p21cip/WAF is a key regulator of long-term radiation damage in mesenchyme-derived tissues.
This study aimed to determine the mechanisms responsible for long-term tissue damage following radiation injury. We irradiated p21-knockout (p21(-/-)) and wild-type (WT) mice and determined the long-term deleterious effects of this intervention on mesenchyme-derived tissues. In addition, we explored the mechanisms of radiation-induced mesenchymal stem cell (MSC) dysfunction in isolated bone marrow-derived cells. p21 expression was chronically elevated >200-fold in irradiated tissues. Loss of p21 function resulted in a >4-fold increase in the number of skin MSCs remaining after radiation. p21(-/-) mice had significantly less radiation damage, including 6-fold less scarring, 40% increased growth potential, and 4-fold more hypertrophic chondrocytes in the epiphyseal plate (P<0.01). Irradiated p21(-/-) MSCs had 4-fold increased potential for bone or fat differentiation, 4-fold greater proliferation rate, and nearly 7-fold lower senescence as compared to WT MSCs (P<0.01). Ectopic expression of p21 in knockout cells decreased proliferation and differentiation potential and recapitulated the WT phenotype. Loss of p21 function markedly decreases the deleterious effects of radiation injury in mesenchyme-derived tissues and preserves tissue-derived MSCs. In addition, p21 is a critical regulator of MSC proliferation, differentiation, and senescence both at baseline and in response to radiation.


Signaling of sphingosine-1-phosphate via the S1P/EDG-family of G-protein-coupled receptors.
The sphingosine-1-phosphate/Endothelial Differentiation Gene (S1P/EDG) family of G-protein-coupled receptors (GPCR) currently includes five different isoforms, which differentially regulate fundamental cellular processes such as migration, proliferation, cytoskeletal organization, adherens junction assembly and morphogenesis. Additionally, specific S1P/EDG isoforms can regulate important physiological processes such as blood vessel maturation, cardiac development and angiogenesis in vivo. Herein, we review the current state of knowledge of the expression patterns, signaling pathways and functional characteristics of the different S1P receptors. Further investigation in this field will likely improve our understanding of cardiovascular development as well as vascular diseases and may lead to novel therapeutic approaches.


Modeling of paclitaxel biosynthesis elicitation in Corylus avellana cell culture using adaptive neuro-fuzzy inference system-genetic algorithm (ANFIS-GA) and multiple regression methods.
Paclitaxel as a microtubule-stabilizing agent is widely used for the treatment of a vast range of cancers. Corylus avellana cell suspension culture (CSC) is a promising strategy for paclitaxel production. Elicitation of paclitaxel biosynthesis pathway is a key approach for improving its production in cell culture. However, optimization of this process is time-consuming and costly. Modeling of paclitaxel elicitation process can be helpful to predict the optimal condition for its high production in cell culture. The objective of this study was modeling and forecasting paclitaxel biosynthesis in C. avellana cell culture responding cell extract (CE), culture filtrate (CF) and cell wall (CW) derived from endophytic fungus, either individually or combined treatment with methyl-β-cyclodextrin (MBCD), based on four input variables including concentration levels of fungal elicitors and MBCD, elicitor adding day and CSC harvesting time, using adaptive neuro-fuzzy inference system (ANFIS) and multiple regression methods. The results displayed a higher accuracy of ANFIS models (0.94-0.97) as compared to regression models (0.16-0.54). The great accordance between the predicted and observed values of paclitaxel biosynthesis for both training and testing subsets support excellent performance of developed ANFIS models. Optimization process of developed ANFIS models with genetic algorithm (GA) showed that optimal MBCD (47.65 mM) and CW (2.77% (v/v)) concentration levels, elicitor adding day (16) and CSC harvesting time (139 h and 41 min after elicitation) can lead to highest paclitaxel biosynthesis (427.92 μg l-1). The validation experiment showed that ANFIS-GA method can be a promising tool for selecting the optimal conditions for maximum paclitaxel biosynthesis, as a case study.


Biotransformation of Methoxyflavones by Selected Entomopathogenic Filamentous Fungi.
The synthesis and biotransformation of five flavones containing methoxy substituents in the B ring: 2'-, 3'-, 4'-methoxyflavones, 2',5'-dimethoxyflavone and 3',4',5'-trimethoxyflavone are described. Strains of entomopathogenic filamentous fungi were used as biocatalysts. Five strains of the species Beauveria bassiana (KCh J1.5, J2.1, J3.2, J1, BBT), two of the species Beauveria caledonica (KCh J3.3, J3.4), one of Isaria fumosorosea (KCh J2) and one of Isaria farinosa (KCh KW 1.1) were investigated. Both the number and the place of attachment of the methoxy groups in the flavonoid structure influenced the biotransformation rate and the amount of nascent products. Based on the structures of products and semi-products, it can be concluded that their formation is the result of a cascading process. As a result of enzymes produced in the cells of the tested strains, the test compounds undergo progressive demethylation and/or hydroxylation and 4-O-methylglucosylation. Thirteen novel flavonoid 4-O-methylglucosides and five hydroxy flavones were isolated and identified.


Nonthermal irreversible electroporation for tissue decellularization.
Tissue scaffolding is a key component for tissue engineering, and the extracellular matrix (ECM) is nature's ideal scaffold material. A conceptually different method is reported here for producing tissue scaffolds by decellularization of living tissues using nonthermal irreversible electroporation (NTIRE) pulsed electrical fields to cause nanoscale irreversible damage to the cell membrane in the targeted tissue while sparing the ECM and utilizing the body's host response for decellularization. This study demonstrates that the method preserves the native tissue ECM and produces a scaffold that is functional and facilitates recellularization. A two-dimensional transient finite element solution of the Laplace and heat conduction equations was used to ensure that the electrical parameters used would not cause any thermal damage to the tissue scaffold. By performing NTIRE in vivo on the carotid artery, it is shown that in 3 days post NTIRE the immune system decellularizes the irreversible electroporated tissue and leaves behind a functional scaffold. In 7 days, there is evidence of endothelial regrowth, indicating that the artery scaffold maintained its function throughout the procedure and normal recellularization is taking place.


A Novel Self-Binding Composite Separator Based on Poly(tetrafluoroethylene) Coating for Li-Ion Batteries.
In this study, a novel composite separator based on polytetrafluoroethylene (PTFE) coating layers and a commercial polyethylene (PE) separator is developed for high performance Li-ion batteries. This composite separator is prepared by immersing a PE separator directly into a commercial PTFE suspension to obtain a self-binding PTFE/PE/PTFE tri-layered structure. Then, the as-prepared composite separator is further treated with a H₂O₂/H₂SO₄ solution to enhance its electrolyte affinity. The results show that the coating layer, consisting of close-packed PTFE particles, possesses a highly ordered nano-porous structure and an excellent electrolyte wettability property, which significantly enhance the ionic conductivity of the composite separator. Due to the presence of the PTFE-based coating layer, the composite separator exhibits better thermal stability compared with the PE separator, reaching the thermal-resistant grade of commercial ceramic-coated separators. By using different separators, CR2032-type unit half-cells composed of a Li anode and a LiFePO₄ cathode were assembled, and their C-rate and cycling performances were evaluated. The cell assembled with the composite separator was proven to have better C-rate capability and cycling capacity retention than the cell with the polyethylene separator. It is expected that the composite separator can be a potential candidate as a coating-type separator for high-performance rechargeable Li-ion batteries.


High frequency ultrasound evaluation of traumatic peripheral nerve injuries.
Accurate diagnosis and localization of peripheral nerve traumatic injury remains difficult. Early diagnosis and repair of nerve discontinuity lesions lead to better outcome than delayed repair. We used new high frequency ultrasound to evaluate 24 patients with 29 traumatic nerve injuries. There were a variety of causes including gunshot wounds, blunt injuries, burns, stabbings, and motor vehicle accidents. The patients were then either treated surgically with nerve status directly observed or followed clinically for recovery of nerve function. The ultrasound findings correspond with the clinical outcome of 28 of the 29 nerves. While this is a study limited by a small patient number, ultrasound evaluation should be considered in the evaluation of nerve injury and can lead to early diagnosis and treatment of surgical nerve injuries.


Alkalis and Skin.
The aim of this editorial is to provide an overview of the chemical interactions occurring in the skin of our patients on contact with alkaline agents. Strongly basic alkali is highly aggressive and will readily hydrolyze (or cleave) key biological molecules such as lipids and proteins. This phenomenon is known as saponification in the case of lipids and liquefactive denaturation for peptides and proteins. A short section on current first-aid concepts is included. A better understanding of the basic science behind alkali burns will make us better teachers and provide an insight into the urgency needed in treating these common and dangerous chemical injuries.


Identification of cerebrospinal fluid biomarkers for parkinsonism using a proteomics approach.
The aim of our study was to investigate cerebrospinal fluid (CSF) tryptic peptide profiles as potential diagnostic biomarkers for the discrimination of parkinsonian disorders. CSF samples were collected from individuals with parkinsonism, who had an uncertain diagnosis at the time of inclusion and who were followed for up to 12 years in a longitudinal study. We performed shotgun proteomics to identify tryptic peptides in CSF of Parkinson's disease (PD, n = 10), multiple system atrophy patients (MSA, n = 5) and non-neurological controls (n = 10). We validated tryptic peptides with differential levels between PD and MSA using a newly developed selected reaction monitoring (SRM) assay in CSF of PD (n = 46), atypical parkinsonism patients (AP; MSA, n = 17; Progressive supranuclear palsy; n = 8) and non-neurological controls (n = 39). We identified 191 tryptic peptides that differed significantly between PD and MSA, of which 34 met our criteria for SRM development. For 14/34 peptides we confirmed differences between PD and AP. These tryptic peptides discriminated PD from AP with moderate-to-high accuracy. Random forest modelling including tryptic peptides plus either clinical assessments or other CSF parameters (neurofilament light chain, phosphorylated tau protein) and age improved the discrimination of PD vs. AP. Our results show that the discovery of tryptic peptides by untargeted and subsequent validation by targeted proteomics is a suitable strategy to identify potential CSF biomarkers for PD versus AP. Furthermore, the tryptic peptides, and corresponding proteins, that we identified as differential biomarkers may increase our current knowledge about the disease-specific pathophysiological mechanisms of parkinsonism.


