Dose-dependent transduction of Hedgehog relies on phosphorylation-based feedback between the G-protein-coupled receptor Smoothened and the kinase Fused.
Smoothened (SMO) is a G-protein-coupled receptor-related protein required for the transduction of Hedgehog (HH). The HH gradient leads to graded phosphorylation of SMO, mainly by the PKA and CKI kinases. How thresholds in HH morphogen regulate SMO to promote switch-like transcriptional responses is a central unsolved issue. Using the wing imaginal disc model in Drosophila, we identified new SMO phosphosites that enhance the effects of the PKA/CKI kinases on SMO accumulation, its localization at the plasma membrane and its activity. Surprisingly, phosphorylation at these sites is induced by the kinase Fused (FU), a known downstream effector of SMO. In turn, activation of SMO induces FU to act on its downstream targets. Overall, our data provide evidence for a SMO/FU positive regulatory loop nested within a multikinase phosphorylation cascade. We propose that this complex interplay amplifies signaling above a threshold that allows high HH signaling.


Novel peptides bearing pyrene and coumarin units with or without beta-cyclodextrin in their side chains exhibit intramolecular fluorescence resonance energy transfer.
Novel peptides bearing the pyrene/coumarin FRET pair in their side chains have been designed and synthesized. Peptide 1 having endogenous beta-cyclodextrin (beta-CD) in the side chain exhibits FRET in aqueous solution, indicating that coumarin, being accommodated into the CD cavity, is separated from pyrene. Guest-induced quenching of the fluorophores in 1 indicates that coumarin, being excluded from the CD cavity, comes into close contact with pyrene. Peptide 2 shows FRET only after addition of external beta-CD that again reflects the idea that beta-CD surely caps the coumarin unit in its hydrophobic cavity, and, therefore, quenching of the fluorophores can be prevented in FRET peptide probes. With this strategy, various peptide-based FRET probes can be developed that would be useful for studying biological phenomena in living cells.


Outcomes and potential surrogate markers for future clinical trials of non-alcoholic steatohepatitis cirrhosis.
Non-alcoholic steatohepatitis has emerged as a major public health problem, and the burden of non-alcoholic steatohepatitis cirrhosis is projected to increase by 64%-156% by 2030. The threat is aggravated by the fact that are currently no approved drugs for the treatment of non-alcoholic steatohepatitis. In this paper, we review the main challenges to drug development in patients with non-alcoholic steatohepatitis cirrhosis, and describe the opportunities brought by the advances in the understanding of the clinical and pathophysiological nuances of cirrhosis. The design of therapeutic regimens for non-alcoholic steatohepatitis cirrhosis will vary according to the specific cirrhosis substage (compensated vs decompensated), and the specific mechanistic basis of therapy, targeted either at improving aetiology-specific pathways and/or at more general aetiology-agnostic processes. The understanding of the probabilistic expectations for the whole range of potential outcomes, rooted at different mechanistic drivers at each specific substage, will be essential in order to choose adequate estimands and therapeutic strategies for clinical trials and individual patients with non-alcoholic steatohepatitis cirrhosis. Finally, we provide a summary of the main pitfalls and uncertainties in the design of clinical trials for non-alcoholic steatohepatitis cirrhosis and discuss potential biomarkers for use in trials and practice for these patients.


Self-propagated chaotic dynamically enhanced optical physical layer encryption communication system based on bidirectional long short-term memory neural network.
The physical layer chaotic encryption of optical communication is considered as an effective secure communication technology, which can protect data and be compatible with existing networks. Theoretically, any chaotic system or chaotic map has ideal complex dynamics. However, due to the limited precision of simulation software and digital equipment, the chaotic system often degrades dynamics, which hinders the further application of digital chaotic system in many fields. In this paper, we propose a self-propagated nonlinear chaotic dynamical enhanced optical physical layer encryption scheme based on bidirectional long short-term memory neural network (Bi-LSTM-NN). The Bi-LSTM-NN is used to train and learn the dynamical enhanced chaotic sequences with different initial values iteratively, and finally the chaotic sequences with self-propagated dynamical enhancement are output. The correlation coefficient (CC) of chaotic sequences by the enhanced chaotic system and Bi-LSTM-NN are more than 0.98. Compared with the original chaotic system, the range of sample entropy above 0.8 is more than 2 times, and the sensitivity of the initial value x0 is up to 2.28 times, and y0 is up to 1.3 times, making the key space reaches 10520. The scheme successfully encrypts constellation points and information in the frequency domain. In addition, the scheme achieves encrypted 16 quadrature amplitude modulation-orthogonal frequency division multiplexing (16QAM-OFDM) signal transmission of 65.9 Gb/s using 2 km 7-core optical fiber. The experimental results show that the scheme can ensure data security, and in the future optical network has a good application prospect.


[Endorphins, opioid receptors and site of action of morphinomimetics].
Each class (mu, delta kappa and epsilon) of opioid receptors has a characteristic pattern of distribution in the nervous system, which may, however, exhibit species differences. The effects of opioid receptor stimulation depend on the class of receptor involved, the localization of these specific receptors and the animal species under investigation. Endogenous ligands of opioid receptors, which include more than twenty peptides, derive from three precursors:proopiomelanocortin (beta-endorphin), proenkephalin A (enkephalins) and prodynorphin (dynorphins, neo-endorphins). Generally, the endogenous ligands do not exhibit a marked selectivity toward a given receptor class. Most of the clinically used morphinomimetics, including morphine, bind preferentially to mu receptors. However, this interaction is not exclusive and these drugs are most often mixed ligands which also bind to the other classes of opioid receptors. Peripheral targets for morphinomimetics have been suspected for a long time, and recent data confirmed that opioids do act on receptors located on peripheral terminals of primary afferent fibers. The dorsal horn of the spinal cord is well known as a central site of action of morphinomimetics. At this level, opioids reduce the activity of spinal neurones that convey the nociceptive messages. The classes of opioid receptors (certainly mu [mu 2?] and a, perhaps kappa) involved in this effect, and their pre- or postsynaptic location are not firmly established to date. Further developments on these points can be expected from the use of new ligands which are highly selective of the various classes of opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)


Therapeutic effects and safety of early use of sacubitril/valsartan after acute myocardial infarction: a systematic review and meta-analysis.
infarction (AMI) can be reduced by the use of sacubitril/valsartan. However, the therapeutic effects of sacubitril/valsartan in clinical settings are inconsistent. In this paper, the related research on the application of sacubitril/valsartan in AMI was comprehensively searched, in order to explore the clinical efficacy and safety of early application of sacubitril/valsartan after AMI. English databases, including American National Library of Medicine, Medline, and Embase, and Chinese databases, including Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure (CNKI), Wanfang, and VIP, were searched using a combination of the following search terms: AMI, acute ST-segment elevation myocardial infarction (STEMI), acute non-ST-segment elevation myocardial infarction (NSTEMI), sacubitril/valsartan sodium tablets, and angiotensin receptor enkephalinase inhibitors. The experimental group was given Sacubitril/Valsartan sodium tablets, while the control group was given angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB). Cochrane Handbook 5.0 risk assessment table were used for quality assessment and bias risk assessment. A total of 5 articles were included in the meta-analysis. The total incidence of adverse cardiovascular events in the sacubitril/valsartan group was significantly lower than that in the control group {relative risk (RR) =0.61 [95% confidence interval (CI): 0.46, 0.82], significance testing Z=3.36, and P=0.0008}. The difference between the rehospitalization rate of the sacubitril/valsartan group and control group was statistically significant [RR =0.67 (95% CI: 0.47, 0.95), significance testing Z=2.23, and P=0.03]. The difference in low blood pressure between the sacubitril/valsartan group and the control group was statistically significant [RR =1.28 (95% CI: 1.18, 1.40), significance testing Z=5.58, and P<0.00001]. The difference in left ventricular ejection fraction (LVEF) between the sacubitril/valsartan group and control group was statistically significant [mean difference (MD) =3.09 (95% CI: 1.69, 4.49), significance testing Z=4.33, and P<0.0001]. Sacubitril/valsartan was found to inhibit ventricular remodeling after AMI, improve cardiac function, and reduce the incidence of adverse cardiovascular events after myocardial infarction, the rehospitalization rate, and the mortality rate.


[Clinical feature and surgical treatment of recurrent craniopharyngiomas].
To explore the clinical feature and surgical treatment of recurrent craniopharyngiomas. The imaging features, intraoperative course, and postoperative outcomes of 83 patients with craniopharyngiomas were retrospectively analyzed. Of the 81 patients that survived, 19 experienced recurrence of the craniopharyngioma 6 to 62 months after the completion of the initial treatment, with recurrence rates of patients with total, subtotal and partial removal being 5.3%, 52.9%, and 100% respectively. Five of the 24 patients aged 6 years or older, who had an incomplete surgical removal, received radiation therapy, and only 1 of them experienced tumor recurrence (20%) whereas as many as 15 of the 19 patients (78.9%) did who did not received it. Surgery resection should be the primary therapeutic option for patients with recurrent craniopharyngioma and radiation therapy should also be considered but only as adjuvant therapy.


Communication: modeling charge-sign asymmetric solvation free energies with nonlinear boundary conditions.
We show that charge-sign-dependent asymmetric hydration can be modeled accurately using linear Poisson theory after replacing the standard electric-displacement boundary condition with a simple nonlinear boundary condition. Using a single multiplicative scaling factor to determine atomic radii from molecular dynamics Lennard-Jones parameters, the new model accurately reproduces MD free-energy calculations of hydration asymmetries for: (i) monatomic ions, (ii) titratable amino acids in both their protonated and unprotonated states, and (iii) the Mobley "bracelet" and "rod" test problems [D. L. Mobley, A. E. Barber II, C. J. Fennell, and K. A. Dill, "Charge asymmetries in hydration of polar solutes," J. Phys. Chem. B 112, 2405-2414 (2008)]. Remarkably, the model also justifies the use of linear response expressions for charging free energies. Our boundary-element method implementation demonstrates the ease with which other continuum-electrostatic solvers can be extended to include asymmetry.


