. Mediator scores improved in all but two areas in intervention staff and parents, with decreases or minimal changes in the control group. The web-based parent element was not well used and should be removed from any subsequent trial. The trial methods were acceptable to managers, staff, Partners and parents. Implementing and evaluating a physical activity and nutrition intervention in nursery settings is feasible and acceptable. A full RCT of NAP SACC UK (with appropriate modifications) is warranted. ISRCTN16287377 (10 Apr 2015).


Metabolic and molecular changes associated with the increased skeletal muscle insulin action 24-48 h after exercise in young and old humans.
The molecular and metabolic mechanisms underlying the increase in insulin sensitivity (i.e. increased insulin-stimulated skeletal muscle glucose uptake, phosphorylation and storage as glycogen) observed from 12 to 48 h following a single bout of exercise in humans remain unresolved. Moreover, whether these mechanisms differ with age is unclear. It is well established that a single bout of exercise increases the translocation of the glucose transporter, GLUT4, to the plasma membrane. Previous research using unilateral limb muscle contraction models in combination with hyperinsulinaemia has demonstrated that the increase in insulin sensitivity and glycogen synthesis 24 h after exercise is also associated with an increase in hexokinase II (HKII) mRNA and protein content, suggesting an increase in the capacity of the muscle to phosphorylate glucose and divert it towards glycogen synthesis. Interestingly, this response is altered in older individuals for up to 48 h post exercise and is associated with molecular changes in skeletal muscle tissue that are indicative of reduced lipid oxidation, increased lipogenesis, increased inflammation and a relative inflexibility of changes in intramyocellular lipid (IMCL) content. Reduced insulin sensitivity (insulin resistance) is generally related to IMCL content, particularly in the subsarcolemmal (SSL) region, and both are associated with increasing age. Recent research has demonstrated that ageing per se appears to cause an exacerbated lipolytic response to exercise that may result in SSL IMCL accumulation. Further research is required to determine if increased IMCL content affects HKII expression in the days after exercise in older individuals, and the effect of this on skeletal muscle insulin action.


Sensitivity and specificity of the APC resistance assay in detection of individuals with factor V Leiden.
Resistance to activated protein C (APC) is the most common cause of familial thrombophilia. The partial thromboplastin time (PTT)-based test for resistance to APC has been widely employed as a screening test for this disorder. However, the utility of this test for screening is not well characterized. More than 90% of patients with resistance to APC have the G1691A mutation in factor V (factor V Leiden). The authors studied the ability of a commercial APC resistance assay to correctly identify the factor V Leiden genotype in 130 individuals. At the recommended assay cut-off value of 2, the sensitivity of the APC resistance assay was 50%, with a specificity of 98%. Increasing the cut-off value increased the sensitivity but decreased the specificity of the test. Receiver operating characteristic (ROC) curve analysis indicated that the test was of intermediate utility. There was considerable overlap in APC ratios in the range of 2 to 3 between subjects with a normal factor V genotype and heterozygotes for factor V Leiden. The authors conclude that the APC resistance assay in its present form is not a useful screening test for factor V Leiden heterozygotes. Until the performance of this assay is improved, patients should have molecular diagnostic testing performed to determine their factor V Leiden status.


Long-lasting training in the Barnes maze prompts hippocampal spinogenesis and habituation in rats.
There is a constant need to assess spatial memory in small rodents to elucidate the basics of cognition in neuroscience experiments. Thus, the significance of the Barnes maze in the biology of hippocampal and cortical neural function cannot be overemphasized. Despite the wide use of the Barnes maze, the effect of maze task training on the structure of hippocampal neurons is yet to be elucidated. Adult Sprague-Dawley rats were subjected to intense training on the Barnes maze (3 months). Subsequently, the hippocampus (cornus ammonis and dentate gyrus) of separate sets of rats was processed for Golgi Colonnier techniques (silver impregnation) and adenoviral-green fluorescent protein labeling (immunohistochemistry). Our results showed that training the animals on the Barne maze increased spinogenesis significantly in the cornus ammonis and dentate gyrus neurons. In addition, we identified a critical time point at which the rats habituated to the trial without escaping box (the probe trial) and could not be tested further in the maze. Taken together, we deduced that a prolonged test on the dry land maze facilitated habituation and caused an increase in hippocampal dendritic spine count. As such, the dry land maze is a suitable paradigm for assessing spatial memory in rats. However, precautions should be taken in selecting suitable experimental controls on the basis of the duration of a study.


Breast augmentation: choosing the optimal incision, implant, and pocket plane.
A retrospective study of 220 patients was performed to review surgical design in breast augmentation. Three specific issues were studied: incision site, implant variables, and pocket plane selection. The influence of these three factors on aesthetic results in both primary and secondary cases was the focus of the analysis. No attempt was made to address long-term issues such as capsular contracture or saline implant deflation rates. In 77 primary augmentation patients and 80 unilateral augmentations for symmetry in breast reconstruction, there were the following untoward results: 11 revisions for unilateral malposition, change to a different implant shape, or change to a larger implant size; four deflations of saline implants requiring replacement; and four conversions of saline to silicone gel implants. In 63 secondary cases, there were two hematomas and two infections requiring implant removal and subsequent replacement. Operative technique in breast augmentation is described, as are recommendations for each of the options associated with the three variables studied.