Communication: Constrained search formulation of the ground state energy as a functional of an idempotent one-matrix.
Despite the fact that idempotent one-particle reduced density matrices are pervasive in quantum chemistry, the understanding of a general energy functional of such idempotent density matrices for the ground state energy has been lacking. By a constrained search, we show the structure of the general functional, illuminating the contributions from various terms. For the examples of the "best idempotent density matrix" and Kohn-Sham idempotent density matrices, we contrast the functional forms and suggest how the best idempotent density matrix approach may be a good starting point for further development.


Lys and fibrinogen binding of wild-type (Trp72) and mutant (Arg72) human apo(a) kringle IV-10 expressed in E coli and CHO cells.
In a previous study, we identified a lysine (Lys)-binding-defective form of human lipoprotein(a) and attributed this defect to the presence of a Trp72-->Arg mutation in apolipoprotein(a) [apo(a)] kringle IV-10. To document this relationship, we expressed both wild-type (wt) and mutant (mut) forms of kringle IV-10 in Escherichia coli (nonglycosylated form) and Chinese hamster ovary (CHO) cells (glycosylated form). The Arg72 mut was prepared by introducing the T-->A mutation in apo(a) kringle IV-10 amplified from human liver mRNA by the reverse-transcriptase polymerase chain reaction technique. All expressed kringles were tested for their ability to bind Lys and plasmin-modified fibrinogen (PM-fibrinogen). wt kringle IV-10 expressed in both E coli and CHO cells bound to Lys-Sepharose with comparable affinity. In contrast, the Arg72 mut expressed in both systems exhibited no Lys-binding capacity. Moreover, the wt kringle IV-10 expressed in both systems bound to PM-fibrinogen and exhibited two binding components, one Lys mediated (inhibitable by epsilon-amino-n-caproic acid) and one Lys insensitive, occurring in about the same proportions. Only the latter type of binding was present in the Arg72 mut expressed in E coli. We conclude that kringle IV-10 of human apo(a) has Lys- and PM-fibrinogen-binding capacities that are independent of glycosylation and require the presence of Trp72, one of the seven amino acids that constitute the Lys-binding site of kringle IV-10. Our results also show that the binding of kringle IV-10 to PM- fibrinogen is more complex than that to Lys, in that the former requires an additional binding site or sites outside the Lys-binding site.


Sensitive determination of THC and main metabolites in human plasma by means of microextraction in packed sorbent and gas chromatography-tandem mass spectrometry.
Cannabis is one of the most available and consumed illicit drug in the world and its identification and quantification in biological specimens can be a challenge given its low concentrations in body fluids. The present work describes a fast and fully validated procedure for the simultaneous detection and quantification of ▵9-tetrahydrocannabinol (▵9_THC) and its two main metabolites 11-hydroxy ▵9_tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-▵9- tetrahydrocannbinol (THC-COOH) in plasma samples using microextraction by packed sorbent (MEPS) and gas chromatography-tandem mass spectrometry (GC-MS/MS). A small plasma volume (0.25mL) pre-diluted (1:20), was extracted with MEPS M1 sorbent as follows: conditioning (4 cycles of 250μL methanol and 4 cycles of 250μL 0.1% formic acid in water); sample load (26 cycles of 250μL); wash (100μL of 3% acetic acid in water followed by 100μL 5% methanol in water); and elution (6 cycles of 100μL of 10% ammonium hydroxide in methanol). The procedure allowed the quantification of all analytes in the range of 0.1-30ng/mL. Recoveries ranged from 53 to 78% (THC), 57 to 66% (11-OH-THC) and 62 to 65% (THC-COOH), allowing the limits of detection and quantification to be set at 0.1ng/mL for all compounds. Intra-day precision and accuracy revealed coefficients of variation (CVs) lower than 10% at the studied concentrations, with a mean relative error within±9%, while inter-day precision and accuracy showed CVs lower than 15% for all analytes at the tested concentrations, with an inaccuracy within±8%.


Effect of Cavity Design on the Strength of Direct Posterior Composite Restorations: An Empirical and FEM Analysis.
The aim of the present study was to verify the hypothesis that cavity design does not affect the strength of direct composite restorations as do material properties. Finite element modeling (FEM) and empirical testing were done for two cavity designs: a box shape (cube) and a concave shape (U). Two microhybrid composites were used to prepare the samples with the help of split stainless steel moulds. Compressive strength was tested. The results were statistically analyzed. Both FEA and empirical testing were complementary to each other in that the concave shape showed a significantly higher strength than box. Material properties affected the values only when box shape was used. The null hypothesis is thus rejected, and it is concluded that design significantly affects the strength of direct composite restorations.


Generation of CFU-C/suppressor T cells in vitro: an experimental model for immune-mediated marrow failure.
T cells were derived from the bone marrow of 8 healthy donors and fractionated, according to their receptors for the Fc fragment of IgG, into TG+ and TG- lymphocytes. These were then cocultured with autologous or allogeneic bone marrow cells in agar in the CFU-C assay. No significant suppresion of colony formation could be detected. Total T, TG+, and TG- cells were then incubated for 18 hr with PWM, washed, and cocultured with bone marrow cells. PWM-treated TG- cells showed no significant CFU-C suppressor activity, whereas PWM-treated total T and TG+ cells inhibited colony formation of both autologous and allogeneic marrow cells. The supernatant of PWM-treated total T and TG+ cells also inhibited colony formation. PWM alone enhanced colony formation. The results of this study indicate that normal T cells can be activated in vitro to become CFU-C/suppressor cells after PWM stimulation, and that this effect is mediated by T cells with the Fc receptor for IgG.


High-output congestive failure in a patient with pulmonary arteriovenous malformations.
Pulmonary arteriovenous malformations are rare vascular malformations that usually present with dyspnea and cyanosis in young adults. With the exception of infants and newborns, pulmonary arteriovenous malformations rarely cause congestive heart failure. The authors describe an unusual case in which an elderly female presented with severe dyspnea, hypoxemia, and high-output heart failure. Spiral CT of the chest and pulmonary angiography revealed three large, lower-lobe arteriovenous malformations that were successfully embolized, leading to resolution of her hypoxemia and symptoms.


Cycloheximide resistance in carrot culture: a differentiated function.
Cultured carrot cells grow as unorganized callus tissue in medium containing auxin. Upon removal of the auxin from the medium, they grow in an organized manner and differentiate into embryos. In the normal cell line, W001C, the callus growth can be inhibited by cycloheximide, but the embryonic growth cannot. A variant cell line, WCH105, whose callus growth is resistant to cycloheximide, was isolated. The mechanism of cycloheximide resistance in embryos of both lines and in WCH105 callus was found to be cycloheximide inactivation. In addition to auxin, bromodeoxyuridine can also promote callus growth in carrot culture. Callus cultures maintained by bromodeoxyuridine behave the same as do those maintained by auxin. WCH105 callus is resistant, whereas W001C callus is sensitive to cycloheximide inhibition. Except for the onset of embryogenesis, cycloheximide inactivation is expressed throughout the embryo developmental stages up to the plantlets. These results suggest that cycloheximide inactivation is a function expressed in the differentiated, but not in the undifferentiated, tissues.


Long-term follow-up and factors predictive of recurrence in Barrett's esophagus treated by argon plasma coagulation and acid suppression.
In several series, argon plasma coagulation (APC) combined with acid suppression has led to short- or medium-term eradication of Barrett's esophagus. The present study was designed to assess the long-term outcome after this treatment. 39 patients with Barrett's esophagus, seven of them with low-grade dysplasia, underwent APC and received 40 mg omeprazole daily for eradication of the metaplastic epithelium. After the treatment period, patients were randomly assigned to receive 20 or 40 mg omeprazole daily for long-term acid suppression. Histological and endoscopic changes were evaluated annually. Univariate and multivariate analyses were used to test the following 10 variables as predictors of sustained reversal of Barrett's esophagus at the end of follow-up: age, gender, length of diseased segment, presence of hiatal hernia, circumferential nature of lesion, presence of low-grade dysplasia at initial biopsy, number of coagulation sessions, result of pH monitoring under protein pump inhibitor (PPI) treatment, omeprazole dosage, and initial response to therapy (after 1 month). The median follow-up period was 36 months (range 12 - 48). The endoscopic and histological relapse rates at 1, 12, and 24 months, and end of follow-up were, respectively, 30 % and 44 % (12/39 and 17/39), 57 % and 54 % (16/28 and 15/28), 60 % and 57 % (17/28 and 16/28), and 62 % for both rates (23/37). According to multivariate analysis, shorter length of diseased segment and normalization of pH with PPI treatment were the only independent predictors of sustained long-term re-epithelialization. Among the seven patients with low-grade dysplasia, four experienced relapse after 1 month, and during the long-term follow-up, one was lost to follow-up and all the others experienced relapse, but only one developed low-grade dysplasia again. Cancer was found in two cases after 12 and 18 months, respectively. Persistence of acid reflux and greater length of diseased segment are the major factors associated with a high relapse rate after successful initial reversal. APC for ablation of Barrett's esophagus cannot be recommended.


Vancomycin Capped with Silver Nanoparticles as an Antibacterial Agent against Multi-Drug Resistance Bacteria.
Purpose: Many antimicrobial medications are available to combat infections. However, the indiscriminate use of antibiotics has produced antibiotic resistance in the case of many bacterial pathogens. This study focuses on the development of nanoparticles (NPs) that enhance the in vitro antibiotic activity of vancomycin against multi-drug resistant (MDR) organisms. Methods: Spherical shaped thioglycolic acid-stabilized silver nanoparticles (TGA-AgNPs) were prepared by using a simple chemical reduction method. Then, vancomycin was conjugated to the terminal carboxyl of TGA in the presence of N-Hydroxysuccinimide (NHS) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC). Afterwards, the antibacterial activity of these nanoconjugates was examined by using the minimum inhibitory concentration (MIC) assay against MDR bacteria. Results: The rate of vancomycin bound to the AgNPs was 19.6%. The MIC values of vancomycin (Van)-capped AgNPs against tested pathogens were in the range of (3.2, 1.6, 0.8, 0.4, 0.2, 0.1, 0.05, and 0.025 µl/ml). The MIC was 0.1 µg/ml for VRE, MIC≤0.02 µg/ml for MRSE, and 0.05 µg/ml for S. aureus. The MIC corresponded to the MBC for all bacterial species. Conclusion: This study indicated that some antimicrobial agents like vancomycin can be conjugated with AgNPs. This can lead to increased antimicrobial activity against MDR microorganisms.