Older people living in the community with delusion.
This study explores the intricate relationship between social interactions and the development of persecutory delusions among older women living alone in Japan. Focusing on the unique perspective of individuals experiencing delusions outside clinical settings, the aim was to understand the impact of interpersonal interactions on delusion formation. Cases of older women living alone with persecutory delusions were selected from records of municipal psychogeriatric services and medical consultations within a community space. This study employed a descriptive approach to propose a hypothesis regarding the possible connection between social interactions and the development of persecutory delusions within this demographic. Two relevant cases were identified, from which a three-step hypothesis emerged regarding the potential link between social interactions and the development of persecutory delusions in this demographic. Insights from these cases suggest that anxiety can trigger hallucinations, which, when unaddressed, evolve into delusional interpretations. Addressing these unmet needs could mitigate the progression of persecutory delusions. The findings of this study underline the critical relationship between social interactions and persecutory delusions among older women living alone. The unmet need for empathy influences the progression from anxiety-driven hallucinations to fully formed delusions. Early intervention can prevent the escalation of delusions and involuntary psychiatric hospitalization. This study underscores the importance of recognizing the link between social isolation and delusion emergence. It advocates for compassionate environments to meet the psychological needs of older individuals grappling with delusions. Geriatr Gerontol Int 2023; ••: ••-••.


2D Superparamagnetic Tantalum Carbide Composite MXenes for Efficient Breast-Cancer Theranostics.
Background: The emergence of two-dimensional MXenes has spurred their versatile applications in broad fields, but the exploring of novel MXene-based family members and their potential applications in theranostic nanomedicine (concurrent diagnostic imaging and therapy) have been rarely explored. In this work, we report the construction of a novel superparamagnetic MXene-based theranostic nanoplatform for efficient breast-cancer theranostics, which was based on intriguing tantalum carbide (Ta4C3) MXene and its further rational surface-superparamagnetic iron-oxide functionalization (Ta4C3-IONP-SPs composite MXenes) for efficient breast-cancer theranostic. Methods: The fabrication of ultrathin Ta4C3 nanosheets was based on an exfoliation strategy and superparamagnetic iron oxide nanoparticles were in-situ grown onto the surface of Ta4C3 MXene according to the redox reaction of MXene. Ta4C3-IONP MXenes were modified with soybean phospholipid (SP) to guarantee high stability in physiological conditions. The photothermal therapy, contrast-enhanced CT, T2-weighted magnetic resonance imaging and the high biocompatibility of these composite nanosheets have also been evaluated in vitro at cellular level and in vivo on mice breast tumor allograft tumor model. Results: The Ta component of Ta4C3-IONP-SPs exhibits high performance for contrast-enhanced CT imaging because of its high atomic number and high X-ray attenuation coefficient, and the integrated superparamagnetic IONPs act as excellent contrast agents for T2-weighted magnetic resonance imaging. Especially, these Ta4C3-IONP-SPs composite nanosheets with high photothermal-conversion efficiency (η: 32.5%) has achieved complete tumor eradication without reoccurrence, verifying their highly efficient breast-tumor photo-ablation performance. Conclusion: This work not only significantly broadens the biomedical applications of MXene-based nanoplatforms (Ta4C3 MXene) by exploring their novel family members and further functionalization strategies (magnetic functionalization in this work), but also provides a novel and efficient theranostic nanoplatform for efficient breast-cancer theranostics.


Hyper-elastic modeling and mechanical behavior investigation of porous poly-D-L-lactide/nano-hydroxyapatite scaffold material.
Poly-D-L-lactide/nano-hydroxyapatite (PDLLA/nano-HA) can be used as the biological scaffold material in bone tissue engineering as it can be readily made into a porous composite material with excellent performance. However, constitutive modeling for the mechanical response of porous PDLLA/nano-HA under various stress conditions has been very limited so far. In this work, four types of fundamental compressible hyper-elastic constitutive models were introduced for constitutive modeling and investigation of mechanical behaviors of porous PDLLA/nano-HA. Moreover, the unitary expressions of Cauchy stress tensor have been derived for the PDLLA/nano-HA under uniaxial compression (or stretch), biaxial compression (or stretch), pure shear and simple shear load by using the theory of continuum mechanics. The theoretical results determined from the approach based on the Ogden compressible hyper-elastic constitutive model were in good agreement with the experimental data from the uniaxial compression tests. Furthermore, this approach can also be used to predict the mechanical behaviors of the porous PDLLA/nano-HA material under the biaxial compression (or stretch), pure shear and simple shear.


Persistent annual permanent pacemaker implantation rate after surgical aortic valve replacement in patients with severe aortic stenosis.
Degenerative aortic valve stenosis (AS) is associated with conduction abnormalities. Pacemaker implantation is encountered after surgical aortic valve replacement (SAVR). Not much is known about the pacemaker implantation rate during midterm follow-up after SAVR. Our objectives were to determine the incidence of permanent pacemaker implantation (PPI) in the midterm after SAVR in a tertiary care facility. We reviewed procedural data of 734 consecutive patients (56% men; mean age, 68.9±9.5 years) with degenerative severe AS who underwent SAVR between January 1, 2003, and December 31, 2008. Perioperative electrocardiograms were assessed for occurrence of conduction abnormalities, and we sought to determine the incidence and indication for PPI with a median follow-up of 3.76 years (interquartile range, 2.44 to 5.59 years). Univariate and multivariate logistic regression models were applied to identify predictors for early (≤30 days) and late (>30 days) PPI. Isolated SAVR was performed in 56%, SAVR with coronary artery bypass grafting in 35%, and SAVR with any other valve therapy in 5.8%. Complete bundle branch block (BBB) was present in 7% and first-degree atrioventricular block in 11%. New BBBs were detected in 63 patients (8.6%). Fifteen patients (2.0%) required a PPI within 30 days after SAVR, and 28 (4.0%) underwent PPI more than 30 days after SAVR. The linearized rate of PPI after SAVR was 1.01%±0.37% per patient-year. Patients with BBB at baseline had a higher PPI incidence after SAVR than patients without BBB, both within 30 days (8% vs 1.5%, p=0.001) and after 30 days (10% vs 2.9%, p=0.006). PPI incidence after 30 days was also significantly higher in patients with a new BBB after SAVR (7.8% vs 2.9%, p=0.038). By multivariate logistic regression analysis, BBB and the combination of AS and regurgitation predicted PPI within 30 days after SAVR (hazard ratio [HR], 470; 95% confidence interval [CI], 1.55 to 14.27; and HR, 1.33; 95% CI, 0.03 to 1.73, respectively). BBB (HR, 3.26; 95% CI, 1.41 to 7.54), previous cardiac operation (HR, 3.40; 95% CI, 1.16 to 9.94), and severe left ventricular dysfunction (HR, 9.82; 95% CI, 2.90 to 33.26) were predictors for PPI after 30 days post-SAVR. Patients with severe AS who underwent SAVR have a persistent 1% annual risk for PPI. Postoperative presence of BBB predicted the need for PPI both within 30 days and after 30 days after SAVR.


Predictive validity of a brief outpatient neuropsychological battery in individuals 1-25 years post traumatic brain injury.
The purpose of this research was to examine the predictive validity of a brief, outpatient neuropsychological battery relative to concurrent functional outcomes 1-25 years post traumatic brain injury. A cross-sectional analysis from an archival database. Participants were 377 persons aged 16-85, 1-25 years post mild-complicated to severe traumatic brain injury. Neuropsychological testing and outcome assessment were completed as part of a routine follow-up associated with enrollment in the Southeastern Michigan Traumatic Brain Injury System project, which is a longitudinal research project. Neuropsychological measures included trail making test, California verbal learning test-II (CVLT-II), word generation, Wisconsin card sort testing - 64 card version, digit vigilance test, and Wechsler test of adult reading (WTAR). Outcome measures included the disability rating scale, Glasgow outcome scale-extended, supervisor rating scale, and employment. Multiple regression analyses revealed that although demographic and injury characteristics were predictive of level of disability, level of supervision, and employment, neuropsychological test scores including CVLT-II total score for learning trials 1-5; Trails B, and the WTAR represented independent predictors across all outcome measures. These findings demonstrate the utility of a brief, outpatient battery in prediction of concurrent outcomes up to 25 years post injury. Given the difficulty in receiving full reimbursement for neuropsychological assessment services, the data provide needed empirical support for use of more economical and efficient testing.


Iron-Doped Nickel Phosphide Nanosheet Arrays: An Efficient Bifunctional Electrocatalyst for Water Splitting.
Exploring efficient and earth-abundant electrocatalysts for water splitting is crucial for various renewable energy technologies. In this work, iron (Fe)-doped nickel phosphide (Ni2P) nanosheet arrays supported on nickel foam (Ni1.85Fe0.15P NSAs/NF) are fabricated through a facile hydrothermal method, followed by phosphorization. The electrochemical analysis demonstrates that the Ni1.85Fe0.15P NSAs/NF electrode possesses high electrocatalytic activity for water splitting. In 1.0 M KOH, the Ni1.85Fe0.15P NSAs/NF electrode only needs overpotentials of 106 mV at 10 mA cm-2 and 270 mV at 20 mA cm-2 to drive the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER), respectively. Furthermore, the assembled two-electrode (Ni1.85Fe0.15P NSAs/NF∥Ni1.85Fe0.15P NSAs/NF) alkaline water electrolyzer can produce a current density of 10 mA cm-2 at 1.61 V. Remarkably, it can maintain stable electrolysis over 20 h. Thus, this work undoubtedly offers a promising electrocatalyst for water splitting.


Neuropsychological Predictors of Trauma Centrality in OIF/OEF Veterans.
This study examined whether reduced performance on two neuropsychological tasks, cognitive flexibility and working memory, were associated with higher levels of trauma centrality. A growing body of research has shown that trauma centrality, the extent to which a person believes a potentially traumatic event has become central to their self-identity and life story, is associated with post-traumatic stress disorder (PTSD). Furthermore, PTSD is often associated with alterations in neuropsychological functioning. The relationship between neuropsychological processes and trauma centrality, however, has yet to be explored. OEF/OIF combat veterans (N = 41) completed the Post-traumatic Diagnostic Scale (PDS), the Beck Depression Inventory-II (BDI-II), the Centrality of Event Scale (CES), and on-line measures of cognitive flexibility and working memory assessed via WebNeuro. Bivariate Pearson correlations showed that CES scores were positively correlated with PDS and BDI scores, and negatively correlated with cognitive flexibility and working memory. Linear regressions revealed that working memory significantly predicted CES when controlling for depression and PTSD severity while cognitive flexibility approached significance when controlling for these same variables. This study employed a cross-sectional design, precluding causality. The small sample size, entirely male sample, and use of an online neuropsychological assessment warrant follow-up research. Although numerous studies have found an association between CES and PTSD, this is the first to suggest that neuropsychological processes underlie the construct of trauma centrality. Given the importance of maladaptive cognitive processes underlying the pathogenesis of PTSD, these data suggest that future studies aimed at examining the link between neuropsychological processes and maladaptive cognitive processes, such as trauma centrality, may help to characterize and treat PTSD.