The centrosomal, putative tumor suppressor protein TACC2 is dispensable for normal development, and deficiency does not lead to cancer.
TACC2 is a member of the transforming acidic coiled-coil-containing protein family and is associated with the centrosome-spindle apparatus during cell cycling. In vivo, the TACC2 gene is expressed in various splice forms predominantly in postmitotic tissues, including heart, muscle, kidney, and brain. Studies of human breast cancer samples and cell lines suggest a putative role of TACC2 as a tumor suppressor protein. To analyze the physiological role of TACC2, we generated mice lacking TACC2. TACC2-deficient mice are viable, develop normally, are fertile, and lack phenotypic changes compared to wild-type mice. Furthermore, TACC2 deficiency does not lead to an increased incidence of tumor development. Finally, in TACC2-deficient embryonic fibroblasts, proliferation and cell cycle progression as well as centrosome numbers are comparable to those in wild-type cells. Therefore, TACC2 is not required, nonredundantly, for mouse development and normal cell proliferation and is not a tumor suppressor protein.


Use of thrombolysis in acute ischemic stroke: analysis of the Nationwide Inpatient Sample 1999 to 2004.
The aim of this study is to characterize hospital and patient characteristics associated with administration of thrombolysis in acute ischemic stroke patients in the United States. This retrospective, observational, cohort study used data from the Nationwide Inpatient Sample, an administrative discharge database. A total of 366,194 hospitalizations admitted through the emergency department with a primary diagnosis of acute ischemic stroke were selected for analysis. The primary outcome considered in this study is whether the patient received thrombolytic therapy on hospital day 0 or 1. Thrombolysis was used in 1.12% (95% confidence interval [CI] 0.95% to 1.32%) of ischemic stroke hospitalizations. Most hospitals (69.5%; 95% CI 68.4% to 70.6%) treating ischemic stroke patients did not use thrombolysis during the study period. For the hospitals that used thrombolysis, the mean annual number of patients treated with thrombolysis per hospital was 3.06 (95% CI 2.68 to 3.44). In the binary logistic regression analysis, hospital characteristics associated with high use of thrombolysis were teaching hospital status and increasing number of stroke patients treated annually. Patient characteristics associated with higher use of thrombolysis were age younger than 55 years, male sex, and low comorbidity as measured by the modified Charlson Index; white race; and private self-pay health insurance. Use of thrombolysis for ischemic stroke in the United States from 1999 to 2004 was infrequent and showed significant differences, depending on hospital and patient demographic characteristics.


Buyang huanwu decoction combined with BMSCs transplantation promotes recovery after spinal cord injury by rescuing axotomized red nucleus neurons.
Buyang huanwu decoction (BYHWD) is a classic recipe in traditional Chinese medicine (TCM) to supplement Qi and activate blood. It has been used to recover the neural function after the injury of central nervous system for hundreds of years in China. This study investigated whether Buyang huanwu decoction (BYHWD) combined with bone marrow mesenchymal stem cells (BMSCs) transplantation had synergistic effect on neuroprotection of red nucleus neurons after spinal cord injury (SCI). Rubrospinal tract (RST) transection model was established and BMSCs were collected. The forelimb locomotor function was recorded using inclined plate test and spontaneous vertical exploration. cAMP level in red nucleus was detected with Enzyme-linked immunosorbent assay (ELISA). Morphology and number of red nucleus neurons was observed using Nissl's staining. Expression of cAMP-response element binding protein (CREB), ras homolog gene family member A (RhoA) and nerve growth factor (NGF) in red nucleus was detected using immunohistochemistry, qRT-PCR and Western-blotting. The combination of BYHWD and BMSCs transplantation could improve the forelimb locomotor function significantly and give the red nucleus somas a better protection. Meanwhile, cAMP level, CREB and NGF increased, while RhoA decreased remarkably in the BYHWD+BMSCs group. BYHWD combined with BMSCs transplantation had synergistic effect on neuroprotection of red nucleus neurons after SCI; the mechanism may be related to up-regulating cAMP level, activating the cAMP/CREB/RhoA signaling pathway, and promoting expression of NGF.


A functional insulator screen identifies NURF and dREAM components to be required for enhancer-blocking.
Chromatin insulators of higher eukaryotes functionally divide the genome into active and inactive domains. Furthermore, insulators regulate enhancer/promoter communication, which is evident from the Drosophila bithorax locus in which a multitude of regulatory elements control segment specific gene activity. Centrosomal protein 190 (CP190) is targeted to insulators by CTCF or other insulator DNA-binding factors. Chromatin analyses revealed that insulators are characterized by open and nucleosome depleted regions. Here, we wanted to identify chromatin modification and remodelling factors required for an enhancer blocking function. We used the well-studied Fab-8 insulator of the bithorax locus to apply a genome-wide RNAi screen for factors that contribute to the enhancer blocking function of CTCF and CP190. Among 78 genes required for optimal Fab-8 mediated enhancer blocking, all four components of the NURF complex as well as several subunits of the dREAM complex were most evident. Mass spectrometric analyses of CTCF or CP190 bound proteins as well as immune precipitation confirmed NURF and dREAM binding. Both co-localise with most CP190 binding sites in the genome and chromatin immune precipitation showed that CP190 recruits NURF and dREAM. Nucleosome occupancy and histone H3 binding analyses revealed that CP190 mediated NURF binding results in nucleosomal depletion at CP190 binding sites. Thus, we conclude that CP190 binding to CTCF or to other DNA binding insulator factors mediates recruitment of NURF and dREAM. Furthermore, the enhancer blocking function of insulators is associated with nucleosomal depletion and requires NURF and dREAM.