Sirolimus-eluting stent in chronic total occlusion: the SICTO study.
Coronary stenting can significantly reduce the restenosis and reocclusion rates after successful balloon angioplasty for chronic total occlusions (CTO). Nevertheless, recanalization of CTO remains among the worst predictors for in-stent restenosis and reocclusion. This multicenter, nonrandomized study assessed the safety and effectiveness of the CYPHER sirolimus-eluting stent in reducing angiographic in-stent late loss in totally occluded native coronary arteries. A total of 25 eligible patients were treated with the CYPHER sirolimus-eluting stent. Baseline clinical and angiographic data were collected and 6-month follow-up angiography and intravascular ultrasound (IVUS) were performed. Clinical follow-up was required at 30 days, 6, 12, 18, and 24 months. Study stent implantation was successful in all patients, with a mean stent length of 28.4 +/- 11 mm. Six-month angiographic outcomes showed that mean lumen diameter stenosis did not change (2.22 +/- 0.56 mm postprocedure; 2.26 +/- 0.60 mm at 6 months follow-up; P = NS). Similarly, mean percent diameter stenosis did not change significantly (15.7 +/- 8.6% postprocedure, 19.3 +/- 11% at follow-up; P = NS). The absolute late lumen loss was -0.03 +/- 0.28 mm with a 6-month in-stent restenosis rate of 0%. IVUS follow-up revealed in-stent obstruction volume of only 4.9 +/- 6.8%. Long-term clinical follow-up showed target lesion revascularization at 12 months was only 4%, with target vessel revascularization of only 12%. The CYPHER sirolimus-eluting stent was safe and effective in the treatment of CTO compared to historical data with bare metal stents.


New monoclonal antibodies on the horizon in multiple myeloma.
Across all cancers, monoclonal antibodies have emerged as a potential strategy for cancer therapy. Monoclonal antibodies target antigens expressed on the surface of cancer cells and accessory cells. This targeted approach uses the host's immune system to promote the killing of cancer cells. Multiple myeloma (MM) is the second most common hematologic malignancy that remains incurable in the majority of patients. The treatment of MM has evolved dramatically over the past decade and continues to evolve with the approval of four new drugs in 2015. Most recently the United States Food and Drug Administration (US FDA) approved two monoclonal antibodies for the treatment of this disease. Monoclonal antibodies are generally well-tolerated and offer a novel method of action for treated relapsed and refractory disease and are now being studied in the upfront setting. In this article, we review the evidence for the existing approved monoclonal antibodies and discuss promising targeted therapies and innovative strategies for the treatment of MM.


Improved chemical composition separation of ethylene-propylene random copolymers by high-temperature solvent gradient interaction chromatography.
High-temperature solvent gradient interaction chromatography (HT-SGIC) is a fast and efficient fractionation technique for the chemical composition analysis of olefin copolymers. The separation of ethylene-propylene random copolymers (EPRs) was achieved on a graphitic stationary phase, Hypercarb, at 160 °C by using linear solvent gradient elution from 1-decanol to 1,2,4-trichlorobenzene (TCB). In the present work, the solvent gradient profile was modified to improve the chromatographic separation of EPRs. With the aim to obtain a better resolution in separation, a slow increase in the volume fraction of TCB was applied. This allowed for a relatively large retention region for linear polyethylene (PE) chains on the column; thereby, a broader elution volume zone between the start of the gradient and the PE elution was achieved. The efficiency of this new gradient profile was demonstrated by analysing two fully amorphous EPR samples. Clear differences in the chemical composition of these EPR samples with similar ethylene contents have been proven by using this modified solvent gradient. The comprehensive chemical composition and microstructure analysis of the SGIC-separated fractions by FTIR revealed that ethylene/propylene (EP) copolymer chains were eluted according to their ethylene/propylene contents and E or P sequence lengths, even though they are distributed in a random manner. These results showed that the solvent composition is an important factor to affect the interactive adsorption or desorption behaviour of EP chains on Hypercarb. In this way, for the first time, the determination of the complex composition and chain structure of EPR samples was achieved within short analysis time, which is not possible till now using other fractionation techniques reported.


[Acute eosinophilic pneumonia associated with aspirin].
A 21-year-old man was admitted to our hospital with acute progressive dyspnea and a high fever. He had started smoking 6 weeks before admission. A chest radiograph showed diffuse infiltrates with Kerley B lines and bilateral pleural effusions. There was no evidence of infection. His condition improved rapidly and without medication. On admission the concentrations of interleukin-5 in bronchoalveolar lavage fluid and in blood were high, but they were normal one week later. Acute eosinophilic pneumonia was diagnosed. A positive result of a lymphocyte stimulation test indicated that the development of symptoms was closely associated with ingestion of aspirin. We know of no previous report of acute eosinophilic pneumonia associated with aspirin.


A Case of Ceruminous Adenocarcinoma Not Otherwise Specified (NOS) in the External Auditory Canal.
External auditory canal cancer is a rare disease which can be treated by surgery or chemoradiation. The most common histological type is squamous cell carcinoma, but rare types such as adenocarcinoma have been reported and are thought to be derived from the ceruminous glands. Here, we present a case of ceruminous adenocarcinoma, not otherwise specified (NOS) in the external auditory canal. A 72-year-old woman was referred to our department with discomfort due to a mass in the external ear canal. No typical symptoms of malignancy, such as pain or bleeding, were noted at the initial examination. The patient underwent a total excision under local anesthesia as a diagnostic treatment. She was diagnosed with ceruminous adenocarcinoma, NOS based on the results of immunostaining of the excised specimen, and is currently being followed up as an outpatient. Adenocarcinoma is thought to originate from the cerumen glands of the ear canal and the lack of specific symptoms may make it difficult to differentiate it from benign tumors. Although adenocarcinoma, NOS has been reported in the head and neck region, there have been no reported cases occurring in the external ear canal, and to the best of our knowledge, this is the first report.


Cetirizine treatment of rhinitis in children with pollen allergy: evidence of its antiallergic activity.
Cetirizine is an antihistamine, largely used in the treatment of allergic rhinoconjunctivitis, which also exerts anti-allergic activity. To evaluate cetirizine as treatment for children with rhinitis due to pollen allergy, and to evaluate its anti-allergic activity in such a clinical condition. The study was designed as parallel groups, double-blind, placebo-controlled, randomized. Twenty allergic children were enroled and subdivided in two groups, receiving a 4 week treatment during the pollen season. The following parameters were monitored: clinical symptoms evaluated by the allergist before and after treatment and by the patients through a daily diary card, inflammatory cells count, expression of ICAM-1 on nasal epithelial cells, inflammatory mediator levels in nasal lavage and peripheral blood before and after treatment, and pollen counts. This study shows that cetirizine treatment is able to reduce: clinical symptoms (P < 0.01), inflammatory cell infiltrate (P < 0.03), ICAM-1 expression on epithelial cells (P < 0.05), and soluble ICAM-1 (P < 0.05) and ECP (P < 0.05) in nasal lavage. Cetirizine is able to clinically improve nasal symptoms due to pollen allergy and to reduce allergic inflammation, which is related to allergen exposure.


Modeling urban decline: a multilevel economic-demographic model for the Dortmund region.
"Selected results of a multilevel dynamic simulation model of the economic and demographic development of the urban region of Dortmund [Federal Republic of Germany] are presented. In particular, the capability of the model to capture both urban growth and urban decline processes is illustrated. The mechanisms that control spatial growth, decline, or redistribution of activities in the model are first outlined, and a demonstration of how the model reproduces the general pattern of past spatial development follows. Finally, results of simulations covering a wide range of potential overall economic and demographic development in the region are discussed." (summary in FRE, ITA, JPN, )


Multicomponent diastereoselective synthesis of tetrahydropyridines as α-amylase and α-glucosidase enzymes inhibitors.
Background: Researchers seeking new drug candidates to treat diabetes mellitus have been exploring bioactive molecules found in nature, particularly tetrahydropyridines (THPs). Methods: A library of THPs (1-31) were synthesized via a one-pot multicomponent reaction and investigated for their inhibition potential against α-glucosidase and α-amylase enzymes. Results: A nitrophenyl-substituted compound 5 with IC50 values of 0.15 ± 0.01 and 1.10 ± 0.04 μM, and a Km value of 1.30 mg/ml was identified as the most significant α-glucosidase and α-amylase inhibitor, respectively. Kinetic studies revealed the competitive mode of inhibition, and docking studies revealed that compound 5 binds to the enzyme by establishing hydrophobic and hydrophilic interactions and a salt bridge interaction with His279. Conclusion: These molecules may be a potential drug candidate for diabetes in the future.


Metabolic interrogation as a tool to optimize chemotherapeutic regimens.
Platinum-based (Pt) chemotherapy is broadly utilized in the treatment of cancer. Development of more effective, personalized treatment strategies require identification of novel biomarkers of treatment response. Since Pt compounds are inactivated through cellular metabolic activity, we hypothesized that metabolic interrogation can predict the effectiveness of Pt chemotherapy in a pre-clinical model of head and neck squamous cell carcinoma (HNSCC).We tested the effects of cisplatin (CDDP) and carboplatin (CBP) on DNA damage, activation of cellular death cascades and tumor cell metabolism, specifically lactate production. Pt compounds induced an acute dose-dependent, transient drop in lactate generation in vitro, which correlated with effects on DNA damage and cell death. Neutralization of free radical stress abrogated these effects. The magnitude of this effect on lactate production correlated with the differential sensitivity of HNSCC cells to Pt compounds (CDDP vs CBP) and p53-driven Pt chemotherapy resistance. Using dual flank xenograft tumors, we demonstrated that Pt-driven effects on lactate levels correlate with effects on tumor growth delay in a dose-dependent manner and that lactate levels can define the temporal profile of Pt chemotherapy-induced metabolic stress. Lactate interrogation also predicted doxorubicin effects on cell death in both solid tumor (HNSCC) and acute myelogenous leukemia (AML) cell lines.Real-time metabolic interrogation of acute changes in cell and tumor lactate levels reflects chemotherapy effects on DNA damage, cell death and tumor growth delay. We have identified a real-time biomarker of chemotherapy effectiveness which can be used to develop adaptive, iterative and personalized treatment regimens against a variety of solid and hematopoietic malignancies.


Stem cells and heart disease - Brake or accelerator?
After two decades of intensive research and attempts of clinical translation, stem cell based therapies for cardiac diseases are not getting closer to clinical success. This review tries to unravel the obstacles and focuses on underlying mechanisms as the target for regenerative therapies. At present, the principal outcome in clinical therapy does not reflect experimental evidence. It seems that the scientific obstacle is a lack of integration of knowledge from tissue repair and disease mechanisms. Recent insights from clinical trials delineate mechanisms of stem cell dysfunction and gene defects in repair mechanisms as cause of atherosclerosis and heart disease. These findings require a redirection of current practice of stem cell therapy and a reset using more detailed analysis of stem cell function interfering with disease mechanisms. To accelerate scientific development the authors suggest intensifying unified computational data analysis and shared data knowledge by using open-access data platforms.