Siva - The Mad Lord: A Puranic perspective.
The eccentricities of Lord Shiva, especially His attire, behavior - particularly the midnight dance at the cremation grounds surrounded by various strange beings, fondness to remain naked, and love for strange pets such as snakes and fawn, have attracted the loving and devout attention from His various adiyargal (devotees). This has resulted in the outpouring of their love for their Lord in the form of Thevaram and Thiruvachakam of Sambandar, Appar, Sundarar, Karaikal Ammaiyar, and Manickavachakar. Along with these writings, the background Puranic myths are mentioned. It is suggested that these ideas could be utilized to destigmatize mental illness among the sufferers and their carers.


Fractional Flow Reserve Assessment of Coronary Artery Stenosis.
Objective proof of focal lesions is mandatory, and the best invasive method of physiological testing is fractional flow r eserve (FFR). The increased trans-stenotic gradient is measured via the guiding catheter and pressure transducer on a 0.014" coronary wire at maximal hyperaemia induced by adenosine. Patients with a FFR of less than 0.8 should undergo myocardial revascularisation by percutaneous coronary intervention or coronary artery bypass graft, particularly if the proximal and middle segments of the main coronary arteries and large side-branches are affected; there is no prognostic revascularisation benefit in patients with moderate stenoses and FFR greater than 0.80. FFR assessment of coronary lesions is superior to other invasive morphological studies, such as intracoronary ultrasound or optical coherence tomography. Its use in non-culprit vessels in acute coronary syndromes is currently under scrutiny. Recent advances in computed tomographic technique allow non-invasive assessment of FFR, but clinical validation has yet to be obtained.


Transient and rapidly resolving intrahepatic portal gas: CT findings.
Hepatic portal gas (HPG) has historically been associated with high (75% or over) mortality rates related to abdominal dramatic conditions and has served as an indicator for urgent exploratory laparotomy. Over the last two decades, the greater availability and higher speed of use of CT as well as improvement in the management of critically ill patients have increased the sensitivity of imaging HPG. HPG has been found associated with a broad range of diseases, some of which are benign and do not necessarily require urgent exploratory laparotomy in the absence of signs of intra-abdominal acute condition or systemic toxicity. We present a case of transient and rapidly resolving HPG found in a 61-year-old male admitted with hypovolemic shock due to upper gastrointestinal occlusion. HPG rapidly resolved after resuscitation of the patient with intensive re-hydration and drastic decompression of the fluid-full stomach through a nasogastric tube. The physiopathology and causes of HPG are briefly reviewed and its potential clinical significance is resituated.


D242N, a KV7.1 LQTS mutation uncovers a key residue for IKs voltage dependence.
KV7.1 and KCNE1 co-assemble to give rise to the IKs current, one of the most important repolarizing currents of the cardiac action potential. Its relevance is underscored by the identification of >500 mutations in KV7.1 and, at least, 36 in KCNE1, that cause Long QT Syndrome (LQTS). The aim of this study was to characterize the biophysical and cellular consequences of the D242N KV7.1 mutation associated with the LQTS. The mutation is located in the S4 transmembrane segment, within the voltage sensor of the KV7.1 channel, disrupting the conserved charge balance of this region. Perforated patch-clamp experiments show that, unexpectedly, the mutation did not disrupt the voltage-dependent activation but it removed the inactivation and slowed the activation kinetics of D242N KV7.1 channels. Biotinylation of cell-surface protein and co-immunoprecipitation experiments revealed that neither plasma membrane targeting nor co-assembly between KV7.1 and KCNE1 was altered by the mutation. However, the association of D242N KV7.1 with KCNE1 strongly shifted the voltage dependence of activation to more depolarized potentials (+50mV), hindering IKs current at physiologically relevant membrane potentials. Both functional and computational analysis suggest that the clinical phenotype of the LQTS patients carrying the D242N mutation is due to impaired action potential adaptation to exercise and, in particular, to increase in heart rate. Moreover, our data identify D242 aminoacidic position as a potential residue involved in the KCNE1-mediated regulation of the voltage dependence of activation of the KV7.1 channel.


Lucio's phenomenon: exuberant case report and review of Brazilian cases.
Lucio's phenomenon is an uncommon reaction characterized by severe necrotizing cutaneous lesions that occurs in patients with Lucio's leprosy and lepromatous leprosy. It is considered by some authors as a variant of type 2 or 3 reaction. Death can occur because of blood dyscrasia or sepsis. Precipitating factors include infections, drugs and pregnancy. We report a 31-year-old female patient exhibiting both clinical and histopathological features of lepromatous leprosy and Lucio's phenomenon presenting favorable response to treatment. We complement our report with a literature review of the Brazilian cases of Lucio's phenomenon published in Portuguese and English.


Sphingolipids metabolism in the salivary glands of rats with obesity and streptozotocin induced diabetes.
Diabetes is considered a major public health problem affecting millions of individuals worldwide. Remarkably, scientific reports regarding salivary glands sphingolipid metabolism in diabetes are virtually non-existent. This is odd given the well-established link between the both in other tissues (e.g., skeletal muscles, liver) and the key role of these glands in oral health preservation. The aim of this paper is to examine sphingolipids metabolism in the salivary glands in (pre)diabetes (evoked by high fat diet feeding or streptozotocin). Wistar rats were allocated into three groups: control, HFD-, or STZ-diabetes. The content of major sphingolipid classes in the parotid (PSG) and submandibular (SMSG) glands was assessed via chromatography. Additionally, Western blot analyses were employed for the evaluation of key sphingolipid signaling pathway enzyme levels. No changes in ceramide content in the PSG were found, whereas an increase in ceramide concentration for SMSG of the STZ group was observed. This was accompanied by an elevation in SPT1 level. Probably also sphingomyelin hydrolysis was increased in the SMSG of the STZ-diabetic rats, since we observed a significant drop in the amount of SM. PSG and SMSG respond differently to (pre)diabetes, with clearer pattern presented by the later gland. An activation of sphingomyelin signaling pathway was observed in the course of STZ-diabetes, that is, metabolic condition with rapid onset/progression. Whereas, chronic HFD lead to an inhibition of sphingomyelin signaling pathway in the salivary glands (manifested in an inhibition of ceramide de novo synthesis and accumulation of S1P).


Stable incidence rates of tuberculosis (TB) among human immunodeficiency virus (HIV)-negative South African gold miners during a decade of epidemic HIV-associated TB.
During the last decade, annual tuberculosis (TB) case-notification rates increased 4-fold, to >4000 cases/100000 person-years, in the study workforce, among whom prevalence of human immunodeficiency virus (HIV) was 30% in 2000. Three separate cohort studies, totalling 6454 HIV-negative participants, were combined and analyzed for time trends. Observed incidence of TB varied between 962 (1991-1994) and 1589 (1999-2000) cases/100000 person-years (P=.17, test for trend). There was, however, a progressive increase in age, and, for each period, older age was associated with increased incidence rates of TB (P<.001). Having adjusted for age differences, there was no significant association between incidence of TB and calendar period (P=.81, test for trend). Relative to 1991-1994, multivariate-adjusted incidence-rate ratios were 0.94, for 1995-1997, 0.96, for 1998-1999, and 1.05, for 1999-2000. Preventing a secondary epidemic of TB among HIV-negative individuals may be achievable with conventional means, even in settings with a high burden of HIV-associated TB.


Zinc oxide/redox mediator composite films-based sensor for electrochemical detection of important biomolecules.
Electrochemical oxidation of serotonin (SN) onto zinc oxide (ZnO)-coated glassy carbon electrode (GCE) results in the generation of redox mediators (RMs) that are strongly adsorbed on electrode surface. The electrochemical properties of zinc oxide-electrogenerated redox mediator (ZnO/RM) (inorganic/organic) hybrid film-coated electrode has been studied using cyclic voltammetry (CV). The scanning electron microscope (SEM), atomic force microscope (AFM), and electrochemical techniques proved the immobilization of ZnO/RM core/shell microparticles on the electrode surface. The GCE modified with ZnO/RM hybrid film showed two reversible redox peaks in acidic solution, and the redox peaks were found to be pH dependent with slopes of -62 and -60 mV/pH, which are very close to the Nernst behavior. The GCE/ZnO/RM-modified electrode exhibited excellent electrocatalytic activity toward the oxidations of ascorbic acid (AA), dopamine (DA), and uric acid (UA) in 0.1M phosphate buffer solution (PBS, pH 7.0). Indeed, ZnO/RM-coated GCE separated the anodic oxidation waves of DA, AA, and UA with well-defined peak separations in their mixture solution. Consequently, the GCE/ZnO/RMs were used for simultaneous detection of DA, AA, and UA in their mixture solution. Using CV, calibration curves for DA, AA, and UA were obtained over the range of 6.0 x 10(-6) to 9.6 x 10(-4)M, 1.5 x 10(-5) to 2.4 x 10(-4)M, and 5.0 x 10(-5) to 8 x 10(-4)M with correlation coefficients of 0.992, 0.991, and 0.989, respectively. Moreover, ZnO/RM-modified GCE had good stability and antifouling properties.


In situ TEM and energy dispersion spectrometer analysis of chemical composition change in ZnO nanowire resistive memories.
Resistive random-access memory (ReRAM) has been of wide interest for its potential to replace flash memory in the next-generation nonvolatile memory roadmap. In this study, we have fabricated the Au/ZnO-nanowire/Au nanomemory device by electron beam lithography and, subsequently, utilized in situ transmission electron microscopy (TEM) to observe the atomic structure evolution from the initial state to the low-resistance state (LRS) in the ZnO nanowire. The element mapping of LRS showing that the nanowire was zinc dominant indicating that the oxygen vacancies were introduced after resistance switching. The results provided direct evidence, suggesting that the resistance change resulted from oxygen migration.