Activation and specificity of human caspase-10.
Two apical caspases, caspase-8 and -10, are involved in the extrinsic death receptor pathway in humans, but it is mainly caspase-8 in its apoptotic and nonapoptotic functions that has been an intense research focus. In this study we concentrate on caspase-10, its mechanism of activation, and the role of the intersubunit cleavage. Our data obtained through in vitro dimerization assays strongly suggest that caspase-10 follows the proximity-induced dimerization model for apical caspases. Furthermore, we compare the specificity and activity of the wild-type protease with a mutant incapable of autoprocessing by using positional scanning substrate analysis and cleavage of natural protein substrates. These experiments reveal a striking difference between the wild type and the mutant, leading us to hypothesize that the single chain enzyme has restricted activity on most proteins but high activity on the proapoptotic protein Bid, potentially supporting a prodeath role for both cleaved and uncleaved caspase-10.


Generalizing Landauer's principle.
In a recent paper [Stud. Hist. Philos. Mod. Phys. 36, 355 (2005)] it is argued that to properly understand the thermodynamics of Landauer's principle it is necessary to extend the concept of logical operations to include indeterministic operations. Here we examine the thermodynamics of such operations in more detail, extending the work of Landauer to include indeterministic operations and to include logical states with variable entropies, temperatures, and mean energies. We derive the most general statement of Landauer's principle and prove its universality, extending considerably the validity of previous proofs. This confirms conjectures made that all logical operations may, in principle, be performed in a thermodynamically reversible fashion, although logically irreversible operations would require special, practically rather difficult, conditions to do so. We demonstrate a physical process that can perform any computation without work requirements or heat exchange with the environment. Many widespread statements of Landauer's principle are shown to be special cases of our generalized principle.


Systems Biology Genetic Approach Identifies Serotonin Pathway as a Possible Target for Obstructive Sleep Apnea: Results from a Literature Search Review.
Overall validity of existing genetic biomarkers in the diagnosis of obstructive sleep apnea (OSA) remains unclear. The objective of this systematic genetic study is to identify "novel" biomarkers for OSA using systems biology approach. Candidate genes for OSA were extracted from PubMed, MEDLINE, and Embase search engines and DisGeNET database. The gene ontology (GO) analyses and candidate genes prioritization were performed using Enrichr tool. Genes pertaining to the top 10 pathways were extracted and used for Ingenuity Pathway Analysis. In total, we have identified 153 genes. The top 10 pathways associated with OSA include (i) serotonin receptor interaction, (ii) pathways in cancer, (iii) AGE-RAGE signaling in diabetes, (iv) infectious diseases, (v) serotonergic synapse, (vi) inflammatory bowel disease, (vii) HIF-1 signaling pathway, (viii) PI3-AKT signaling pathway, (ix) regulation lipolysis in adipocytes, and (x) rheumatoid arthritis. After removing the overlapping genes, we have identified 23 candidate genes, out of which >30% of the genes were related to the genes involved in the serotonin pathway. Among these 4 serotonin receptors SLC6A4, HTR2C, HTR2A, and HTR1B were strongly associated with OSA. This preliminary report identifies several potential candidate genes associated with OSA and also describes the possible regulatory mechanisms.


The harms of medicalisation: intersex, loneliness and abandonment.
This article develops loneliness as a political and social justice issue by illustrating the harmful personal and social consequences of the medical jurisdiction over and constitution of variations in sex characteristics. Whilst connections between loneliness, health and illness have been well established, this work customarily identifies the ways illness can lead to, or be caused by, loneliness. Instead, I provide an account of the central role of medicalisation and medical management in producing loneliness. By doing so, I underline the imperative for medical practice to consider its influence upon social and personal, as well as physical, wellbeing. Drawing on stories shared through solicited diaries followed by in-depth interviews with seven people with sex variations and two parents in the UK, I show how accounts of loneliness help to illuminate the violence of abandonment, silencing and marginalisation that often goes unheard, together with hidden or normalised systems of harm. Building on concepts of ethical loneliness and ontological loneliness, I show how structural violations operate to injure trust and self-worth, leading to social unease. I argue for the importance of people with sex variations finding sites of comfort and acceptance, but note the ways that some forms of medicalisation can inhibit alliances and community formation, despite diagnoses also carrying the potential to facilitate informal support structures and collective identities. By bringing together intersex studies with discourses of loneliness, I develop a better understanding of loneliness as a product of social and systemic violence, and the ways in which medical discourses tie in with larger structures of oppression, coercion and control. This article concludes by underlining the need for structural change in our approach to and understanding of sex variations, and with a call for us to become more attentive to these stories of medical harm, to ensure that they are heard and to seek necessary justice.


A new method of measuring shoulder hand behind back movement: Reliability, values in symptomatic and asymptomatic people, effect of hand dominance, and side-to-side variability.
Shoulder hand behind back (HBB) range of motion (ROM) is a useful measure of impairment and treatment outcome. The purpose of this repeated measures study was to identify inter- and intra-rater reliability, of a new simplified method of measuring HBB ROM. Two experienced raters measured HBB ROM with a bubble inclinometer on 25 people (aged 42-75 years, 14 female) with unilateral shoulder dysfunction and 25 age- and gender-matched asymptomatic subjects on two different occasions. Statistical analysis included calculation of intra-class correlation coefficients (ICCs), minimal detectable change (MDC), standard error of measurement (SEM), Pearson correlation coefficient (r), coefficient of determination (R(2)), and the lower bound score. Mean HBB ROM was 108.6° (SD = 16.3) and 23.9° (SD = 10.5) on the pain-free and symptomatic side, respectively. Both intra-rater and inter-rater reliability were high (ICC > 0.80). For asymptomatic people the SEM was at most 3° and MDC was 8° with a strong correlation between the dominant and nondominant sides (r > 0.72). The mean absolute values and lower bound scores were at most 10.2° and 26.0°, respectively. These results indicate that this new and novel method of measuring HBB ROM is accurate, has good inter- and intra-rater reliability, and provides normal values for between-limb ROM variability.


Effect of growth in highly salinized media on the enzymes of the photosynthetic apparatus in pea seedlings.
The rate of chlorophyll formation in initially etiolated pea seedlings (Pisum sativum) that are growing in the light in salinized media is slower than in similar plants not subjected to salinity. However, the final steady state level of chlorophyll is the same under both conditions. Growth under saline conditions did not change the ratio of dry weight to wet weight in the plant leaves nor the specific concentration of soluble protein in leaf extracts. Changes in the specific activity of 11 enzymes in leaf extracts during growth in the light were measured. At least six of these enzymes are known to be part of the photosynthetic apparatus and that their synthesis is subject to photocontrol. The changes in specific activity that were observed were slower in the salt-treated plants, but the final steady state concentration of each was the same as in the control plants. It is concluded that salinity impairs growth of pea plants but that formation of enzymes and other proteins are always in balance with growth.


Right gastroepiploic artery used for coronary artery bypass grafting. Evaluation of flow characteristics and size.
Questions remain concerning the physiologic capabilities of the right gastroepiploic artery as a bypass graft in the clinical setting. Our last 90 consecutive pedicle right gastroepiploic artery grafts were prepared with intraluminal papaverine and verapamil. Our series comprised 81 male and 9 female patients with average body surface areas of 1.92 m2. Ages ranged from 11 to 79 years (mean 57.2 years). A second to fourth revascularization was undertaken in 32 patients (35.5%). The following arteries were bypassed: posterior descending artery, 63; right coronary artery, 23; distal right, 4; circumflex, 2; left anterior descending, 1; and diagonal, 1. Free flow rates ranged from 42 to 660 ml/min (mean 179.96 ml/min). Internal diameters measured 1.5 to 4.0 mm (mean 2.20 mm) at the anastomotic sites. Pedicle lengths ranged from 16 to 26 cm (mean 19.2 cm). Inotropic support was required in 11 patients (12%) and had no adverse effects on right gastroepiploic artery grafts. There were 2 hospital deaths (2.2%). Angina has recurred in 6 patients. One patient with cardiomyopathy required transplantation 2 years after coronary bypass grafting. Repeat angiography showed widely patent grafts in 18 patients and generalized narrowing in 4 grafts. In only 2 patients of our total experience has right gastroepiploic artery grafting been aborted because of inadequate conduit size. One right gastroepiploic artery had visible atherosclerosis. This study shows that distal right gastroepiploic artery sizes are comparable with sizes of target coronary arteries. However, neither flow nor size is as consistent when compared with internal thoracic artery grafts. Higher flow rates are related to graft anatomic characteristics and larger body surface areas. Spasm, secondary to harvest in these vasoreactive grafts, can be managed appropriately by intraluminal vasodilating drugs. However, use of the right gastroepiploic artery should be avoided in a setting with possible competition of flow.


The fecal microbiome of ALS patients.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative motor neuron disease accompanied by both systemic and central nervous system-specific inflammation as well as deregulated energy metabolism. These potential pathogenetic factors have recently been found to mutually interact with the gut microbiota, raising the hypothesis of a link between microbiome alterations and ALS pathogenesis. The aim of our study was to assess whether ALS is associated with an altered composition of the fecal microbiota. We compared the fecal microbiota of 25 ALS patients with 32 age- and gender-matched healthy persons using 16S rRNA gene sequencing analysis. Confounding factors and secondary disease effects on the microbiome were minimized by selection of patients without dysphagia, gastrostomy, noninvasive ventilation, or reduced body mass index. Comparing the 2 carefully matched groups, the diversity and the abundance of the bacterial taxa on the different taxonomic levels as well as PICRUSt-predicted metagenomes were almost indistinguishable. Significant differences between ALS patients and healthy controls were only observed with regard to the overall number of microbial species (operational taxonomic units) and in the abundance of uncultured Ruminococcaceae. Conclusively, ALS patients do not exhibit a substantial alteration of the gut microbiota composition.


Correlation between glioblastoma stem-like cells and tumor vascularization.
Glioblastoma multiforme (GBM) is the most lethal type of brain tumor. The formation of abnormal, dysfunctional tumor vasculature and glioblastoma stem-like cells (GSCs) are believed to be the major components of the inability to treat these tumors effectively. We analyzed 70 glioblastoma samples by immunohistochemistry and double immunofluorescence staining. The immunohistochemical expression of the putative brain tumor stem cell markers CD133 and Nestin in paraffin sections was analyzed using morphometry. In all GBM samples, CD133 or Nestin was expressed in tumor and endothelial cells. Double immunofluorescence stainings showed that the two different marked GSCs were found accumulated around the CD31+ blood vessels and CD133/CD31 or Nestin/CD31 co-expression was found in the endothelial cells and GSCs. Furthermore, the vascular endothelial growth factor (VEGF) and the endothelial marker CD31 were co-expressed in GSCs. Therefore, GSCs not only showed distinct perivascular distribution but were capable of differentiating into endothelial cells. We demonstrate that GSCs contribute directly to the tumor vasculature by endothelial cell differentiation. GSCs and tumor vascularization are closely related to each other, not only in the regional distribution but also in biological function. These findings describe a new mechanism for tumor vasculo-genesis and may provide new insights for targeted therapy against brain tumors.


Detection of paroxysmal atrial fibrillation in acute stroke patients.
Atrial fibrillation (AF) is a frequent cause of stroke, but detecting paroxysmal AF (pAF) poses a challenge. We investigated whether continuous bedside ECG monitoring in a stroke unit detects pAF more sensitively than 24-hour Holter ECG, and tested whether examining RR interval dynamics on short-term ECG recordings using an automated screening algorithm (ASA) for pAF detection is a useful tool to predict the risk of pAF outside periods of manifest AF. Patients >60 years with acute ischemic stroke or transient ischemic attacks (TIA) were prospectively enrolled unless initial ECG revealed AF or they had a history of paroxysmal or persistent AF. ASA was performed on 1- to 2-hour ECG recordings in the emergency room and patients were classified into 5 risk categories for pAF. All patients underwent continuous bedside ECG monitoring for >48 h. Additionally, 24-hour Holter ECG was performed. 136 patients were enrolled (median age: 72 years, male: 58.8%). In 29 (21.3%), pAF was newly diagnosed by continuous bedside ECG monitoring. pAF increased with age (p = 0.031). Median time to first pAF detection on continuous bedside ECG monitoring was 36 h. In 16 patients, pAF was detected by continuous bedside ECG monitoring prior to the performance of 24-hour Holter ECG. Thirteen of the remaining patients were pAF positive on continuous bedside ECG monitoring, but 24-hour Holter detected only 3 patients. Accordingly, the sensitivity of 24-hour Holter was 0.23. Sensitivity of higher-risk categories of ASA compared to continuous bedside ECG monitoring was 0.72, and specificity 0.63. Continuous bedside ECG monitoring is more sensitive than 24-hour Holter ECG for pAF detection in acute stroke/TIA patients. Screening patients for pAF outside AF episodes using ASA requires further development.


[Causes and affecting factors of unplanned reoperations in cancer patients].
To investigate the causes and affecting factors of unplanned reoperations in cancer patients. All patients, who underwent surgery and unplanned surgical reoperations in Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between November 1, 2012 and October 1, 2013, were included in this study. The causes and affecting factors of unplanned reoperations were retrospectively analyzed with logistic regression model. A total of 16, 362 operations were performed in that period, in which 126 cases underwent unplanned reoperation. The incidence rate of unplanned reoperation was 0.77%. The top three causes for unplanned reoperation were bleeding or hematoma in 44 cases (34.92%), wound infection or split in 37 cases (29.37%), and anastomotic leak in 14 cases (11.11%). Logistic regression analysis showed that tumor classification, surgery grade and gender were independent factors for the unplanned reoperations. The main causes of unplanned reoperation are bleeding or hematoma, wound infection or split and anastomotic leak. Tumor classification, surgery grade and gender are the independent factors for unplanned reoperations.


Algal photosynthetic aeration increases the capacity of bacteria to degrade organics in wastewater.
Wastewater treatment is an energy-intensive process and a net emitter of greenhouse gas emissions. A large fraction of these emissions is due to intensive aeration of aerobic bacteria to facilitate break-down of organic compounds. Algae can generate dissolved oxygen at levels in excess of saturation, and therefore hold the potential to partially displace or complement mechanical aeration in wastewater treatment processes. The objective of this study was to develop an internally consistent experimental and modeling approach to test the hypothesis that algal photosynthetic aeration can speed the removal of organic constituents by bacteria. This framework was developed using a simplified wastewater treatment process consisting of a model bacteria (Escherichia coli), a model algae (Auxenochlorella protothecoides), and a single carbon source that was consumable by bacteria only. This system was then tested both with and without the presence of algae. A MATLAB model that considered mass transfer and biological kinetics was used to estimate the production and consumption of O2 and CO2 by algae and bacteria. The results indicated that the presence of algae led to 18-66% faster removal of COD by bacteria, and that roughly one-third of biochemical oxygen demand was offset by algal photosynthetic aeration.


Effect of pod removal on leaf senescence in soybeans.
Depodding soybean (Glycine max [L] Merr. cv Wye) plants results in an apparent inhibition of senescence as indicated by leaf chlorophyll and soluble protein retention. However, leaf photosynthesis and ribulose bisphosphate carboxylase (Rubisco) levels begin to decline earlier in depodded than in control, podded plants. The initial decline in photosynthesis is correlated with a decrease in leaf transpiration, while the latter decline is associated with the loss of Rubisco. Total soluble protein remains high in depodded plants because several polypeptides, three in particular, increase in amounts sufficient to offset the loss of Rubisco. Thus, depodding appears to change the function of the leaf rather than simply delaying or preventing the decline in leaf function. Changes in specific leaf weight and starch content following depodding suggest that the leaf may be changing to a storage organ.


Validity of an Internet version of the Multiple Sclerosis Neuropsychological Questionnaire.
Neuropsychological batteries are long and require expertise to administer. For this reason, the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) was developed as it is quick and easy to complete. The informant version of the scale has proven to be a useful screen for cognitive impairment in multiple sclerosis (MS). The objective was to validate an Internet version of the MSNQ. The following psychometric data were collected at home over the Internet in 82 MS patients: (a) patient self-report version MSNQ (P-MSNQ), (b) informant version MSNQ (I-MSNQ), and (c) Center for Epidemiological Studies Depression Scale (CES-D). Thereafter patients underwent in-office testing with the Brief Repeatable Battery of Neuropsychological Tests (BRB-N). The sensitivity and specificity of the Internet MSNQ to detect cognitive impairment relative to the BRB-N was determined using receiver operating characteristic (ROC) curve analysis. Thirty-five percent of the sample was cognitively impaired. The P-MSNQ was correlated with depression and two tests of the BRB-N. The I-MSNQ was correlated with depression and all five tests of the BRB-N. A cut-off score of 26 on the I-MSNQ gave a sensitivity and specificity of 72% and 60% respectively. Test-retest and internal reliability analyses were strong for both the P-MSNQ and I-MSNQ. This is the first attempt at an Internet validation of the MSNQ. The modest sensitivity and specificity values suggest that further research is needed before either the patient or informant version of the MSNQ can be used for neuropsychological screening purposes over the Internet.


Biodegradable intraocular therapies for retinal disorders: progress to date.
In general, it is difficult to achieve effective levels of drugs in the vitreous and the retina via topical and/or systemic administration. Intraocular drug delivery systems that achieve longer duration of pharmacological effect with lower administration frequency are urgently needed. Intraocular sustained drug release via implantable devices or injectable particles has been investigated for the treatment of various vitreoretinal disorders. Several non-biodegradable implants are available in clinical practice or in the late developmental phase: Vitrasert (ganciclovir intravitreal implant) for cytomegalovirus retinitis, Retisert (fluocinolone acetonide intravitreal implant) for non-infectious uveitis, Iluvien (fluocinolone acetonide intravitreal implant) for diabetic macular oedema, and NT-501 (a polymer implant containing human retinal epithelial cells genetically modified to secrete ciliary neurotrophic factor) for non-neovascular (dry) age-related macular degeneration and/or retinitis pigmentosa. Many biodegradable formulations, including different shapes of rods, nail-like plugs, discs, or micro- or nanoparticles, have also been investigated, but are not available as yet for the treatment of vitreoretinal disorders. The most developed biodegradable device, Ozurdex (dexamethasone intravitreal implant), is approved as first-line therapy for the treatment of macular oedema following branch retinal vein occlusion or central retinal vein occlusion. In this article, we review the progress of major biodegradable drug delivery systems currently in clinical trials or in experimental stages for the treatment of vitreoretinal disorders.


Vulnerability of polar oceans to anthropogenic acidification: comparison of arctic and antarctic seasonal cycles.
Polar oceans are chemically sensitive to anthropogenic acidification due to their relatively low alkalinity and correspondingly weak carbonate buffering capacity. Here, we compare unique CO2 system observations covering complete annual cycles at an Arctic (Amundsen Gulf) and Antarctic site (Prydz Bay). The Arctic site experiences greater seasonal warming (10 vs 3°C), and freshening (3 vs 2), has lower alkalinity (2220 vs 2320 μmol/kg), and lower summer pH (8.15 vs 8.5), than the Antarctic site. Despite a larger uptake of inorganic carbon by summer photosynthesis, the Arctic carbon system exhibits smaller seasonal changes than the more alkaline Antarctic system. In addition, the excess surface nutrients in the Antarctic may allow mitigation of acidification, via CO2 removal by enhanced summer production driven by iron inputs from glacial and sea-ice melting. These differences suggest that the Arctic system is more vulnerable to anthropogenic change due to lower alkalinity, enhanced warming, and nutrient limitation.


N and C NMR determination of allantoin metabolism in developing soybean cotyledons.
The metabolism of allantoin by immature cotyledons of soybean (Glycine max L. cv Elf) grown in culture was investigated using solid state (13)C and (15)N nuclear magnetic resonance. All of the nitrogens of allantoin were incorporated into protein in a manner similar to that of each other and to the amide nitrogen of glutamine. The C-2 of allantoin was not incorporated into cellular material; presumably it was lost as CO(2). About 50% of the C-5 of allantoin was incorporated into cellular material as a methylene carbon; the other 50% was presumably also lost as CO(2). The (13)C-(15)N bonds of [5-(13)C;1-(15)N] and [2-(13)C;1,3-(15)N]allantoin were broken prior to the incorporation of the nitrogens into protein. These data are consistent with allantoin's degradation to two molecules of urea and one two-carbon fragment. Cotyledons grown on allantoin as a source of nitrogen accumulated 21% of the nitrogen of cotyledons grown on glutamine. Only 50% of the nitrogen of the degraded allantoin was incorporated into the cotyledon as organic nitrogen; the other 50% was recovered as NH(4) (+) in the media in which the cotyledons had been grown. The latter results suggests that the lower accumulation of nitrogen by cotyledons grown on allantoin was in part due to failure to assimilate NH(4) (+) produced from allantoin. The seed coats had a higher activity of glutamine synthetase and a higher rate of allantoin degradation than cotyledons indicating that seed coats play an important role in the assimilation and degradation of allantoin.