Addition of e-aq and H atoms to hypoxanthine and inosine and the reactions of alpha-hydroxyalkyl radicals with purines. A pulse radiolysis and product analysis study.
The reactions of hydrated electrons e-aq with hypoxanthine and inosine were followed using pulse radiolysis methods. In a neutral solution the electron adduct of inosine is immediately protonated at the heteroatoms of the purine ring by water (k >> 2.5 x 10(6)s-1) to give In(N,O-H).. These N,O-protonated intermediates have a single absorption maximum at 300 nm. In basic solution the protonation of the electron adduct of inosine by water leads to other intermediate products with an absorption maximum at 350 nm. These intermediates are believed to be the C-protonated electron adducts of inosine (In(N,O-H).). In (N,O-H). and In(C-H). differ strongly in their ability to reduce p-nitroacetophenone (PNAP). In(N,O-H). are strong reductants and reduce PNAP quantitatively to PNAP.-. Based on the pH dependence of PNAP.- yields, two types of tautomers of In(C-H). could be distinguished. One of the tautomers can reduce PNAP, albeit with slower rate than In(N,O-H)., the other tautomer has no reducing properties. The latter is the one with the higher pKa and therefore thermodynamically more stable. The absorption spectrum of the intermediates produced in the reaction of e-aq with hypoxanthine at neutral pH is very similar to that of In(N,O-H). with a maximum at 300 nm. However, no build-up at 350 nm was observed in basic solution as in the case of the electron adduct of inosine. The reaction of H atoms with inosine produces in basic solution intermediate radicals with the same absorption spectrum as the C-protonated electron adducts of inosine. It is suggested that both the reactions of e-aq and H. with inosine in basic solution produce the same radical, namely the H-adduct of inosine (In(C-H)) with the highest pKa. alpha-Hydroxyalkyl radicals were found to react very slowly with purine bases and nucleosides in neutral to basic solutions. In acidic solution their reactivity increases and a number of rate constants were determined by pulse radiolysis measurements at pH 0.4. The intermediates from the reaction of 2-hydroxy-2-propyl radicals with inosine could be observed pulse spectrometrically in neutral and in basic solutions. In basic solution this reaction leads to intermediates with the same absorption maximum at 350 nm as that of the H-adduct of inosine. Furthermore, the yield of acetone was found to increase strongly in basic pH.(ABSTRACT TRUNCATED AT 400 WORDS)


Basic fibroblast growth factor expression in human omental microvascular endothelial cells and the effect of phorbol ester.
The human omentum contains a potent, not yet identified angiogenic activity. The omentum is very vascularized. Therefore, we investigated whether human omental microvascular endothelial cells (HOME cells) express the angiogenic peptide basic fibroblast growth factor (bFGF). Cytosol prepared from HOME cells stimulated DNA synthesis in bovine epithelial lens cells (BEL cells). The mitogenic activity could be neutralized by an anti-bFGF antibody. Basic FGF-like material from the HOME cell cytosol was bound onto a heparin-Sepharose column at 0.6 M and was eluted at 3 M NaCl. The 3 M NaCl eluted material reacted with the specific anti-bFGF antibody in an ELISA and stimulated DNA synthesis. It did not react with a specific anti-acidic fibroblast growth factor (aFGF) antibody. Western blotting experiments using the same bFGF antibody showed the presence of a major band of 17 Kd and a doublet of 20-22 Kd. Northern blotting of non-stimulated HOME cells using a specific 1.4 kb bFGF probe showed the presence of 5 molecular species of 6.6, 3.7, 2.2, 2.0, and 1.0 kb. No aFGF mRNA was detected with a specific previously characterized 4.04 kb probe. 12-O-tetradecanoylphorbol 13-acetate (TPA) did not influence significantly the expression of bFGF at the protein and mRNA level in HOME cells. Thus, protein kinase C activation by TPA did not appear to modulate significantly the expression of bFGF for that cell type. Contrastingly, human umbilical vein endothelial cells (HUVE cells), which expressed no bFGF and aFGF mRNA at a basal level, were induced to express bFGF but not aFGF mRNA when stimulated by TPA. These results suggest that the described angiogenic activity could be the bFGF-like mitogen contained in HOME cells and that these cells are different from endothelial cells derived from large vessels (HUVE cells) regarding the expression of bFGF.


Trauma and multi-impulsivity in the eating disorders.
Multiple impulsive behaviours are common in the eating disorders, and multi-impulsive patients appear to do more poorly in treatment. However, comparatively little is known about the origins of multi-impulsivity in such cases. This study addresses the links between reported childhood trauma and multi-impulsivity in the eating disorders, examining whether specific types of trauma are predictive of specific impulsive behaviours in this population. The sample consisted of 102 individuals who met strict criteria for an eating disorder, and who were interviewed regarding trauma history and comorbid impulsive behaviours. Any reported history of childhood trauma was associated with a higher number of impulsive behaviours and with the presence of multi-impulsivity. Childhood sexual abuse was particularly important, and was associated with self-cutting, alcohol abuse, and substance abuse (amphetamines, cocaine, cannabis and 'other substances', including ketamine and benzodiazepines). These findings indicate the importance of considering the psychological consequences of trauma during both assessment and treatment of the eating disorders. In particular, eating-disordered women who report a history of childhood sexual abuse should be examined for a pattern of comorbid impulsive behaviours.


Exogenous spermidine ameliorates tubular necrosis during cisplatin nephrotoxicity.
The hallmark of cisplatin-induced acute kidney injury is the necrotic cell death in the kidney proximal tubules. However, an effective approach to limit cisplatin nephrotoxicity remains unknown. Spermidine is a polyamine that protects against oxidative stress and necrosis in aged yeasts, and the present study found that exogenous spermidine markedly attenuated tubular necrosis and kidney dysfunction, but not apoptosis, during cisplatin nephrotoxicity. In addition, exogenous spermidine potently inhibited oxidative/nitrative DNA damage, poly(ADP-ribose) polymerase 1 (PARP1) activation and ATP depletion after cisplatin injection. Conversely, inhibition of ornithine decarboxylase (ODC) via siRNA transfection in vivo significantly increased DNA damage, PARP1 activation and ATP depletion, resulting in acceleration of tubular necrosis and kidney dysfunction. Finally, exogenous spermidine removed severe cisplatin injury induced by ODC inhibition. In conclusion, these data suggest that spermidine protects kidneys against cisplatin injury through DNA damage and tubular necrosis, and this finding provides a novel target to prevent acute kidney injury including nephrotoxicity.


Enzyme-mediated polymerization inside engineered protein cages.
Engineered variants of the capsid-forming enzyme lumazine synthase, AaLS, were used as nanoreactors for an enzyme-mediated polymerization. Oxidation of 3,3-diaminobenzidine (DAB) by the engineered ascorbate peroxidase APEX2 encapsulated in AaLS capsids resulted in templated formation of polyDAB-capsid nanoparticles of homogeneous size and shape.


The pathogenesis of ovarian hyperstimulation syndrome: a continuing enigma.
Our purpose was to review the available literature concerning the pathogenesis of ovarian hyperstimulation syndrome and, in light of the most recent information, to attempt to provide further insight on this iatrogenic complication associated with the induction of ovulation. Published studies related to this topic were identified through a computerized bibliographic search. The exact mechanism for the development of ovarian hyperstimulation syndrome is still obscure. It is well established that the syndrome is associated with the process of ovulation induced by either luteinizing hormone or human chorionic gonadotropin. Following ovulation, one or more substances produced by the ovary are liberated in excess, increasing capillary permeability, resulting in the clinical features of the syndrome. It may well be that the syndrome is not triggered by a single mechanism but by the production and secretion of several substances acting in concert. These may include prostaglandins, cytokines, the ovarian reninangiotensin system, vascular endothelial growth factor, and nitric oxide.


Seborrhoeic dermatitis: current treatment practices.
Seborrhoeic dermatitis (SD) is a recurrent, chronic inflammation of the skin that occurs on sebum rich areas such as the face, scalp and chest, characterised by red scaly lesions. The are many studies indicating that Malassezia yeasts play an important role in the aetiology of this condition, most of the evidence for which comes from demonstrated responsiveness to treatment with antifungal agents. Its aetiology, however, is far from being resolved. Some believe that it is the immune response of the skin to the Malassezia that is the cause of the disease. Traditional treatments of SD have been the use of keratolytic agents or corticosteroids. Since the discovery of ketoconazole, a considerable amount of research has been focused on determining the efficacy of various antifungal agents. This article reviews clinical trial data on treatment options available for SD.


Effects of the volatile anesthetic agents on sinus node function and atrioventricular conduction in dogs: a comparison with chloralose anesthesia.
The effects of equipotent concentrations (1.5 times minimum alveolar concentration) of the inhalational agents halothane, enflurane, and isoflurane on sinus node function, and atrioventricular (A-V) conduction and refractoriness were compared with chloralose anesthesia in 49 mongrel dogs. Sinus node function was assessed using corrected sinus node recovery time. Atrial-His and His-ventricular conduction times were measured at paced heart rates of 150, 180, and 200 beats/min, and A-V refractoriness was assessed by Wenckebach periodicity. There was no evidence that sinus node function was impaired by any of the inhalational agents. Enflurane anesthesia was associated with a significant prolongation of atrial-His conduction at paced heart rates of 180 and 200 beats/min when compared to chloralose anesthesia and the other two inhalational agents (P < .001). Atrioventricular refractoriness was impaired by enflurane (P < .001) and halothane (P < .05), but not isoflurane, when compared with chloralose anesthesia. Ventricular-His conduction was not altered by any of the agents. The authors conclude that enflurane is associated with a greater impairment of A-V conduction and refractoriness than halothane or isoflurane, and that these changes are related to the anesthetic agent and not the anesthetic state.


Extracellular ATP and adenosine induce cell apoptosis of human hepatoma Li-7A cells via the A3 adenosine receptor.
1. Extracellular ATP is a potent signaling molecule that modulates a myriad of cellular functions through the activation of P2 purinergic receptors and is cytotoxic to a variety of cells at higher concentrations. The mechanism of ATP-elicited cytotoxicity is not fully understood. In this study, we investigated the effect of extracellular ATP on the human hepatoma Li-7A cells. 2. We observed a time- and dose-dependent growth inhibition of Li-7A cells by ATP, which is accompanied by an increase in the active form of caspase-3 as well as increased cleavage of its substrate, poly (ADP-ribose) polymerase. The cytotoxic effect of extracellular ATP was not mediated by the P2X7 receptor, since (1).the effect was not abolished by the P2X7 receptor antagonists oxidized ATP and KN-62, and (2).extracellular ADP, AMP, and adenosine were also cytotoxic. 3. We found that ATP and ADP were degraded to adenosine by Li-7A cells and that treatment of Li-7A cells by adenosine resulted in growth inhibition and caspase-3 activation, indicating that adenosine is the apoptotic agent. Using adenosine receptor agonists and antagonists, as well as inhibitors of adenosine transport and deamination, we showed that the cytotoxic effect of adenosine is specifically mediated by the A3 receptor even though transcripts of A1, A2A, A2B, and a splice variant of the P2X7 receptors were detected in Li-7A cells by RT-PCR. 4. Cytotoxicity caused by exogenous ATP and adenosine was completely abolished by the caspase-3 inhibitor Z-DEVD-FMK, demonstrating the central role of caspase-3 in apoptosis of Li-7A cells.


Fine-tuning ER-beta structure with PTMs.
Estrogen receptor beta is differentially regulated by alternative O-GlcNAcylation/O-phosphorylation at Ser(16). NMR, CD, and molecular dynamics analyses of model peptides show that these alternative modifications induce different peptide conformations, providing a molecular basis for their differential regulation of protein function.