Amelanotic malignant melanomas of the oral mucosa.
Oral amelanotic melanomas are rare and the prognosis is poorer than that of pigmented melanomas because of delays in establishing the correct diagnosis and in the initiation of treatment. Amelanotic forms are also thought to be biologically more aggressive than pigmented melanomas. We have seen three cases of oral amelanotic melanomas since 1970, in two of whom the diagnosis was long delayed. Two lesions were not pigmented but one had slight pigmentation. One patient simultaneously had both an amelanotic and a pigmented melanoma in the oral cavity. Lymph node metastases and distant metastases developed in all patients, two of whom eventually died of the disease. Early diagnosis by histological examination together with immunostaining with S100 and HMB-45 are the keys to improve survival for patients with amelanotic melanoma.


Purification and Characterization of a Fucoidanase (FNase S) from a Marine Bacterium Sphingomonas paucimobilis PF-1.
The Search for enzyme activities that efficiently degrade marine polysaccharides is becoming an increasingly important area for both structural analysis and production of lower-molecular weight oligosaccharides. In this study, an endo-acting fucoidanase that degrades Miyeokgui fucoidan (MF), a sulfated galactofucan isolated from the sporophyll (called Miyeokgui in Korean) of Undaria pinnatifida, into smaller-sized galactofuco-oligosaccharides (1000-4000 Da) was purified from a marine bacterium, Sphingomonas paucimobilis PF-1, by ammonium sulfate precipitation, diethylaminoethyl (DEAE)-Sepharose column chromatography, and chromatofocusing. The specific activity of this enzyme was approximately 112-fold higher than that of the crude enzyme, and its molecular weight was approximately 130 kDa (FNase S), as determined by native gel electrophoresis and 130 (S1), 70 (S2) and 60 (S3) kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The optimum pH and temperature of FNase S were pH 6.0-7.0 and 40-45 °C, respectively. FNase S activity was enhanced by Mn2+ and Na+ (115.7% and 131.2%), but it was inhibited by Ca2+, K+, Ba2+, Cu2+ (96%, 83.7%, 84.3%, and 89.3%, respectively), each at 1 mM. The Km, Vmax and Kcat values of FNase S on MF were 1.7 mM, 0.62 mg·min-1, and 0.38·S-1, respectively. This enzyme could be a valuable tool for the structural analysis of fucoidans and production of bioactive fuco-oligosaccharides.


Forum on stigma, discrimination, and health: policies and research challenges. Introduction.
This introduction outlines the Forum on stigma, discrimination, and health: policies and research challenges, including four articles and a final commentary. The first article reviews the development of international research on the relationship between discrimination and health. The second analyzes the recent Brazilian research output on AIDS, stigma, and discrimination. The third article addresses conceptual and methodological aspects of the relations between discrimination and health from an epidemiological perspective. The forth examines the process of affirming sexual rights in Brazil, involving the judiciary system, public policies, and the executive and legislative branches of government, among others. The fifth paper presents comments and questions on the contents discussed in the first four articles. The reflections aim to provide conceptual and methodological contributions for research and health policies on stigma and discrimination, given the gaps identified in the international and Brazilian literature.


Identification of a novel NDM variant, NDM-13, from a multidrug-resistant Escherichia coli clinical isolate in Nepal.
A novel New Delhi metallo-β-lactamase, NDM-13, was identified in a carbapenem-resistant Escherichia coli clinical isolate obtained from the urine of a patient in Nepal. The enzymatic activity of NDM-13 against β-lactams was similar to that of NDM-1. However, NDM-13 displayed significantly higher k cat/Km ratios for cefotaxime. The genetic environment of bla NDM-13 was determined to be tnpA-IS30-bla NDM-13-ble MBL-trpF-dsbC-cutA-groES-groL, with bla NDM-13 located within the chromosome.


[Cancer and work conditions: improving scientific knowledge for new preventive strategies].
In this article, the issue of occupational cancer is discussed by studying the correlation between work conditions and health-related social disparity.Without aiming to furnish a review of the pertinent scientific literature in this field, some matters for discussion will be advanced to initiate scientific and political debate. Keeping in mind the major socio-health disparities still present in European countries, the objective is to address the issue of knowledge generation pertinent to occupational cancer in a complex scenario with numerous obstacles posed both by employers and by the issue of differing methodological approaches, which require cooperation between various disciplines such as epidemiology, toxicology, statistics, and sociology of health. Such cooperation cannot be effective unless both the political and the scientific aspects are addressed in the investigative process and the decisive role of mobilization of the workforce is acknowledged. Finally, the article discusses the particular condition of women, highly underestimated in the scientific literature concerning health issues in the workplace. We have observed that albeit current understanding in this field is insufficient, intervention strategies and prevention policies are inadequate even when measured against this knowledge base. In order for prevention to be effective, public policies on industry, territorial health, environmental protection, and the workplace must be integrated, figures able to act as prime movers in the change process need to be identified, and replacement of carcinogenic substances and production processes must be favoured.


Domestication of olive fly through a multi-regional host shift to cultivated olives: comparative dating using complete mitochondrial genomes.
The evolutionary history of the olive fly, Bactrocera oleae, was reconstructed in a phylogenetic and coalescent framework using full mitochondrial genome data from 21 individuals covering the entire worldwide distribution of the species. Special attention was given to reconstructing the timing of the processes under study. The early subdivision of the olive fly reflects the Quaternary differentiation between Olea europea subsp. europea in the Mediterranean area and the two lineages of Olea europea subsp. cuspidata in Africa and Asia, pointing to an early and close association between the olive fly and its host. The geographic structure and timing of olive fly differentiation in the Mediterranean indicates a clear connection with the post-glacial recolonization of wild olives in the area, and is irreconcilable with the early historical process of domestication and spread of the cultivated olive from its Levantine origin. Therefore, we suggest an early co-history of the olive fly with its wild host during the Quaternary and post-glacial periods and a multi-regional shift of olive flies to cultivated olives as these cultivars gradually replaced wild olives in historical times.


Detection of double-stranded DNA breaks and apoptosis induced by bleomycin in mouse intestine.
The gastrointestinal tract is exposed to a myriad of mutagens, making the DNA damage response (DDR) essential to maintain intestinal homeostasis. In vivo models to study DDRs are necessary to understand the mechanisms of disease development caused by genetic disorders such as colorectal cancer. A double-stranded break (DSB) in DNA is the most toxic type of DNA damage; it can be induced by either X-rays or chemicals, including anticancer agents. If DSBs in DNA cannot be repaired, cells can die by apoptosis to be removed from tissues. Here, we show that the DDRs observed as the phosphorylation of H2AX (γH2AX) and caspase-3-dependent apoptosis-induction are under critical control in the intestine of C57BL mice that were injected intraperitoneally with bleomycin, a natural glycopeptide used clinically as an antitumor agent. We found a significant increase in γH2AX expression 2-6 hr post-treatment in mouse ileum, cecum, and colon tissues by Western blotting and immunostaining. Apoptotic cells were observed after 6-24 hr by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and immunofluorescence of active caspase-3. We observed that γH2AX expression and apoptotic cells were distributed in the lower part of the crypt. The experimental protocol described here is a simple procedure that can be used generally as an in vivo intestinal toxicity assay. Our experimental approach provides a useful method for examining the effects of various bioactive compounds on the DDR, which is essential for understanding intestinal homeostasis.


Abdominal aortic aneurysm and Behçet's disease.
A case of abdominal aortic aneurysm with Bechçet's disease and a review of two similar cases previously reported are presented. This case and additional review of other reported major vascular complications of Behçet's disease lead us to conclude that the pathogenesis of the abdominal aneurysm is related to involvement of the aortic wall or vasa vasorum by the Behçet's disease process. Surgical treatment of this rare complication by Behçet's disease should include extra-anatomic bypass if the possibility of infection cannot be definitely excluded.


Diffuse myoepithelial hamartoma of the duodenum associated with adenocarcinoma.
A 56-year-old man presented with obstructive jaundice was found to have diffuse cystic glandular malformation of the second part of the duodenum, in association with adenocarcinoma of the periampullary area. Comparison of the pathological findings with myoepithelial hamartoma and diffuse cystic glandular malformation of the stomach reveals resemblances and differences.


SNP rs2470152 in CYP19 is correlated to aromatase activity in Chinese polycystic ovary syndrome patients.
CYP19 encodes aromatase, a key enzyme essential for estrogen biosynthesis. Single nucleotide polymorphism (SNP) rs2470152 in CYP19 is associated with serum estradiol (E2) level and the E2/T (estradiol/testosterone) ratio. A case‑control study including 661 individuals [364 polycystic ovary syndrome (PCOS) patients and 297 controls] was conducted to assess the association of SNP rs2470152 with PCOS. The subjects were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. Hormone levels were analyzed among various genotypes. The genotypic distributions of rs2470152 did not differ in PCOS patients when compared to the controls. However, differences in the E2/T ratio were detected, exhibiting a lower ratio in the heterozygous TC genotype in PCOS patients (p=0.01036) and controls (p=0.000). Testosterone levels also differed between the three genotypes of PCOS patients (p=0.00625), with a higher level in the TC genotype. Therefore, rs2470152 in CYP19 was not a major etiological factor for PCOS; however, the heterozygous TC genotype may inhibit aromatase activity, resulting in hyperandrogenism, particularly in PCOS patients.


Noninvasive diagnostic tool for inflammation-induced oxidative stress using electron spin resonance spectroscopy and an extracellular cyclic hydroxylamine.
Inflammation is one of the leading causes of the many pathological states associated with oxidative stress. A crucial role in the development of inflammation-induced oxidative stress is played by reactive oxidant species (ROS), which are very difficult to detect in vivo. One of the most sensitive and definitive methods in the detection of ROS is electron spin resonance, especially as used in conjunction with spin trapping. Unfortunately, the commonly used nitrone spin traps have a very low efficacy for trapping superoxide radicals, and their radical adducts are not stable. To address this deficiency, we have developed negatively charged cyclic hydroxylamines such as 1-hydroxy-4-phosphonooxy-2,2,6,6-tetramethylpiperidine (PP-H) for the detection of reactive oxidant species as a diagnostic tool for extracellular inflammation-induced oxidative stress. We used inflammation induced by a bacterial endotoxin lipopolysaccharide (LPS) as a model. ROS formation was tested in cultured macrophages, in blood and in vivo. PP-H reacts with reactive oxidant species generating the stable nitroxide radical 4-phosphonooxy-TEMPO. It was shown that a 5-h treatment of macrophages with LPS (1 microg/ml) leads to a threefold increase in superoxide formation as demonstrated using superoxide dismutase. Formation of reactive oxidant species 5 h after LPS (1 mg/kg) treatment of Fischer rats was analyzed in arterial blood; formation of reactive oxidant species in LPS-treated animals increased by a factor of 2.2 and was dependent upon the LPS dose. Diphenyleneiodonium (0.1 mM) inhibited formation of LPS-stimulated reactive oxidant species by 80%. We suggest that this test could be used as a noninvasive diagnostic tool for inflammation-induced oxidative stress.


Improved repeatability of subsolid nodule measurement in low-dose lung screening with monoenergetic images: a phantom study.
To investigate whether monoenergetic images captured with dual-layer spectral computed tomography (CT) can improve the repeatability of subsolid nodule measurement, and whether this approach can further reduce the radiation dose of CT while maintaining its measurement repeatability. An anthropomorphic phantom with simulated subsolid nodules at three different levels was repeatedly scanned with both conventional single-energy CT and dual-layer spectral CT. A proxy for the measurement repeatability in the National Lung Screening Trial (proxy for NLST) was calculated with the typical CT protocol used in NLST. Using the dual-layer spectral CT, monoenergetic images of 40 to 110 keV, with an interval of 10 keV, were generated. The average diameter and volume of a total of 15,120 nodules in 840 CT images were measured by using a commercially-available computer-aided detection (CAD) system. The repeatability coefficient (RC), %RC, and 95% confidence intervals (CIs) of each image set were calculated and compared. At the same tube voltage and tube current-time product, monoenergetic images resulted in significantly lower RC than the proxy for NLST, indicating that measurement repeatability was enhanced. When the radiation dose was lowered by 30% or 55%, monoenergetic images showed significantly lower RC at high-energy keV than the proxy for NLST. The estimated measurement repeatability from monoenergetic images with 30% or 55% lower radiation dose was comparable to the repeatability from conventional single-energy CT images with standard radiation dose and iterative reconstruction. Monoenergetic images captured by using dual-layer spectral CT can improve the repeatability of subsolid nodule measurement. The use of monoenergetic images would allow lung cancer screening with a lower radiation dose, while maintaining comparable measurement repeatability.


[Ageing and necrotic form of "unwanted" cells].
Collecting experimental data testify that cellular necrosis is the same component of "unwanted" cell system elimination in a metaphyte, as well as apoptosis. The essential role of the last in definition of rates of ageing is expressed, in particular, in secretion by phagocytes of the factors overwhelming inflammatory reactions which are rather characteristic for such illnesses as an atherosclerosis, a diabetes and others. Apparently, infringement of balance between necrotic and apoptotic forms "unwanted" cell elimination from an organism can be the important factor of ageing and the reason of reduction of life expectancy as a result of supression of renewal processes in an organism, occurrence and weights of development of some senile illness.


A pilot study on dasatinib in patients with Waldenström macroglobulinemia progressing on ibrutinib.
The hematopoietic cell kinase (HCK) regulates BTK activation and represents a potential therapeutic target in Waldenstrom macroglobulinemia (WM). We investigated dasatinib, a potent HCK inhibitor, in patients with WM progressing on ibrutinib. Study treatment consisted of dasatinib administered at 100 mg by mouth once daily in four-week cycles for up to 24 cycles. This study was registered under ClinicalTrials.Gov ID NCT04115059. Three participants were enrolled and received at least one cycle of dasatinib. The best response was stable disease. Two patients received 5 months and one patient received 1 month of therapy. The dose of dasatinib was decreased in one participant due to volume overload. Based on the lack of responses observed, the study was terminated. Dasatinib might not be effective in patients with WM progressing on ibrutinib.


Cloning of human immunoglobulin mu gene and comparison with mouse mu gene.
We have cloned a 12 kb DNA segment containing human mu gene and its flanking sequence from human fetal liver DNA library using mouse mu gene as a probe. Partial nucleotide sequence determination shows that the cloned DNA contains the sequence encoding human mu chain. This is the first constant region gene of the human heavy chain that is cloned. We have compared human and mouse mu genes by heteroduplex analysis and Southern blot hybridization. The results clearly show that not only the sequence encoding the CH4 domain but also the 5'-flanking (S mu) sequence is conserved between human and mouse mu genes, suggesting that the nucleotide sequence in the S mu region has an important biological function, presumably a recognition signal for the class switch recombinant as proposed previously.


A basic protein, N25, from a mollusk modifies calcium carbonate morphology and shell biomineralization.
Biomineralization is a widespread biological process in the formation of shells, teeth, or bones. Matrix proteins in biominerals have been widely investigated for their roles in directing biomineralization processes such as crystal morphologies, polymorphs, and orientations. Here, we characterized a basic matrix protein, named mantle protein N25 (N25), identified previously in the Akoya pearl oyster (Pinctada fucata). Unlike some known acidic matrix proteins containing Asp or Glu as possible Ca2+-binding residues, we found that N25 is rich in Pro (12.4%), Ser (12.8%), and Lys (8.8%), suggesting it may perform a different function. We used the recombinant protein purified by refolding from inclusion bodies in a Ca(HCO3)2 supersaturation system and found that it specifically affects calcite morphologies. An X-ray powder diffraction (XRD) assay revealed that N25 could help delay the transformation of vaterites (a metastable calcium carbonate polymorph) to calcite. We also used fluorescence super-resolution imaging to map the distribution of N25 in CaCO3 crystals and transfected a recombinant N25-EGFP vector into HEK-293T cells to mimic the native process in which N25 is secreted by mantle epithelial cells and integrated into mineral structures. Our observations suggest N25 specifically affects crystal morphologies and provide evidence that basic proteins lacking acidic groups can also direct biomineralization. We propose that the attachment of N25 to specific sites on CaCO3 crystals may inhibit some crystal polymorphs or morphological transformation.


Effect of a short maximal physical exercise on coagulation, fibrinolysis, and complement system.
In 11 healthy young subjects, the plasma concentrations of the thrombin-antithrombin III complex, fibrinopeptide A, tissue-plasminogen activator, complement fragments C3a and C4a, and histamine were measured before and after a graded maximal bicycle exercise test. The analyses were carried out 30 min before and immediately before exercise, immediately after exercise, and 30 and 60 min later. All post-exercise values were corrected for plasma volume changes, which were calculated from hematocrit and hemoglobin values. Immediately post-exercise, thrombin-antithrombin III, tissue-plasminogen activator, complement fragments C3a and C4a, and histamine were all significantly elevated (p less than 0.01), compared with the pre-exercise values; 30 and 60 min later the values normalized and significant differences from the pre-exercise values could no longer be measured. Fibrinopeptide A did not change significantly after exercise. The present results provide evidence for a simultaneous activation of coagulation, fibrinolysis, and complement system as well as for a release of histamine after a short maximal exercise.


Three-dimensional reaching tasks: effect of reaching height and width on upper limb kinematics and muscle activity.
In previous studies, upper limb coordination was usually analyzed during two-dimensional (2D) arm movements. Based on joint kinematics and muscle activity, it has been demonstrated that the shoulder joint controls the multi-joint movement. This study focused on three-dimensional (3D) reaching tasks and examined if the coordination strategies previously described in 2D can be transferred to 3D movements and if reaching to different locations in space has an effect on kinematic and upper limb muscle strategies. Ten healthy subjects reached to nine different targets in 3D space placed at arm length. Kinematic data of the shoulder and elbow and electrical activity of 10 upper limb muscles were registered. Differences in kinematics and EMG were compared between different reaching conditions. Activity of shoulder muscles increased earlier than elbow muscles inducing shoulder elevation prior to elbow extension. Reaching at different widths only influenced shoulder kinematics, whereas reaching at different heights influenced both shoulder and elbow joints. Modulation of reaching height induced an immediate adaptation of elbow flexion followed by an adaptation of shoulder elevation. As previously described in 2D, the shoulder joint leads the movement during 3D reaching tasks. Changing the 3D nature of a reaching task influenced the interaction between shoulder and elbow joint, with reaching height primarily affecting the elbow coordination strategy.


Genetics of hypertension: what we know and don't know.
Human arterial hypertension is likely a multifactorial trait resulting from multiple measurable monogenes, blended polygenes, shared family environment, and individual environment. Familial aggregation of hypertension and familial correlation of blood pressure appears to be more due to genes than to shared family environment. Total genetic heritability of 80% with some recessive major gene effects have been found for several traits associated with hypertension including urinary kallikrein excretion, intraerythrocytic sodium, and sodium-lithium countertransport. Other interesting factors regarding hypertension genetics include: non-modulation of the renin angiotensin system, intralymphocytic sodium, ionized calcium, and several genetic markers such as haptoglobin, HLA, and MNS blood type. Probably the most clinically useful information regarding the genetics of hypertension is evolving in several studies reporting a strong association of hypertension with dyslipidemia, diabetes, and obesity.


The prevalence of epilepsy in the Nakhichevan Autonomous Republic of Azerbaijan.
Epilepsy is a devastating neurological disorder in which those afflicted can gain benefit from specific treatments based on their genetics and geographic location. Currently the prevalence of epilepsy is estimated at 0.5-3% of the world-wide population, and is increasing in developing countries. In order to make more accurate assessments of the prevalence of epilepsy, we applied the capture-recapture method in a 12-month study of epilepsy in a population from the Sharur district of Nakhichevan Autonomous Republic, Azerbaijan with 114,451 people from sixty nine villages and towns. The following methods were applied to determine epilepsy: Door To Door (DTD) survey, Non-Medical Source (NMS), and Medical Source. Using these three techniques, 1,032 patients with epilepsy (9.02/1000) were included in our study. The DTD survey determined 627 patients with epilepsy (5.48/1000) and 247 (2.16/1000) from the NMS methods versus 158 (1.38/1000) from the Medical Source (MS) methods. Applying the capture-recapture method, NMS, and DTD methods, the number of epilepsy cases increased to 1,330 (11.62/1000) [95% CI: 10.21-13.03]. The combinations of these methods show that 887 people (7.75/1000) have a diagnosis of epilepsy. Multiple epidemiological tasks used in our study can be used to estimate clinical signs and/or markers in future applications for the determination and development of treatment strategies for this devastating disease in the third world countries such as the Nakhichevan Autonomous Republic of Azerbaijan.