Student's perception of school bullying and its impact on academic performance: A longitudinal look.
Bullying among peers has immediate and long-term consequences, as it affects children's health-related quality of life. The aim was to examine the association between the frequency, type and dynamics of children's involvement in bullying situations and their academic performance over the school year. Longitudinal study conducted in 2015 in 9 to 12 year-olds in schools of Bahía Blanca, Argentina. Outcome measures: children's involvement in bullying situations, frequency of participation in bullying and academic performance. Bullying categories were obtained through the Preconceptions of Bullying and Intimidation Among Peers (PRECONCIMEI) questionnaire and academic performance as reflected by each child's school grades. The survey included 375 children, of which 22.1% (83/375) were repeatedly involved and 30.12% (113/375) were occasionally involved in bullying situations (20.27% [76/375] reported having participated by the year end but not at the beginning, and 9.85% [37/375] showed the opposite behavior). No statistically significant differences were found, regardless of the course subject analyzed. Grades were found to have improved by school year-end, in all groups assessed. No association was found between bullying and academic performance.


Pseudorheumatoid disability man with chronic tophaceous gout: a case report.
Gout is a type of inflammatory arthropathy that affects the peripheral joints and results from the accumulation of monosodium urate (MSU) crystals in the synovial fluid and other tissues. This disease is the most common form of inflammatory arthritis in men over 40 years of age. The fundamental biochemical abnormality in gout is an increase in serum urate (SU) concentration. These needle-like crystals induce not only acute episodes of inflammatory process into the surrounding area, but also, in the long-term history of the disease, chronic inflammation that is associated with changes in articular and periarticular structures. The next step caused by deposited MSU crystals is represented by the tophus formation and chronic gouty synovitis. The presence of tophi has been associated with greater physical functional disability in gout patients. We presented a case of severe chronic tophaceous gout in a 48-year-old man with chronic hand arthritis and urolithiasis, to point the significance of complex assessment (clinical, functional, imagistic and histological exams) in the diagnosis of a soft tissue lesion, especially in hands.


System-wide biochemical analysis reveals ozonide antimalarials initially act by disrupting Plasmodium falciparum haemoglobin digestion.
Ozonide antimalarials, OZ277 (arterolane) and OZ439 (artefenomel), are synthetic peroxide-based antimalarials with potent activity against the deadliest malaria parasite, Plasmodium falciparum. Here we used a "multi-omics" workflow, in combination with activity-based protein profiling (ABPP), to demonstrate that peroxide antimalarials initially target the haemoglobin (Hb) digestion pathway to kill malaria parasites. Time-dependent metabolomic profiling of ozonide-treated P. falciparum infected red blood cells revealed a rapid depletion of short Hb-derived peptides followed by subsequent alterations in lipid and nucleotide metabolism, while untargeted peptidomics showed accumulation of longer Hb-derived peptides. Quantitative proteomics and ABPP assays demonstrated that Hb-digesting proteases were increased in abundance and activity following treatment, respectively. Ozonide-induced depletion of short Hb-derived peptides was less extensive in a drug-treated K13-mutant artemisinin resistant parasite line (Cam3.IIR539T) than in the drug-treated isogenic sensitive strain (Cam3.IIrev), further confirming the association between ozonide activity and Hb catabolism. To demonstrate that compromised Hb catabolism may be a primary mechanism involved in ozonide antimalarial activity, we showed that parasites forced to rely solely on Hb digestion for amino acids became hypersensitive to short ozonide exposures. Quantitative proteomics analysis also revealed parasite proteins involved in translation and the ubiquitin-proteasome system were enriched following drug treatment, suggestive of the parasite engaging a stress response to mitigate ozonide-induced damage. Taken together, these data point to a mechanism of action involving initial impairment of Hb catabolism, and indicate that the parasite regulates protein turnover to manage ozonide-induced damage.


Case report: Tisagenlecleucel for treatment of relapsed B- acute lymphoblastic leukemia in a patient with CHEK2 mutation.
Germline Checkpoint Kinase 2 gene (CHEK2) mutations can increase the risk of solid tumors. Recently, they have been identified as risk factors for hematologic malignancies. However, to the best of our knowledge, B-acute lymphoblastic leukemia (B-ALL) has never been described as a presenting manifestation of germline CHEK2 mutation. Chimeric antigen receptor-T (CAR-T) cell therapy directed against CD19 antigen (tisagenlecleucel) is a novel cellular therapy for treatment of relapsed/refractory (R/R) B-ALL. The use of tisagenlecleucel has not been described in patients with CHEK2 mutation. We describe a case of a pediatric patient with a heterozygous pathogenic germline CHEK2 mutation (c.1100delC; p.Thr367Metfs*15) successfully treated with tisagenlecleucel for relapsed B-ALL to avoid hematopoietic cell transplant (HCT). The twelve-year-old boy was diagnosed with National Cancer Institute (NCI) high-risk B-ALL (white blood cell count >50,000/mcL), with no extramedullary disease. Cytogenetic analysis revealed normal karyotype but fluorescent in situ hybridization (FISH) showed 93% positivity for CRLF2::P2RY8 rearrangement. He was treated as per Children's Oncology Group (COG) AALL1131 therapy and achieved a complete remission. Seven months after diagnosis, he was found to have papillary thyroid carcinoma with no evidence of metastatic disease. The patient underwent a total thyroidectomy with central lymph node biopsy and radioactive iodine therapy. The patient's biological mother and fraternal twin brother carry the same germline CHEK2 mutation with no history of malignancy. The biological father tested negative for the familial mutation. The patient's genetic panel also identified three variants of unclear significance: CDKN2A (c.37 °C > T; p.Arg124Cys), FLCN (c.62G > A; p.Cys21Tyr) and SDHAF2 (c.139A > G; p.Met47Val). Extended family history also revealed a diagnosis of anaplastic thyroid cancer in maternal uncle at the age of 44 years. Fifteen months after diagnosis the patient had a relapse of B-ALL (both medullary and extramedullary with blasts in CSF), which was successfully treated with tisagenlecleucel. The patient remains in remission 3 years after receiving tisagenlecleucel. As conventional chemotherapy and radiation can potentially increase the risk of DNA damage and development of secondary malignancies, CD19 CAR-T therapy (tisagenlecleucel) can be used as a substitute for intensive re-induction chemotherapy and HCT in patients with a germline CHEK2 mutation.


Slice-selective RF pulses for in vivo B1+ inhomogeneity mitigation at 7 tesla using parallel RF excitation with a 16-element coil.
Slice-selective RF waveforms that mitigate severe B1+ inhomogeneity at 7 Tesla using parallel excitation were designed and validated in a water phantom and human studies on six subjects using a 16-element degenerate stripline array coil driven with a butler matrix to utilize the eight most favorable birdcage modes. The parallel RF waveform design applied magnitude least-squares (MLS) criteria with an optimized k-space excitation trajectory to significantly improve profile uniformity compared to conventional least-squares (LS) designs. Parallel excitation RF pulses designed to excite a uniform in-plane flip angle (FA) with slice selection in the z-direction were demonstrated and compared with conventional sinc-pulse excitation and RF shimming. In all cases, the parallel RF excitation significantly mitigated the effects of inhomogeneous B1+ on the excitation FA. The optimized parallel RF pulses for human B1+ mitigation were only 67% longer than a conventional sinc-based excitation, but significantly outperformed RF shimming. For example the standard deviations (SDs) of the in-plane FA (averaged over six human studies) were 16.7% for conventional sinc excitation, 13.3% for RF shimming, and 7.6% for parallel excitation. This work demonstrates that excitations with parallel RF systems can provide slice selection with spatially uniform FAs at high field strengths with only a small pulse-duration penalty.


A conversation with Drs. Kaplan and Moser about conflicting data, confusing results, and some recent treatment recommendations for the management of hypertension.
Following a hypertension symposium in Baltimore, MD, on June 1, 2005, Dr. Wendy Post from the Johns Hopkins University School of Medicine, Baltimore, MD, had the opportunity to interview two of the outstanding hypertension experts in the United States on several controversial issues in hypertension management. Dr. Norman Kaplan is Clinical Professor of Medicine at the Southwestern Health Science Center in Dallas, TX, and Dr. Marvin Moser is Clinical Professor of Medicine at the Yale University School of Medicine, New Haven, CT. Both have been leaders in the field of hypertension treatment and education for more than 40 years. Dr. Kaplan's book Clinical Hypertension has been a standard textbook since 1973 and is now in its ninth edition. Dr. Marvin Moser was the Senior Medical Consultant to the National High Blood Pressure Education Program from 1974 to 2002 and was Chairman of the first Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure and a member of the six subsequent committees. His book Clinical Management of Hypertension is in its seventh edition. Drs. Moser and Kaplan were corecipients of the 2004 International Society of Hypertension Award for Outstanding Contributions to Hypertension Treatment and Education and have lectured extensively throughout the United States and overseas.


Effect of Process Parameters on Thermal and Mechanical Properties of Filament Wound Polymer-Based Composite Pipes.
The aim of this study was to investigate the mechanical and thermal properties of composite pipes based on epoxy resin and glass fibers produced by filament winding (FW) technology. Epoxy resins are widely used polymers in FW composite structures. The thermal characterization of the neat epoxy resin, curing, and post-curing characteristics for the determination of polymerization and glass transition temperature was performed, which is important for the mechanical properties of polymer composite pipes. In the present work, the applicability of the full factorial experimental design in predicting the hoop tensile and compressive strengths of glass fiber/epoxy resin composite pipes was investigated. The composite pipes in accordance with the 23 full factorial experimental design by using of three parameters and two levels of variation were prepared. The winding speed of the composites was taken to be the first factor, the second was the fiber tension, and the third was winding angle. To approximate the response, i.e., the mechanical properties of the composite pipes within the study domain, the first-order linear model with the interaction was used. The influence of each individual factor to the response function was established, as well as the influence of the interaction of the two and three factors. Additionally, those results were completed with the thermal characterization of the polymer composite pipes. From received results from mechanical and thermal characterization, it was concluded that the properties of composite specimens were highly affected by the analyzed parameters in filament winding technology. It was found that the estimated first-degree regression equation with the interaction gave a very good approximation of the experimental results of the hoop tensile and the compressive strengths of composite pipes within the study domain.


Characterization of L-leucine-induced germination of Trichophyton mentagrophytes microconidia.
l-Leucine and several amino acids were effective germination inducers of microconidia of Trichophyton mentagrophytes. During germination, phase-darkening and swelling occurred concomitantly with the loss of resistance to heat and stain, reduction of dry weight and specific gravity, and development of active glucose utilization. Germination induced by l-leucine was significantly stimulated by a pretreatment of the spores with sublethal doses of heat. No nucleosides or nucleotides were stimulatory to the l-leucine-induced germination of the microconidia. d-Leucine was almost an equally effective germinant as its l form. No carbohydrates, salts, vitamins, or other compounds tested induced germination of the fungus spore. Other factors that affected l-leucine-induced germination of the microconidia included the concentration of leucine, the inoculum size of the spores, temperature, and pH. The anaerobic condition and the presence or absence of carbon dioxide had no significant effects on the germination. Short germ tubes usually developed when the germinated spores were further incubated either in the presence or absence of l-leucine. The cytological study of the germinating microconidia revealed that the fragmentation of lipid granules was the major structural change associated with the germination.


Diversity of Cercomonad Species in the Phyllosphere and Rhizosphere of Different Plant Species with a Description of Neocercomonas epiphylla (Cercozoa, Rhizaria) a Leaf-Associated Protist.
Cercomonads are among the most abundant and diverse groups of heterotrophic flagellates in terrestrial systems and show an affinity to plants. However, we still lack basic knowledge of plant-associated protists. We isolated 75 Cercomonadida strains from the phyllosphere and rhizosphere of plants from three functional groups: grasses (Poa sp.), legumes (Trifolium sp.) and forbs (Plantago sp.), representing 28 OTUs from the genera Cercomonas, Neocercomonas and Paracercomonas. The community composition differed clearly between phyllosphere and rhizosphere, but was not influenced by plant species identity. From these isolates we describe three novel cercomonad species including Neocercomonas epiphylla that was consistently and exclusively isolated from the phyllosphere. For each new species we provide a detailed morphological description as well as an 18S rDNA gene sequence as a distinct marker of species identity. Our data contribute to a better resolution of the systematics of cercomonads and their association with plants, by describing three novel species and adding gene sequences of 10 new cercomonad genotypes and of nine previously described species. In view of the functional importance of cercozoan communities in the phyllosphere and rhizosphere of plants, a more detailed understanding of their composition, function and predator-prey interactions are clearly required.


Characteristics and Outcomes of Second Malignant Neoplasms after Childhood Cancer Treatment: Multi-Center Retrospective Survey.
This retrospective study investigated the clinical characteristics and outcomes of second malignant neoplasms (SMNs) in survivors of childhood cancer from multiple institutions in Korea. A total of 102 patients from 11 institutions who developed SMN after childhood cancer treatment between 1998 and 2011 were retrospectively enrolled. The most common primary malignant neoplasms (PMNs) were central nervous system (CNS) tumors (n = 17), followed by acute lymphoblastic leukemia (n = 16), non-Hodgkin lymphoma (n = 13), and osteosarcoma (n = 12). The most common SMNs were therapy-related myeloid neoplasms (t-MNs; acute myeloid leukemia [AML], 29 cases; myelodysplastic syndrome [MDS], 12 cases), followed by thyroid carcinomas (n = 15) and CNS tumors (n = 10). The median latency period was 4.9 years (range, 0.5-18.5 years). Among 45 patients with solid tumors defined as an SMN, 15 (33%) developed the lesion in a field previously subjected to radiation. The 5-year overall survival (OS) rate of patients with an SMN was 45% with a median follow-up time of 8.6 years. Patients with AML, MDS, and CNS tumors exhibited the poorest outcomes with 5-year OS rates of 18%, 33%, and 32%, respectively, whereas those with second osteosarcoma showed comparable outcomes (64%) to patients with primary counterpart and those with second thyroid carcinoma had a 100% OS rate. Further therapeutic efforts are recommended to improve the survival outcomes in patients with SMNs, especially in cases with t-MNs and CNS tumors.


Using a trait-based approach to optimize mixotrophic growth of the red microalga Porphyridium purpureum towards fatty acid production.
Organic carbon sources have been reported to simultaneously increase the growth and lipid accumulation in microalgae. However, there have been no studies of the mixotrophic growth of Porphyridium purpureum in organic carbon media. In this study, three organic carbon sources, glucose, sodium acetate, and glycerol were used as substrates for the mixotrophic growth of P. purpureum. Moreover, a novel trait-based approach combined with Generalized Additive Modeling was conducted to determine the dosage of each organic carbon source that optimized the concentration of cell biomass or fatty acid. A 0.50% (w/v) dosage of glucose was optimum for the enhancement of the cell growth of P. purpureum, whereas sodium acetate performed well in enhancing cell growth, arachidonic acid (ARA) and eicosapentaenoic acid (EPA) content, and glycerol was characterized by its best performance in promoting both cell growth and ARA/EPA ratio. The optimum dosages of sodium acetate and glycerol for the ARA concentration were 0.25% (w/v) and 0.38% (v/v), respectively. An ARA concentration of 211.47 mg L-1 was obtained at the optimum dosage of glycerol, which is the highest ever reported. The results suggested that a comprehensive consider of several traits offers an effective strategy to select an optimum dosage for economic and safe microalgae cultivation. This study represents the first attempt of mixotrophic growth of P. purpureum and proved that both biomass and ARA accumulation could be enhanced under supplements of organic carbon sources, which brightens the commercial cultivation of microalgae for ARA production.


A Comparative Study of Morphine and Clonidine as an Adjunct to Ropivacaine in Paravertebral Block for Modified Radical Mastectomy.
Background General anesthesia (GA) is a standard for breast malignant surgery. The issue of postoperative pain as well as the high occurrence of nausea and vomiting have prompted the quest for a superior methodology for tormenting the executives with fewer complications. Over the most recent couple of years, paravertebral block (PVB) has acquired huge fame either in combination with GA or alone for anesthetic management. In this study, we aim to evaluate the efficacy of morphine and clonidine as an adjunct to ropivacaine in PVB in breast cancer patients undergoing modified radical mastectomy. Methods In this study, a total of 90 patients were divided into the following three groups (30 each) based on a computer-generated random table. Group C (control): PVB with 0.25% ropivacaine (19 ml) 1 ml saline; Group M: PVB with 0.25% ropivacaine (19 ml) + 20 microgram/kg body weight morphine; Group N: PVB with 0.25% ropivacaine (19 ml) + 1.0 microgram/kg body weight clonidine. The postoperative pain intensity was recorded using the visual analog scale (VAS), and sedation was observed by the Ramsay Sedation Scale (RSS) score. Results The VAS was similar at zero hours, two hours, and four hours in the postoperative period among all the groups. There was a significant (p = 0.003) difference in VAS from six hours to 20 hours in the postoperative period among the groups. A significant (p < 0.05) difference was observed among the groups at eight hours to 20 hours. The first requirement of analgesia was significantly (p = 0.001) higher in Group N (7.70 ± 1.74) than in Group C (4.43 ± 1.43) and Group M (7.33 ± 2.21). Conclusion Morphine in the PVB provides better postoperative analgesia. The consumption of rescue analgesia was significantly reduced in the morphine group as compared to the clonidine group. The procedure also proved to be safe as no complication was encountered in the PVB in our study.


Nicotine promotes cell proliferation and induces resistance to cisplatin by α7 nicotinic acetylcholine receptor‑mediated activation in Raw264.7 and El4 cells.
Although nicotine is a risk factor for carcinogenesis and atherosclerosis, epidemiological data indicate that nicotine has therapeutic benefits in treating Alzheimer's disease. Our previous studies also showed that nicotine-treated dendritic cells have potential antitumor effects. Hence, the precise effects of nicotine on the biological characterizations of cells are controversial. The aim of the present study was to assess the roles of α7 nicotinic acetylcholine receptors (nAChRs), Erk1/2-p38-JNK and PI3K-Akt pathway in nicotine-mediated proliferation and anti-apoptosis effects. The results firstly showed that nicotine treatment clearly augmented cell viability and upregulated PCNA expression in both Raw264.7 and El4 cells. Meanwhile, nicotine afforded protection against cisplatin-induced toxicity through inhibiting caspase-3 activation and upregulating anti-apoptotic protein expression. Further exploration demonstrated that nicotine efficiently abolished cisplatin-promoted mitochondria translocation of Bax and the release of cytochrome c. The pretreatment of α-bungarotoxin and tubocurarine chloride significantly attenuated nicotine-augmented cell viability, abolished caspase-3 activation and α7 nAChR upregulation. Both Erk-JNK-p38 and PI3K-Akt signaling pathways could be activated by nicotine treatment in Raw264.7 and El4 cells. Notably, when Erk-JNK and PI3K-Akt activities were inhibited, nicotine-augmented cell proliferation and anti-apoptotic effects were abolished accordingly. The results presented here indicate that nicotine could achieve α7 nAChR-mediated proliferation and anti-apoptotic effects by activating Erk-JNK and PI3K-Akt pathways respectively, providing potential therapeutic molecules to deal with smoking-associated human diseases.


The physician executive: role in the adaptation of American medicine.
In the arena of managed care and large delivery systems, professional associations find it increasingly difficult to influence the environments in which their members practice. Physician executives appear likely to play key roles in the response of medicine to change. This article discusses how an analysis of the work of physicians involved in management fails to yield a clear analytic distinction between physicians engaged in management and the behavior of others who have managerial responsibility.


Investigation into avian pneumovirus persistence in poults and chicks using cyclosporin A immunosuppression.
One-day-old poults or two-week old chicks were infected oculonasally with avian pneumovirus. Cloacal swabs were collected for virus isolation as were selected tissues (Harderian gland, turbinates, trachea, lungs and kidneys) from birds killed at regular intervals up to 33 days post infection (p.i.) for poults, and up to 40 days p. i. for chicks. In an attempt to induce virus re-excretion, the T-cell-suppressor cyclosporin A (CSA) was given for 12 days starting from three weeks p.i. in poults and from four weeks p.i. in chicks. Birds were sampled for virus isolations up to day 12 post CSA treatment. Virus was recovered only up to day nine p.i. in poults, and day five p.i. in chicks during the acute phase of the infection. Despite T-cell suppression, there was no evidence of re-excretion of the virus, and hence no evidence for the persistence of virus in the tissues examined.