Reduction of colorectal cancer risk in patients with Crohn's disease.
Patients with inflammatory bowel disease (IBD)-either Crohn's disease (CD) or ulcerative colitis (UC)-are at increased risk for developing cancers of the gastrointestinal tract, particularly colorectal cancer (CRC). Because of the relative rarity of IBD in the general population, it has been difficult to quantify this risk; nonetheless, within particular subsets of IBD patients, the cumulative risk of developing dysplasia and CRC may be substantial. Efforts to reduce this risk have included both prophylactic surgery and endoscopic screening programs. Despite the impact this disease has on quality of life and life expectancy, an optimal strategy for reducing the risk has yet to be defined. This article reviews the current literature relating to the risk of cancer for patients with IBD and methods available to help reduce this risk.


[Percentile curves of functional residual capacity of newborn infants].
Helium dilution or nitrogen washout techniques are commonly used to measure the functional residual capacity (FRC) in newborn babies. For both techniques equipment is available. Its clinical application, however, was difficult since there were no FRC reference ranges for the different weight groups of newborn infants; reference studies are very time consuming and cause several technical and ethical problems. Statistical methods were used to evaluate several results from the literature and to exclude significantly differing data of some authors. Measured values of FRC were related to body weight, and the percentiles of FRC/kg were estimated by the smoothed cumulative distribution function of the pooled data. No significant differences were found between the results of helium dilution and nitrogen washout techniques. The distribution of 178 results showed a significant skewedness (x5% = 18.3 ml/kg; x50% = 27.5 ml/kg x95% = 42.8 ml/kg), which could also be seen in the percentile curves calculated approximately, assuming a linear development of functional residual capacity with body weight. Percentile curves describe best the development and interindividual variability of FRC in newborn babies as our evaluation could show. We conclude that the nonparametric estimation of percentiles is more adequate for the description than the use of simple regression models.


Fast evaluation of 69 basal cell carcinomas with ex vivo fluorescence confocal microscopy: criteria description, histopathological correlation, and interobserver agreement.
Fluorescence confocal microscopy (FCM) represents a first step toward a rapid "bedside pathology" in the Mohs surgery setting and in other fields of general pathology. To describe and validate FCM criteria for the main basal cell carcinoma (BCC) subtypes and to demonstrate the overall agreement with classic pathologic analysis of hematoxylin-eosin-stained samples. DESIGN A total of 69 BCCs from 66 patients were prospectively imaged using ex vivo FCM. Confocal mosaics were evaluated in real time and compared with classic pathologic analysis. Department of Dermatology, Hospital Clínic of Barcelona, Barcelona, Spain, between November 2010 and July 2011. Patients with BCC attending the Mohs Surgery Unit. Presence or absence of BCC and histological subtype (superficial, nodular, and infiltrating) in the confocal mosaics. Eight criteria for BCC were described, evaluated, and validated. Although there were minor differences among BCC subtypes, the most BCC-defining criteria were peripheral palisading, clefting, nuclear pleomorphism, and presence of stroma. These criteria were validated with independent observers (κ values >0.7 [corrected] for most criteria). We herein propose, describe, and validate FCM criteria for BCC diagnosis. Fluorescence confocal microscopy is an attractive alternative to histopathologic analysis of frozen sections during Mohs surgery because large areas of freshly excised tissue can be assessed in real time without the need for tissue processing while minimizing labor and costs.


Risk prediction models for delirium in the intensive care unit after cardiac surgery: a systematic review and independent external validation.
Numerous risk prediction models are available for predicting delirium after cardiac surgery, but few have been directly compared with one another or been validated in an independent data set. We conducted a systematic review to identify validated risk prediction models of delirium (using the Confusion Assessment Method-Intensive Care Unit tool) after cardiac surgery and assessed the transportability of the risk prediction models on a prospective cohort of 600 consecutive patients undergoing cardiac surgery at a university hospital in Hong Kong from July 2013 to July 2015. The discrimination (c-statistic), calibration (GiViTI calibration belt), and clinical usefulness (decision curve analysis) of the risk prediction models were examined in a stepwise manner. Three published high-quality intensive care unit delirium risk prediction models (n=5939) were identified: Katznelson, the original PRE-DELIRIC, and the international recalibrated PRE-DELIRIC model. Delirium occurred in 83 patients (13.8%, 95% CI: 11.2-16.9%). After updating the intercept and regression coefficients in the Katznelson model, there was fair discrimination (0.62, 95% CI: 0.58-0.66) and good calibration. As the original PRE-DELIRIC model was already validated externally and recalibrated in six countries, we performed a logistic calibration on the recalibrated model and found acceptable discrimination (0.75, 95% CI: 0.72-0.79) and good calibration. Decision curve analysis demonstrated that the recalibrated PRE-DELIRIC risk model was marginally more clinically useful than the Katznelson model. Current models predict delirium risk in the intensive care unit after cardiac surgery with only fair to moderate accuracy and are insufficient for routine clinical use.


Diagnosis and management of hemolysis, elevated liver enzymes, and low platelets syndrome.
Pregnancies complicated by hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome require a well-formulated management plan. The development of this syndrome after 34 weeks' gestation or with documentation of maternal or fetal compromise is an indication for delivery. Acute fatty liver of pregnancy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura may present with signs, symptoms, and laboratory abnormalities that may be confused with HELLP syndrome. Thorough investigation is warranted because of the differences in proper management among these various complications of pregnancy. Expectant management in patients with HELLP syndrome remote from term and the use of corticosteroids to improve postpartum maternal outcome remain experimental.


Inhibition of autophagy increased AGE/ROS-mediated apoptosis in mesangial cells.
The aim of our study was to investigate the role of autophagy, a homeostatic process involved in the lysosomal degradation of damaged cell organelles and proteins, in regulating the survival of mesangial cells treated with advanced glycation end products (AGEs). In the present study, AGEs induced mitochondrial depolarization and led to mitochondrial-dependent apoptosis in mesangial cells, as shown by the loss of the mitochondrial membrane potential; increased Bax processing; increased Caspase-9, Caspase-3 and PARP cleavage; and decreased Bcl-2 expression. Meanwhile, AGEs also triggered autophagy flux in mesangial cells, as confirmed by the presence of autophagic vesicles, the conversion of LC3II/LC3I and the increase/decrease in Beclin-1/p62 expression. Interestingly, this study reported apparent apoptosis and autophagy that were dependent on reactive oxygen species (ROS) production. Scavenging ROS with N-acetyl-l-cysteine could prevent the appearance of the autophagic features and reverse AGE-induced apoptosis. Moreover, AGE-triggered mitophagy, which was confirmed by the colocalization of autophagosomes and mitochondria and Parkin translocation to mitochondria, played a potential role in reducing ROS production in mesangial cells. Additionally, inhibition of autophagy significantly enhanced AGE-induced cell apoptosis. Taken together, our data suggest that ROS were the mediators of AGE-induced mesangial cell apoptosis and that autophagy was likely to be the mechanism that was triggered to repair the ROS-induced damage in the AGE-treated cells and thereby promote cell survival. This study provides new insights into the molecular mechanism of autophagy involved in AGE-induced apoptosis in mesangial cells.


Cognitive processes as mediators of the relation between mindfulness and change in social anxiety symptoms following cognitive behavioral treatment.
The present study examined whether pretreatment mindfulness exerts an indirect effect on outcomes following cognitive-behavioral therapy (CBT). Cognitive processes of probability and cost bias (i.e., overestimations of the likelihood that negative social events will occur, and that these events will have negative consequences when they do occur) were explored as potential mediators of the relation between mindfulness and social anxiety symptom change. People with higher levels of mindfulness may be better able to benefit from treatments that reduce biases because mindfulness may aid in regulation of attention. Sixty-seven individuals with a primary diagnosis of social phobia identifying public speaking as their greatest fear received eight sessions of one of two types of exposure-based CBT delivered according to treatment manuals. Participants completed self-report measures of mindfulness, probability bias, cost bias, and social anxiety symptoms. Mediation hypotheses were assessed by a bootstrapped regression using treatment outcome data. Pretreatment mindfulness was not related to change in social anxiety symptoms from pre- to posttreatment. However, mindfulness had an indirect effect on treatment outcome via its association with probability bias, but not cost bias, at midtreatment. These findings were consistent across three metrics of social anxiety symptoms. Mindfulness may play a role in response to CBT among individuals with social phobia through its relation with probability bias--even when the treatment does not target mindfulness.


Mortality and costs following extracorporeal membrane oxygenation in critically ill adults: a population-based cohort study.
Extracorporeal membrane oxygenation (ECMO) is used as temporary cardiorespiratory support in critically ill patients. Little is known about population-level short- and long-term outcomes following ECMO, including healthcare use and health system cost across a wide range of sectors. Population-based cohort study in Ontario, Canada (October 1, 2009-March 31, 2017) of adult patients (≥ 18 years) receiving ECMO for cardiorespiratory support. We captured outcomes through linkage to health administrative databases. Primary outcome was mortality during hospitalization, as well as at 7 days, 30 days, 1 year, 2 years, and 5 years following ECMO initiation. We analyzed health system costs (in Canadian dollars) in the 1 year following the date of the index admission. A total of 692 patients were included. Mean (standard deviation [SD]) age was 51.3 (16.0) years. Median (interquartile range [IQR]) time to ECMO initiation from date of admission was 2 (0-9) days. In-hospital mortality was 40.0%. Mortality at 1 year, 2 years, and 5 years was 45.1%, 49.0%, and 57.4%, respectively. Among survivors, 78.4% were discharged home, while 21.2% were discharged to continuing care. Median (IQR) total costs in the 1 year following admission among all patients were Canadian $130,157 (Canadian $58,645-Canadian $240,763), of which Canadian $91,192 (Canadian $38,507-Canadian $184,728) were attributed to inpatient care. Hospital mortality among critically ill adults receiving ECMO for advanced cardiopulmonary support is relatively high, but does not markedly increase in the years following discharge. Survivors are more likely to be discharged home than to continuing care. Median costs are high, but largely reflect inpatient hospital costs, and not costs incurred following discharge.