Coumarins as Powerful Photosensitizers for the Cationic Polymerization of Epoxy-Silicones under Near-UV and Visible Light and Applications for 3D Printing Technology.
In this study, eight coumarins (coumarins 1-8) are proposed as near-UV and blue light sensitive photoinitiators/photosensitizers for the cationic polymerization (CP) of epoxysilicones when combined with 4-isopropyl-4'-methyldiphenyliodonium tetrakis(pentafluorophenyl)borate (IOD). Among these coumarins, four of them (coumarins 1, 2, 6 and 8) have never been reported in the literature, i.e., these structures have been specifically designed to act as photoinitiators for silicones upon near UV and visible irradiation. Good final reactive epoxy function conversions (FCs) and also high rates of polymerization (Rp) were achieved in the presence of the newly proposed coumarin-based systems. The polymers generated from the photopolymerization of epoxysilicones can be considered as attractive candidates for several applications such as: elastomers, coatings, adhesives, and so on. The goal of this study focuses also on the comparison of the new proposed coumarins with well-established photosensitizers i.e., 1-chloro-4-propoxythioxanthone (CPTX), 9,10-dibutoxyanthracene (DBA) or some commercial coumarins (Com. Coum). As example of their high performance, the new proposed coumarins were also used for laser write experiments upon irradiation with a laser diode at 405 nm in order to develop new cationic 3D printing systems.


[Changes in the ultrastructure of the chloride cells of sturgeon during adaptation to a hypertonic medium].
Alterations in the ultrastructure of chloride cells of young sturgeons Acipenser guldenstadti Brandt in the process of adaptation to hypertonic medium (S=105%) were under study. In the process of this adaptation thread-shaped long mitochondria became shorter, their random position was substituted by orientation in parallel to the axis of the cell. The amount of mitochrondria increased. A great number of vacuoles appeared in the cytoplasm. The character of the endoplasmic reticulum changed. The obtained data on the ultrastructure of chloride cells of the sturgeon confirm and supplement earlier light microscopy investigations of chloride cells of the sturgeon. The changes of the ultrastructure of chloride cells are interpreted as functional and adaptational ones.


Bio-synthesized iron oxide nanoparticles for cancer treatment.
Various living organisms, such as bacteria, plants, and animals can synthesize iron oxide nanoparticles (IONP). The mechanism of nanoparticle (NP) formation is usually described as relying on the reduction of ferric/ferrous iron ions into crystallized nanoparticulate iron that is surrounded by an organic stabilizing layer. The properties of these NP are characterized by a composition made of different types of iron oxide whose most stable and purest one appears to be maghemite, by a size predominantly comprised between 5 and 380 nm, by a crystalline core, by a surface charge which depends on the nature of the material coating the iron oxide, and by certain other properties such as a sterility, stability, production in mass, absence of aggregation, that have apparently only been studied in details for IONP synthesized by magnetotactic bacteria, called magnetosomes. In the majority of studies, bio-synthesized IONP are described as being biocompatible and as not inducing cytotoxicity towards healthy cells. Anti-tumor activity of bio-synthesized IONP has mainly been demonstrated in vitro, where this type of NP displayed cytotoxicity towards certain tumor cells, e.g. through the anti-tumor activity of IONP coating or through IONP anti-oxidizing property. Concerning in vivo anti-tumor activity, it was essentially highlighted for magnetosomes administered in different types of glioblastoma tumors (U87-Luc and GL-261), which were exposed to a series of alternating magnetic field applications, resulting in mild hyperthermia treatments at typical temperatures of 41-45 °C, leading to the full disappearance of these tumors without any observable side effects.


[Developing a system to promote good prenatal and postnatal care, and good preschool education based on the cellphone platform].
Good prenatal and postnatal care and good preschool education are important approaches to raise the diatheses of population for the chinese nation. This article suggests that the cell phone platform can be used to communicate with each other among the hospitals, the government and the common people, through which the useful informations could be transmitted to the relative persons in time. It's also a new way for propaganda of family planning. This article introduces the structure of the system, the creation of the expert database, and the connection to the telecommunication system.


The Medicago truncatula SUNN gene encodes a CLV1-like leucine-rich repeat receptor kinase that regulates nodule number and root length.
Four Medicago truncatula sunn mutants displayed shortened roots and hypernodulation under all conditions examined. The mutants, recovered in three independent genetic screens, all contained lesions in a leucine-rich repeat (LRR) receptor kinase. Although the molecular defects among alleles varied, root length and the extent of nodulation were not significantly different between the mutants. SUNN is expressed in shoots, flowers and roots. Although previously reported grafting experiments showed that the presence of the mutated SUNN gene in roots does not confer an obvious phenotype, expression levels of SUNN mRNA were reduced in sunn-1 roots. SUNN and the previously identified genes HAR1 (Lotus japonicus) and NARK (Glycine max) are orthologs based on gene sequence and synteny between flanking sequences. Comparison of related LRR receptor kinases determined that all nodulation autoregulation genes identified to date are the closest legume relatives of AtCLV1 by sequence, yet sunn, har and nark mutants do not display the fasciated clv phenotype. The M. truncatula region is syntenic with duplicated regions of Arabidopsis chromosomes 2 and 4, none of which harbor CLV1 or any other LRR receptor kinase genes. A novel truncated copy of the SUNN gene lacking a kinase domain, RLP1, is found immediately upstream of SUNN and like SUNN is expressed at a reduced level in sunn-1 roots.


Psychological Capital Profiles and Their Relationship With Internal Learning in Teams of Undergraduate Students.
This study aims to analyze the relationship between psychological capital profiles and internal learning in teams. The participants in this study were 480 undergraduate students. We performed a cluster analysis using the SPSS and yielded four distinct psychological capital profiles. The student profile with the highest scores in self-efficacy, optimism, hope, and resilience (Profile 2-Fully PsyCap) exhibited also the highest scores of internal learning in teams. On the other hand, the student profile with the lowest scores in self-efficacy, optimism, hope, and resilience (Profile 1- Empty PsyCap) presented the lowest scores of internal learning in teams. It is also noteworthy that there was no significant relationship between the profile with a positive combination between self-efficacy and hope (profile 4) and the profile that presents the optimism as the only positive psychological capability (profile 3), in the way they relate to internal learning in teams, which led us to reject the second hypothesis of the study. This study reinforces the role of psychological capital in academic settings and suggests that psychological capital profiles can affect internal learning in teams differentially.


Diagnosis and management of infectious complications of childhood rheumatic diseases.
Progress in the diagnosis and management of pediatric rheumatic disease has improved complications from underlying disease and the survival of children. However, as a consequence, infection has now become one of the leading causes of morbidity and mortality. Differentiating between infections and disease flares in children with rheumatic conditions can often pose diagnostic quandaries. Children with rheumatic diseases are at risk of infection, not only because of the use of immune-modulating medications but also because of underlying immune dysfunction associated with their disease. Although bacterial infections are the most common, any organism can potentially be a causative agent and, at times, more invasive measures of diagnosis, for example bronchoscopy and tissue biopsies may be necessary. Maintaining a high index of suspicion of infection with prompt diagnosis and treatment are important to further improve patient outcomes.


Hydroxyurea treatment for sickle cell anemia during pregnancy and lactation: Current evidence and knowledge gaps.
Sickle cell anemia (SCA) is a life-threatening genetic condition contributing to high-risk pregnancies affecting both the mother and fetus. With improved management of children with SCA, this life-threatening hematological disorder has evolved into a chronic disease of adults, and consequently parenthood has now become a possible and important life goal for many patients. Providing continuous management with healthy red blood cell function and avoiding SCA-associated complications, such as pain crises, acute chest syndrome, and stroke, are crucial for a healthy pregnancy. Despite its excellent safety profile in non-pregnant adults and children, and based on theoretical concerns derived from data using animal models and supraphysiological dosing, hydroxyurea is currently contraindicated for pregnant and lactating women with SCA. Clinical experience of hydroxyurea use during pregnancy is increasingly reported, however, and has shown inconsistent results of fetal or infant adverse effects. How the hydroxyurea exposure level may correlate with pregnancy outcomes is still unclear. Accordingly, efforts should be made to systemically evaluate exposure and safety of hydroxyurea treatment during pregnancy and lactation. Novel approaches such as physiologically based pharmacokinetic (PBPK) modeling, coupled with the ex vivo human placental cotyledon perfusion assay, provide opportunities to understand hydroxyurea exposure not only in pregnant women but also in the developing fetus. Combined with animal data, research using these approaches might be able to define safe and effective hydroxyurea dosing regimens for pregnant and lactating women with SCA, when the benefits of continuing hydroxyurea treatment likely outweigh the risks of non-treatment, by avoiding substantial morbidity and even mortality for both mothers and infants.


Use of platelet rich plasma in human infertility.
Successful embryo implantation requires good quality embryo but also needs a receptive endometrium site. In our clinical practice, we daily verify that an adequate endometrial growth is reached for successful implantation. To understand whether platelet rich plasma (PRP) can improve endometrium thickness and performance, PRP treatment was carried out after at least three of the classic medical protocols currently in use had been unsuccessfully adopted. Eight patients with more than 3 cryo-transfers cancelled because of failure of endometrial growth, defined as endometrium less than 6 mm, with negative hysteroscopic screening for endometrial pathology, and with negative bacteriologic screening, before present and all previous treatment, were selected to undergo PRP treatment. In 7 out of 8 treatments, an endometrial thickness greater than 6.5 mm (mean 6.9 mm) was reached, with endometrial three-layer pattern, before progesterone administration and embryo transfer was performed. In 6 out of 7 patients, who underwent embryo transfer, beta-HCG were positive, with 2 biochemical abortions, one miscarriage at 6-week pregnancy, two babies born and one drop-out. In this study, 8 patients had extraordinarily poor endometrial quality, and the endometrium was non-responsive to conventional estrogenic therapy, resulting in cycle cancellation. After application of PRP, the endometrial thickness was satisfactory in all the patients except one. Of these, beta-HCG was positive in 6 women, the pregnancy was progressing normally in 2 women, and one had an early miscarriage. We can suppose that the multiple implantation failures were caused by inefficient expression adhesion molecules, which can hypothetically be more represented after PRP application.


Origin of the transmitted virus in HIV infection: infected cells versus cell-free virus.
All human immunodeficiency virus type 1 (HIV-1)-infected inocula, such as genital secretions, breast milk, and blood, contain both cell-free virus and infected cells. The relative contributions of cell-free and/or cell-associated virus in establishing an infection in a naive host during the different modes of HIV-1 acquisition remains unclear. Studies aim to elucidate the source of the acquired virus because strategies to prevent acquisition may have differential efficacy against the different modes of transmission. In this review, I will detail some of the challenges in identifying the source of the transmitted virus, genotypic and phenotypic differences among cell-free compared with cell-associated HIV-1, and implications on the efficacy for prevention strategies.


Forensic Facial Reconstruction: Relationship Between the Alar Cartilage and Piriform Aperture.
During forensic facial reconstruction, facial features may be predicted based on the parameters of the skull. This study evaluated the relationships between alar cartilage and piriform aperture and nose morphology and facial typology. Ninety-six cone beam computed tomography images of Brazilian subjects (49 males and 47 females) were used in this study. OsiriX software was used to perform the following measurements: nasal width, distance between alar base insertion points, lower width of the piriform aperture, and upper width of the piriform aperture. Nasal width was associated with the lower width of the piriform aperture, sex, skeletal vertical pattern of the face, and age. The current study contributes to the improvement of forensic facial guides by identifying the relationships between the alar cartilages and characteristics of the biological profile of members of a population that has been little studied thus far.


Latent tuberculosis infection: approach and therapeutic schemes.
Tuberculosis continues to be a major public health problem. A priority objective is the implementation of early diagnosis, contact investigation and latent tuberculosis infection (LTBI) testing. World Health Organization (WHO) concludes that there is no gold standard for the diagnosis of LTBI; both the tuberculin test and IGRA (interferon gamma release assays) indirectly identify tuberculosis infection; both tests are considered acceptable but imperfect. WHO recommends that regimens that include rifamycins are equally effective but less toxic and more adherent than long regimens with isoniazid.


Silencing c-MYC expression by targeting quadruplex in P1 promoter using locked nucleic acid trap.
The nuclease hypersensitive element of P1 promoter in c-MYC gene harbors a potential of unusual structure called quadruplex, which is involved in molecular recognition and function. This Hoogsteen bonded structure is in dynamic equilibrium with the usual Watson-Crick duplex structure, and these competing secondary structures undergo interconversion for execution of their respective biological roles. Herein, we investigate the sensitivity of the c-MYC quadruplex-duplex equilibrium by employing a locked nucleic acid (LNA) modified complementary strand as a pharmacological agent. Our biophysical experiments indicate that the c-MYC quadruplex under physiological conditions is stable and dominates the quadruplex-WC duplex equilibrium in both sodium and potassium buffers. This equilibrium is perturbed upon introducing the LNA modified complementary strand, which demonstrates efficient invasion of stable c-MYC quadruplex and duplex formation in contrast to the unmodified complementary strand. Our data indicate that LNA modifications confer increased thermodynamic stability to the duplex and thus favor the predominance of the duplex population over that of the quadruplex. Further, we demonstrate that this perturbation of equilibrium by a pharmacological agent results in altered gene expression. Our in vivo experiment performed using the LNA modified complementary strand suggests the influence of the quadruplex-duplex structural switch in the modulation of gene expression. We believe that this exploratory approach utilizing the selectivity and specificity of Watson-Crick base pairing of LNA bases would allow the modulation of quadruplex regulated gene expression.


Efficient amplification of melanoma-specific CD8+ T cells using artificial antigen presenting complex.
In vitro large amplification of tumor-specific cytotoxic T lymphocytes (CTLs) and adoptive transfer of these cells is one of the most promising approaches to treat malignant diseases in which an effective immune response is not achieved by active immunization. However, generating sufficient numbers of tumor-specific CTLs stimulated with autologous antigen presenting cells (APCs) in vitro is one of the most problematic steps in the adoptive cell transfer (ACT) therapy. To circumvent this problem, we have developed an artificial antigen presenting complex (aAPCs) using MHC class I molecules loaded with a melanoma-specific TRP-2 peptide epitope. Our results show that TRP-2-specific CD8+ T cells elicited by immunization with recombinant adenovirus expressing the mini-gene epitope are efficiently stimulated and amplified in vitro to a greater extent by aAPCs than by natural splenic APCs. These aAPC-induced CTLs recognized endogenously processed antigens present on B16F10 melanoma cells. Efficient stimulation and proliferation of antigen- specific T cells was also confirmed using ovalbumin peptide-loaded aAPCs and OT-I TCR transgenic cells. These results demonstrate that prior in vivo immunization, which increases the precursor frequency, simplifies posterior expansion of tumor- specific CD8+ T cells, and aAPCs is superior to autologous APC for in vitro amplification. This "prime and expand" regimen can be an alternative method for large amplification of rare tumor-specific CTLs and aAPCs should be a useful tool for ACT immunotherapy.


A pH-responsive sensor based on intramolecular internal standard for reproducible detection of strong acids and bases via 19F NMR spectroscopy.
Numerous methods, including pH meters and optical sensors, have been developed for the detection of pH, which is an important indicator in various fields. However, those methods are susceptible to errors in strongly acidic and basic ranges and inaccurate pH measurement due to sample turbidity, hindering their application such as photographic industries and wastewater treatment facilities. Eco-friendly and non-invasive 19F NMR spectroscopy is a promising technique for measurement of strong acids and bases owing to its high sensitivity and little interference; nevertheless, inconsistencies in reproducibility impede its widespread adoption. Herein, we developed a19F NMR-based pH sensor by introducing an intramolecular internal standard strategy into a pH-responsive fluorinated material. Based on the acceptable deviation (ΔδF = 17-19 ppb) in the evaluation of the internal standard signal, this pH-sensing platform enabled reproducible pH measurements in strongly acidic and basic environments. Moreover, its 19F NMR response showed reversibility and high stability to potential interfering factors, and the low absolute difference (0.026-0.086 in pH) for real samples such as diet Coke suggests its potential suitability for various acidic beverages.


Chemoprevention by cyclooxygenase-2 inhibition reduces immature myeloid suppressor cell expansion.
Selective inhibitors of cyclooxygenase-2 (COX-2) enzyme activity have shown chemopreventive activity in carcinogen-induced and transgenic rodent tumor models and clinically for colon cancer. However, the mechanism(s) by which COX-2 inhibitors reduce carcinogenesis remains controversial. We report herein that administration of the selective COX-2 inhibitor, celecoxib, significantly reduces the number of Gr1(+)CD11b(+) immature myeloid suppressor cells (IMSCs) during chemoprevention of 1,2-dimethylhydrazine diHCl-(1,2-DMH-) induction of large intestinal tumors in Swiss mice. Celecoxib administration also increased splenic lymphatic number and tumor infiltration by lymphocytes. The 1,2-DMH induction of large intestinal tumors was associated with a four-fold increase in IMSCs, and a decrease in splenic T cell number and function. Concordant with the changes in the IMSC frequency, messenger ribonucleic acid (mRNA) levels of inducible nitric oxide synthase (NOS-2) and arginase (Arg) were increased in the spleen of the tumor-bearing mice and normalized by celecoxib administration. In addition to delaying tumor induction, reducing tumor number, and increasing lymphocyte infiltration of tumors, celecoxib therapy reversed CD4(+) T cell loss, decreased IMSC numbers and increased mRNA levels of NOS-2 and Arg in the spleen. In summary, our results suggest that celecoxib chemoprevention of autochthonous intestinal tumors can regulate IMSCs and CD4(+) T cell numbers.


Shoe drop has opposite influence on running pattern when running overground or on a treadmill.
Minimalist running shoes are designed to induce a foot strike made more with the forepart of the foot. The main changes made on minimalist shoe consist in decreasing the height difference between fore and rear parts of the sole (drop). Barefoot and shod running have been widely compared on overground or treadmill these last years, but the key characteristic effects of minimalist shoes have been yet little studied. The purpose of this study is to find whether the shoe drop has the same effect regardless of the task: overground or treadmill running. Twelve healthy male subjects ran with three shoes of different drops (0, 4, 8 mm) and barefoot on a treadmill and overground. Vertical ground reaction force (vGRF) (transient peak and loading rate) and lower limb kinematics (foot, ankle and knee joint flexion angles) were observed. Opposite footwear effects on loading rate between the tasks were observed. Barefoot running induced higher loading rates during overground running than the highest drop condition, while it was the opposite during treadmill running. Ankle plantar flexion and knee flexion angles at touchdown were higher during treadmill than overground running for all conditions, except for barefoot which did not show any difference between the tasks. Shoe drop appears to be a key parameter influencing running pattern, but its effects on vGRF differ depending on the task (treadmill vs. overground running) and must be considered with caution. Unlike shod conditions, kinematics of barefoot condition was not altered by treadmill running explaining opposite conclusions between the tasks.


Severe sporotrichoid infection with Mycobacterium szulgai.
Mycobacterium szulgai is a nontuberculous, acid-fast bacillus or atypical mycobacteria, which prior to 1972 was not thought of as a pathogen. Since then most cases reported in the literature have been of pulmonary disease with only a few case reports of cutaneous disease. Our patient, who had an underlying, uncategorized, immunosuppressive condition, presented with multiple severe ulcers spreading proximally up the arms in a sporotrichoid pattern with more scatttered lesions on his legs. He made a full recovery with appropriate antimicrobial treatment.


Loop mediated isothermal amplification assay using hydroxy naphthol blue, conventional polymerase chain reaction and real-time PCR in the diagnosis of intraocular tuberculosis.
This study is a comparative evaluation (Chi-square test) of a closed tube loop mediated isothermal amplification assay using hydroxy naphthol blue dye (HNB-LAMP), real-time polymerase chain reaction (PCR) and conventional PCR in the diagnosis of intraocular tuberculosis. Considering clinical presentation as the gold standard in 33 patients, the sensitivity of HNB-LAMP assay (75.8%) was higher (not significant, P value 0.2) than conventional PCR (57.6%) and lower than real-time PCR (90.9%). Specificity was 100% by all three methods. No amplification was observed in negative controls (n = 20) by all three methods. The cost of the HNB-LAMP assay was Rs. 500.00 and it does not require thermocycler, therefore, it can be used as an alternative to conventional PCR in resource-poor settings.


Iodopovidone pleurodesis: experience of a tertiary hospital in Kolkata.
The management of recurrent pleural effusion or pneumothorax has always been a cause for serious concern among chest physicians. Among the wide variety of agents that are available for pleurodesis, povidone iodine is now perhaps the most sought after agent as it is cheap, easily available, effective and safe. This study was conducted to establish the efficacy and safety of povidone iodine as an agent for pleurodesis in patients with recurrent pleural effusion and pneumothorax. A total of 38 consecutive patients with symptomatic malignant or recurrent pleural effusion and pneumothorax received povidone iodine for pleurodesis over a period of 18 months. The mean follow-up period was 10.2 months, with a standard deviation of 2.9 months. Out of the 38 patients, 29 had malignant pleural effusion, eight had recurrent pneumothorax and one had tubercular pleural effusion which was nonresponsive to antitubercular therapy. A complete response with no recurrence during follow-up was obtained in 34 (89.5 percent) patients. All the cases of failure had malignant pleural effusion. Three (7.9 percent) patients experienced intense chest pains after the installation of sclerosing agent, but they recovered with immediate symptomatic management. Recurrent pleural effusion or pneumothorax due to any cause may be managed effectively and safely by chemical pleurodesis with povidone iodine. It may be considered as the agent of choice to achieve pleurodesis, especially in resource constrained countries like India, as it is inexpensive and easily available.